Fitzpatricks Dermatology in General Medicine 8ed

Fitzpatricks
Dermatology in
General Medicine
LOWELL A. GOLDSMITH, MD, MPH
Emeritus Professor of Dermatology

University of North Carolina School of Medicine
Chapel Hill, North Carolina
Dean Emeritus
University of Rochester School of Medicine and Dentistry
Rochester, NY
STEPHEN I. KATZ, MD, PhD
Fellow, American Academy of Dermatology

Schaumburg, IL;
Past President, Society of Investigative Dermatology
Cleveland, OH;
Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health
Bethesda, MD
BARBARA A. GILCHREST, MD
Chair Emerita and Professor of Dermatology

Department of Dermatology
Boston University School of Medicine
Boston, MA
AMY S. PALLER, MD
Walter J. Hamlin Professor and Chair of Dermatology

Professor of Pediatrics
Feinberg School of Medicine
Northwestern University
Chicago, IL
DAVID J. LEFFELL, MD
David Paige Smith Professor of Dermatology and Surgery

Chief, Section of Dermatologic Surgery and Cutaneous Oncology
Yale University School of Medicine
New Haven, CT
KLAUS WOLFF, MD, FRCP

Professor of Dermatology
Chairman Emeritus
Medical University of Vienna
Vienna, Austria
Fitzpatricks
Dermatology in
General Medicine
Eighth Edition
EDITORS
LOWELL A. GOLDSMITH, MD, MPH
STEPHEN I. KATZ, MD, PhD
BARBARA A. GILCHREST, MD
AMY S. PALLER, MD
DAVID J. LEFFELL, MD
KLAUS WOLFF, MD, FRCP
New York Chicago San Francisco Lisbon London Madrid Mexico City
Milan New Delhi San Juan Seoul Singapore Sydney Toronto
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Contents
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxxi
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxxiii
Volume One
PART 1 INTRODUCTION
Section 1. General Considerations
1 The Epidemiology and Burden of
Skin Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Martin A. Weinstock, MD, PhD &
Mary-Margaret Chren, MD
Section 3. Overview of Biology,

Development, and Structure of Skin
7 Development and Structure of Skin. . . . . . . . . . . . 58
David H. Chu, MD, PhD
8 Genetics in Relation to the Skin . . . . . . . . . . . . . . . 75
John A. McGrath, MD, FRCP &
W. H. Irwin McLean, FRSE, FMedSci
9 Racial Considerations: Skin of Color. . . . . . . . . . . 91
Kavitha K. Reddy, MD, Yolanda M. Lenzy, MD,
MPH, Katherine L. Brown, MD, MPH, &
Barbara A. Gilchrest, MD
ART 2 Disorders Presenting in

P
Skin and Mucous Membranes
2 Evidence-Based Dermatology. . . . . . . . . . . . . . . . . . 9
Michael Bigby, MD,
Rosamaria Corona, DSc, MD, &
Moyses Szklo, MD, MPH, DrPH
Section 4. Inflammatory Disorders

Based on T-Cell Reactivity and
Dysregulation
3 Global Health in Dermatology. . . . . . . . . . . . . . . . 15

Roderick J. Hay, DM, FRCP, FRCPath, FMedSci
10 Innate and Adaptive Immunity in the Skin. . . . 105

Robert L. Modlin, MD, Lloyd S. Miller, MD, PhD,
Christine Bangert, MD, & Georg Stingl, MD
4 Public Health in Dermatology. . . . . . . . . . . . . . . . . 21

Hywel C. Williams, MSc, PhD, FRCP,
Sinad M. Langan, MRCP, MSc, PhD, &
Carsten Flohr, BM, BCh (Hons), MA, Mphil,
MRCPCH, MSc, PhD
Section 2. Approach to
Dermatologic Diagnosis
5 Structure of Skin Lesions and Fundamentals
of Clinical Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . 26
Amit Garg, MD, Nikki A. Levin, MD, PhD, &
Jeffrey D. Bernhard, MD, FRCP (Edin)
6 Basic Pathologic Reactions of the Skin. . . . . . . . . . 42
Martin C. Mihm Jr., MD, FACP,
Abdul-Ghani Kibbi, MD, FAAD, FACP,
George F. Murphy, MD &
Klaus Wolff, MD, FRCP
11 Cytokines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Ifor R. Williams, MD, PhD &
Thomas S. Kupper, MD, FAAD
12 Chemokines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Anke S. Lonsdorf, MD &
Sam T. Hwang, MD, PhD
13 Allergic Contact Dermatitis. . . . . . . . . . . . . . . . . . 152
Mari Paz Castanedo-Tardan, MD &
Kathryn A. Zug, MD
14 Atopic Dermatitis (Atopic Eczema). . . . . . . . . . . 165
Donald Y.M. Leung, MD, PhD,
Lawrence F. Eichenfield, MD, &
Mark Boguniewicz, MD
15 Nummular Eczema, Lichen Simplex
Chronicus, and Prurigo Nodularis. . . . . . . . . . . . 182
Susan Burgin, MD
16 Vesicular Palmoplantar Eczema . . . . . . . . . . . . . . 187

Daven N. Doshi, MD, Carol E. Cheng, MD, &
Alexa B. Kimball, MD, MPH
17 Autosensitization Dermatitis. . . . . . . . . . . . . . . . . 194
Donald V. Belsito, MD
18 Psoriasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Johann E. Gudjonsson, MD, PhD &
James T. Elder, MD, PhD
19 Psoriatic Arthritis. . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Dafna D. Gladman, MD, FRCPC &
Vinod Chandran, MBBS, MD, DM
Contents
20 Reactive Arthritis. . . . . . . . . . . . . . . . . . . . . . . . . . . 243

John D. Carter, MD
21 Pustular Eruptions of Palms and Soles . . . . . . . . 253
Ulrich Mrowietz, MD
22 Seborrheic Dermatitis. . . . . . . . . . . . . . . . . . . . . . . 259
Chris D. Collins, MD, FAAD &
Chad Hivnor, MD
23 Exfoliative Dermatitis. . . . . . . . . . . . . . . . . . . . . . . 266
Jane Margaret Grant-Kels, MD,
Flavia Fedeles, MD, MS, & Marti J. Rothe, MD
24 Pityriasis Rubra Pilaris. . . . . . . . . . . . . . . . . . . . . . 279
Daniela Bruch-Gerharz, MD &
Thomas Ruzicka, Prof. Dr. med. Dr. h.c.
25 Parapsoriasis and Pityriasis Lichenoides. . . . . . . 285
Gary S. Wood, MD, Chung-Hong Hu, MD &
Rosemarie Liu, MD
26 Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
Mazen S. Daoud, MD & Mark R. Pittelkow, MD
27 Lichen Nitidus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Mazen S. Daoud, MD &
Mark R. Pittelkow, MD
32 Acute Febrile Neutrophilic Dermatosis

(Sweet Syndrome). . . . . . . . . . . . . . . . . . . . . . . . . . 362
Philip R. Cohen, MD, Herbert Hnigsmann, MD, &
Razelle Kurzrock, MD, FACP
33 Pyoderma Gangrenosum. . . . . . . . . . . . . . . . . . . . 371
Frank C. Powell, FRCPI, FAAD,
Bridget C. Hackett, MB BCh, BAO, MRCPI, &
Daniel Wallach, MD
34 Granuloma Faciale. . . . . . . . . . . . . . . . . . . . . . . . . . 380
David A. Mehregan, MD &
Darius R. Mehregan, MD
35 Subcorneal Pustular Dermatosis (Sneddon
Wilkinson Disease). . . . . . . . . . . . . . . . . . . . . . . . . . 383
Franz Trautinger, MD &
Herbert Hnigsmann, MD
36 Eosinophils in Cutaneous Diseases . . . . . . . . . . . 386
Kristin M. Leiferman, MD &
Margot S. Peters, MD
Section 6. Inflammatory Diseases

Based on Abnormal Humoral
Reactivity and Other Inflammatory
Diseases
37 Humoral Immunity and Complement. . . . . . . . . 401
Lela A. Lee, MD
38 Urticaria and Angioedema. . . . . . . . . . . . . . . . . . . 414
Allen P. Kaplan, MD
39 Erythema Multiforme. . . . . . . . . . . . . . . . . . . . . . . 431
Jean-Claude Roujeau, MD
28 Graft-Versus-Host Disease. . . . . . . . . . . . . . . . . . . 316

Edward W. Cowen, MD, MHSc
40 Epidermal Necrolysis (StevensJohnson

Syndrome and Toxic Epidermal Necrolysis). . . . . 439
L. Valeyrie-Allanore, MD & Jean-Claude Roujeau, MD
29 Skin Disease in Acute and Chronic

Immunosuppression. . . . . . . . . . . . . . . . . . . . . . . . 330
Benjamin D. Ehst, MD, PhD &
Andrew Blauvelt, MD
41 Cutaneous Reactions to Drugs . . . . . . . . . . . . . . . 449

Neil H. Shear, MD, FRCPC &
Sandra R. Knowles, BScPhm
Section 5. Inflammatory Diseases

Based on Neutrophils and
Eosinophils
vi
31 Regulation of the Production and

Activation of Eosinophils. . . . . . . . . . . . . . . . . . . . 351
Kristin M. Leiferman, MD, Lisa A. Beck, MD, &
Gerald J. Gleich, MD
30 Regulation of the Production and

Activation of Neutrophils . . . . . . . . . . . . . . . . . . . 345
Steven M. Holland, MD
42 Pityriasis Rosea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458

Andrew Blauvelt, MD
43 Erythema Annulare Centrifugum and Other
Figurate Erythemas. . . . . . . . . . . . . . . . . . . . . . . . . 463
Walter H.C. Burgdorf, MD
44 Granuloma Annulare . . . . . . . . . . . . . . . . . . . . . . . 467
Julie S. Prendiville, MB, FRCPC
59 Pemphigoid Gestationis (Herpes Gestationis). . . 630

Jeff K. Shornick, MD, MHA
45 Epidermal Stem Cells . . . . . . . . . . . . . . . . . . . . . . . 473

Rebecca J. Morris, PhD
60 Epidermolysis Bullosa Acquisita. . . . . . . . . . . . . . 634

David T. Woodley, MD & Mei Chen, PhD
46 Epidermal Growth and Differentiation. . . . . . . . 478

Pierre A. Coulombe, PhD,
Stanley J. Miller, MD, & Tung-Tien Sun, PhD
61 Dermatitis Herpetiformis. . . . . . . . . . . . . . . . . . . . 642

Arash Ronaghy, MD, PhD,
Stephen I. Katz, MD, PhD, &
Russell P. Hall III, MD
47 Skin as an Organ of Protection. . . . . . . . . . . . . . . 486

Ehrhardt Proksch, MD, PhD &
Jens-Michael Jensen, MD
62 Inherited Epidermolysis Bullosa. . . . . . . . . . . . . . 649

M. Peter Marinkovich, MD
48 Irritant Contact Dermatitis. . . . . . . . . . . . . . . . . . . 499

Antoine Amado, MD, Apra Sood, MD, &
James S. Taylor, MD, FAAD
Section 9. Disorders of the Dermal

Connective Tissue
49 The Ichthyoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507

Philip Fleckman, MD & John J. DiGiovanna, MD
50 Inherited Palmoplantar Keratodermas . . . . . . . . 538
Mozheh Zamiri, BSc (Hons), MBChB, MRCP, MD,
Maurice A. M. van Steensel, MD, PhD, &
Colin S. Munro, MD, FRCP (Glasg)
51 Acantholytic Disorders of the Skin. . . . . . . . . . . . 550
Susan Burge, OBE, DM, FRCP &
Alain Hovnanian, MD, PhD
52 Porokeratosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
Grainne M. ORegan, MRCPI &
Alan D. Irvine, MD, FRCP, FRCPI
Section 8. Disorders of Epidermal

and DermalEpidermal Adhesion
and Vesicular and Bullous
Disorders
53 Epidermal and EpidermalDermal Adhesion. . . . 569
Leena Bruckner-Tuderman, MD &
Aimee S. Payne, MD, PhD
54 Pemphigus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
Aimee S. Payne, MD, PhD &
John R. Stanley, MD
55 Paraneoplastic Pemphigus. . . . . . . . . . . . . . . . . . . 600
Grant J. Anhalt, MD & Daniel Mimouni, MD
56 Bullous Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . 608
Donna A. Culton, MD, PhD, Zhi Liu, PhD, &
Luis A. Diaz, MD
57 Cicatricial Pemphigoid. . . . . . . . . . . . . . . . . . . . . . 617
Kim B. Yancey, MD
58 Linear Immunoglobulin A Dermatosis and
Chronic Bullous Disease of Childhood . . . . . . . . 623
Caroline L. Rao, MD & Russell P. Hall III, MD
63 Collagens, Elastic Fibers, and Other Extracellular

Matrix Proteins of the Dermis. . . . . . . . . . . . . . . . 666
Thomas Krieg, MD, Monique Aumailley,
Manuel Koch, PhD, Mon-Li Chu, PhD, &
Jouni Uitto, MD, PhD
Contents
Section 7. Disorders of Epidermal

Differentiation and Keratinization
64 Morphea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
Stephanie Saxton-Daniels, MD &
Heidi T. Jacobe, MD, MSCS
65 Lichen Sclerosus. . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
Ulrich R. Hengge, MD, MBA
66 Dermal Hypertrophies and Benign
Fibroblastic/Myofibroblastic Tumors . . . . . . . . . 707
Christine J. Ko, MD
67 Anetoderma and Other Atrophic
Disorders of the Skin. . . . . . . . . . . . . . . . . . . . . . . . 718
Catherine Maari, MD &
Julie Powell, MD, FRCPC
68 Ainhum and Pseudoainhum. . . . . . . . . . . . . . . . . 724
Robert T. Brodell, MD & Stephen E. Helms, MD
69 Acquired Perforating Disorders . . . . . . . . . . . . . . 727
Julia S. Minocha, MD &
Bethanee J. Schlosser, MD, PhD
Section 10. Disorders of

Subcutaneous Tissue
70 Panniculitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 732
Iris K. Aronson, MD, Patricia M. Fishman, MD, &
Sophie M. Worobec, MD, FAAD
71 Lipodystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755
Abhimanyu Garg, MD
Section 11. Disorders of

Melanocytes
72 Biology of Melanocytes. . . . . . . . . . . . . . . . . . . . . . 765
Hee-Young Park, PhD & Mina Yaar, MD
vii
73 Albinism and Other Genetic Disorders of

Pigmentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
Thomas J. Hornyak, MD, PhD
74 Vitiligo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
Stanca A. Birlea, MD, PhD,
Richard A. Spritz, MD & David A. Norris, MD
Contents
75 Hypomelanoses and Hypermelanoses . . . . . . . . 804

Hilde Lapeere, MD, PhD, Barbara Boone, MD, PhD,
Sofie De Schepper, MD, PhD, Evelien Verhaeghe, MD,
Mireille Van Gele, PhD, Katia Ongenae, MD, PhD,
Nanja Van Geel, MD, PhD, Jo Lambert, MD, PhD, &
Lieve Brochez, MD, PhD
Section 12. Disorders of the Oral

and Genital Integument
76 Biology and Pathology of the Oral Cavity. . . . . . 827
Sook-Bin Woo, DMD
77 Diseases and Disorders of the Male Genitalia . . . 852
Christopher B. Bunker, MD, FRCP
78 Diseases and Disorders of the Female
Genitalia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
Lynette J. Margesson, MD, FRCPC &
F. William Danby, MD, FRCPC, FAAD
PART 3 Disorders of the

Skin Appendages
Section 13. Disorders of the
Sebaceous Glands
79 Biology of Sebaceous Glands. . . . . . . . . . . . . . . . . 893
Amanda M. Nelson, PhD &
Diane M. Thiboutot, MD
80 Acne Vulgaris and Acneiform Eruptions. . . . . . . 897
Andrea L. Zaenglein, MD,
Emmy M. Graber, MD, & Diane M. Thiboutot, MD
81 Rosacea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918
Michelle T. Pelle, MD
82 Perioral Dermatitis. . . . . . . . . . . . . . . . . . . . . . . . . . 925
Leslie P. Lawley, MD & Sareeta R.S. Parker, MD
Section 14. Disorders of the Eccrine

and Apocrine Glands
83 Biology of Eccrine and Apocrine Glands. . . . . . . 929
Theodora M. Mauro, MD
viii
84 Disorders of the Eccrine Sweat Glands and

Sweating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
Robert D. Fealey, MD & Adelaide A. Hebert, MD
85 Disorders of the Apocrine Sweat Glands. . . . . . . 947

Christos C. Zouboulis, MD, PhD &
Fragkiski Tsatsou, MD, MSc, BSc
Section 15. Disorders of the

Hair and Nails
86 Biology of Hair Follicles. . . . . . . . . . . . . . . . . . . . . 960
George Cotsarelis, MD &
Vladimir Botchkarev, MD, PhD
87 Keratosis Pilaris and Other Inflammatory
Follicular Keratotic Syndromes. . . . . . . . . . . . . . . 973
Paradi Mirmirani, MD &
Maureen Rogers, MBBS, FACD
88 Hair Growth Disorders. . . . . . . . . . . . . . . . . . . . . . 979
Nina Otberg, MD &
Jerry Shapiro, MD, FRCPC, FAAD
89 Biology of Nails and Nail Disorders. . . . . . . . . . 1009
Antonella Tosti, MD &
Bianca Maria Piraccini, MD, PhD
PART 4 Disorders Due to the

Environment
Section 16. Disorders Due to
Ultraviolet Radiation
90 Fundamentals of Cutaneous Photobiology and
Photoimmunology. . . . . . . . . . . . . . . . . . . . . . . . . 1031
Irene E. Kochevar, PhD,
Charles R. Taylor, MD, & Jean Krutmann, MD
91 Abnormal Responses to Ultraviolet Radiation:
Idiopathic, Probably Immunologic, and
Photoexacerbated. . . . . . . . . . . . . . . . . . . . . . . . . . 1049
Travis W. Vandergriff, MD &
Paul R. Bergstresser, MD
92 Abnormal Responses to Ultraviolet
Radiation: Photosensitivity Induced by
Exogenous Agents. . . . . . . . . . . . . . . . . . . . . . . . . 1066
Henry W. Lim, MD
Section 17. Skin Changes Due to

Other Physical and Chemical
Factors
93 Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . 1075
Dean L. Kellogg, Jr., MD, PhD
94 Cold Injuries. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079
Grald E. Pirard, MD, PhD,
Pascale Quatresooz, MD, PhD, &
Claudine Pirard-Franchimont, MD, PhD
95 Thermal Injuries. . . . . . . . . . . . . . . . . . . . . . . . . . . 1089

Robert L. Sheridan, MD
96 Skin Problems in Amputees. . . . . . . . . . . . . . . . . 1095
Calum C. Lyon, MA, FRCP &
Michael H. Beck, FRCP, MBChB
97 Skin Problems in Ostomates . . . . . . . . . . . . . . . . 1104
Calum C. Lyon, MA, FRCP &
98 Corns and Calluses . . . . . . . . . . . . . . . . . . . . . . . . 1111
Thomas M. DeLauro, DPM &
Nicole M. DeLauro, DPM
100 Decubitus (Pressure) Ulcers . . . . . . . . . . . . . . . . 1121

Jennifer G. Powers, MD, Lillian Odo, MD, &
Tania J. Phillips, MD, FRCP, FRCPC
101 Body Art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129
Anne Laumann, MBChB, MRCP(UK), FAAD
PART 5 Neurocutaneous and

Psychocutaneous Aspects
of Skin Disease
109 Aging of Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1213

Mina Yaar, MD & Barbara A. Gilchrest, MD
PART 7 NEOPLASIA
Section 20. Carcinogenesis
110 Genome Instability, DNA Repair, and
Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
Thomas M. Rnger, MD, PhD &
Kenneth H. Kraemer, MD
111 Chemical Carcinogenesis. . . . . . . . . . . . . . . . . . . 1239
Adam B. Glick, PhD & Andrzej A. Dlugosz, MD
112 Ultraviolet Radiation Carcinogenesis . . . . . . . . 1251
Masaoki Kawasumi, MD, PhD &
Paul Nghiem, MD, PhD
Section 21. Epidermal and

Appendageal Tumors
113 Epithelial Precancerous Lesions. . . . . . . . . . . . . 1261
Karynne O. Duncan, MD,
John K. Geisse, MD & David J. Leffell, MD
Section 18. Neurocutaneous and

Psychocutaneous Skin Disease
114 Squamous Cell Carcinoma. . . . . . . . . . . . . . . . . . 1283

Douglas Grossman, MD, PhD & David J. Leffell, MD
102 Neurobiology of the Skin. . . . . . . . . . . . . . . . . . . 1137

Martin Steinhoff, MD, PhD &
Thomas A. Luger, MD
115 Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . 1294

John A. Carucci, MD, PhD,
David J. Leffell, MD & Julia S. Pettersen, MD
103 Pathophysiology and Clinical Aspects

of Pruritus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146
Gil Yosipovitch, MD &
Tejesh S. Patel, MBBS (Lon), BSc (Hons)
116 Basal Cell Nevus Syndrome . . . . . . . . . . . . . . . . 1304

Anthony E. Oro, MD, PhD &
Jean Y. Tang, MD, PhD
104 Psychocutaneous Skin Disease . . . . . . . . . . . . . . 1158

Evan Rieder, MD & Francisco A. Tausk, MD
105 Cutaneous Manifestations of Drug Abuse. . . . . 1166
Haley Naik, MD & Richard Allen Johnson, MDCM
106 Skin Signs of Physical Abuse. . . . . . . . . . . . . . . . 1177
Howard B. Pride, MD
PART 6SKIN CHANGES ACROSS

THE SPAN OF LIFE
Section 19. From Birth to Old Age
107 Neonatal, Pediatric, and Adolescent
Dermatology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185
Mary Wu Chang, MD
Contents
99 Sports Dermatology. . . . . . . . . . . . . . . . . . . . . . . . 1115

Dirk M. Elston, MD
108 Skin Changes and Diseases in Pregnancy. . . . . 1204

Julie K. Karen, MD &
Miriam Keltz Pomeranz, MD
117 Keratoacanthoma. . . . . . . . . . . . . . . . . . . . . . . . . . 1312

Lorenzo Cerroni, MD & Helmut Kerl, MD
118 Benign Epithelial Tumors,
Hamartomas, and Hyperplasias. . . . . . . . . . . . . 1319
Valencia D. Thomas, MD, Nicholas R. Snavely, MD,
Ken K. Lee, MD & Neil A. Swanson, MD
119 Appendage Tumors and Hamartomas
of the Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337
Divya Srivastava, MD & R. Stan Taylor, MD
120 Merkel Cell Carcinoma. . . . . . . . . . . . . . . . . . . . . 1362
Andrew Tegeder, MS, Olga Afanasiev, BA, &
121 Mammary and Extramammary
Pagets Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1371
Sherrif F. Ibrahim, MD, PhD, Roy C. Grekin, MD, &
Isaac M. Neuhaus, MD
ix
Section 22. Melanocytic Tumors

122 Benign Neoplasias and Hyperplasias of
Melanocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1377
James M. Grichnik, MD, PhD,
Arthur R. Rhodes, MD, MPH, &
Arthur J. Sober, MD
123 Atypical (Dysplastic) Melanocytic Nevi. . . . . . 1410
James M. Grichnik, MD, PhD &
Margaret A. Tucker, MD
Contents
124 Cutaneous Melanoma. . . . . . . . . . . . . . . . . . . . . . 1416

Evans C. Bailey, MD, PhD,
Arthur J. Sober, MD, Hensin Tsao, MD, PhD,
Martin C. Mihm Jr, MD, FACP, &
Timothy M. Johnson, MD
Section 23. Tumors and

Hyperplasias of the Dermis and
Subcutaneous Fat
125 Malignant Fibrous, Fibrohistiocytic, and
Histiocytic Tumors of the Dermis. . . . . . . . . . . . 1445
Jrgen C. Becker, MD, PhD,
Bernadette Liegl-Atzwanger, MD & Selma Ugurel, MD
126 Vascular Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 1456
Erin F. Mathes, MD & Ilona J. Frieden, MD
127 Neoplasias and Hyperplasias of
Muscular and Neural Origin. . . . . . . . . . . . . . . . 1470
Lucile E. White, MD, Ross M. Levy, MD, &
Murad Alam, MD, MSci
134 Systemic Autoinflammatory Diseases. . . . . . . . 1584

Chyi-Chia Richard Lee, MD, PhD &
Raphaela Goldbach-Mansky, MD, MHS
135 Xanthomatoses and Lipoprotein Disorders. . . . 1600
Ernst J. Schaefer, MD & Raul D. Santos, MD, PhD
136 Fabry Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1613
Atul B. Mehta, MD, FRCP, FRCPath &
Catherine H. Orteu, MBBS, BSc, MD, FRCP
137 Lipoid Proteinosis and Heritable
Disorders of Connective Tissue. . . . . . . . . . . . . . 1624
Jonathan A. Dyer, MD
138 Cutaneous Mineralization and Ossification. . . . 1649
Janet A. Fairley, MD
139 Hereditary Disorders of Genome
Instability and DNA Repair. . . . . . . . . . . . . . . . . 1654
Thomas M. Rnger, MD, PhD,
John J. DiGiovanna, MD, &
140 Tuberous Sclerosis Complex . . . . . . . . . . . . . . . . 1671
Thomas N. Darling, MD, PhD
141 The Neurofibromatoses. . . . . . . . . . . . . . . . . . . . 1680
Robert Listernick, MD & Joel Charrow, MD
128 Kaposis Sarcoma and Angiosarcoma. . . . . . . . 1481

Erwin Tschachler, MD
142 Ectodermal Dysplasias. . . . . . . . . . . . . . . . . . . . . 1691

Alanna F. Bree, MD, Nnenna Agim, MD, &
Virginia P. Sybert, MD
129 Neoplasms of Subcutaneous Fat. . . . . . . . . . . . . 1489

Thomas Brenn, MD, PhD, FRCPath
143 Genetic Immunodeficiency Diseases. . . . . . . . . 1703

Ramsay L. Fuleihan, MD & Amy S. Paller, MD
Volume Two
PART 8 THE SKIN IN SYSTEMIC
DISEASE
Section 25. Skin Manifestations of

Bone Marrow or Blood Chemistry
Disorders
144 Hematologic Diseases. . . . . . . . . . . . . . . . . . . . . . 1726
Warren W. Piette, MD
Section 24. Skin in Nutritional,

Metabolic, and Heritable Disease
145 Cutaneous Lymphoma. . . . . . . . . . . . . . . . . . . . . 1745

Marc Beyer, MD & Wolfram Sterry, Prof. Dr.
130 Cutaneous Changes in Nutritional Disease. . . . 1499

Melinda Jen, MD & Albert C. Yan, MD
146 Inflammatory Diseases That Simulate Lymphomas:

Cutaneous Pseudolymphomas. . . . . . . . . . . . . . . 1767
Gary S. Wood, MD
131 Cutaneous Changes in Errors of

Amino Acid Metabolism. . . . . . . . . . . . . . . . . . . . 1525
Peter H. Itin, MD
133 Amyloidosis of the Skin. . . . . . . . . . . . . . . . . . . . 1574

Helen J. Lachmann, MD, FRCP &
Philip N. Hawkins, PhD, FRCP, FRCPath, FMedSci
132 The Porphyrias. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1538

David R. Bickers, MD & Jorge Frank, MD, PhD
147 Cutaneous Langerhans Cell Histiocytosis. . . . . 1782

Carlo Gelmetti, MD
148 Non-Langerhans Cell Histiocytosis . . . . . . . . . . 1795
Carlo Gelmetti, MD
149 Mastocytosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1809

Michael D. Tharp, MD
Section 26. Skin Manifestations of

Internal Organ Disorders
150 The Skin and Disorders of the Alimentary
Tract, the Hepatobiliary System, the Kidney,
and the Cardiopulmonary System. . . . . . . . . . . 1819
Graham A. Johnston, MBChB, FRCP &
Robin A.C. Graham-Brown, BSc, MB, FRCP, FRCPCH
152 Sarcoidosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1869

Richard M. Marchell, MD, Bruce Thiers, MD, &
Marc A. Judson, MD
153 Cutaneous Manifestations of Internal
Malignant Disease: Cutaneous
Paraneoplastic Syndromes. . . . . . . . . . . . . . . . . . 1880
Christine A. DeWitt, MD,
Lucinda S. Buescher, MD, & Stephen P. Stone, MD
Section 27. The Skin in

Vascular and Connective
Tissue and Other Autoimmune
Disorders
154 Mechanisms of Autoimmune Disease. . . . . . . . 1901
Insoo Kang, MD & Joseph Craft, MD
155 Lupus Erythematosus. . . . . . . . . . . . . . . . . . . . . . 1909
Melissa I. Costner, MD &
Richard D. Sontheimer, MD
156 Dermatomyositis. . . . . . . . . . . . . . . . . . . . . . . . . . 1926
Richard D. Sontheimer, MD,
Christopher B. Hansen, MD, &
Melissa I. Costner, MD
157 Scleroderma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1942
P. Moinzadeh, MD,
Christopher P. Denton, PhD, FRCP, T. Krieg, MD, &
Carol M. Black, MD, FRCP, FMedSci
158 Scleredema and Scleromyxedema. . . . . . . . . . . . 1957
Roger H. Weenig, MD, MPH &
159 Relapsing Polychondritis. . . . . . . . . . . . . . . . . . . 1962
Camille Francs, MD
160 Rheumatoid Arthritis, Rheumatic
Fever, and Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . 1965
Section 28. The Skin in

Inflammatory and Other
Vascular Disorders
162 Endothelium in Inflammation and
Angiogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986
Peter Petzelbauer, MD, Robert Loewe, MD, &
Jordan S. Pober, MD, PhD
163 Cutaneous Necrotizing Venulitis . . . . . . . . . . . . 2003
Nicholas A. Soter, MD
164 Systemic Necrotizing Arteritis. . . . . . . . . . . . . . . 2013
Peter A. Merkel, MD, MPH &
Paul A. Monach, MD, PhD
Contents
151 Diabetes Mellitus and Other Endocrine

Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1840
Andrea A. Kalus, MD,
Andy J. Chien, MD, PhD, &
John E. Olerud, MD
161 Sjgrens Syndrome. . . . . . . . . . . . . . . . . . . . . . . . 1976

Gabor Illei, MD, PhD, MHS &
Stamatina Danielides, MD
165 Erythema Elevatum Diutinum . . . . . . . . . . . . . . 2029

Nneka I. Comfere, MD &
Lawrence E. Gibson, MD
166 AdamantiadesBehet Disease. . . . . . . . . . . . . . 2033
Christos C. Zouboulis, MD, PhD
167 Kawasaki Disease. . . . . . . . . . . . . . . . . . . . . . . . . . 2042
Anne H. Rowley, MD
168 Pigmented Purpuric Dermatoses . . . . . . . . . . . . 2049
Theresa Schroeder Devere, MD &
Anisha B. Patel, MD
169 C
ryoglobulinemia and
Cryofibrinogenemia. . . . . . . . . . . . . . . . . . . . . . . . 2055
Holger Schmid, MD, MSc PD &
Gerald S. Braun, MD
170 Raynaud Phenomenon. . . . . . . . . . . . . . . . . . . . . 2065
John H. Klippel, MD
171 Malignant Atrophic Papulosis
(Degos Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . 2072
Dan Lipsker, MD, PhD
172 Vascular Malformations. . . . . . . . . . . . . . . . . . . . 2076
Laurence M. Boon, MD, PhD &
Miikka Vikkula, MD, PhD
173 Cutaneous Changes in Peripheral
Arterial Vascular Disease. . . . . . . . . . . . . . . . . . . 2094
Veerendra Chadachan, MD
Steven M. Dean, DO, FACP, RPVI, &
Robert T. Eberhardt, MD, FACC, FSVM, RPVI
174 Cutaneous Changes in Peripheral
Venous and Lymphatic Insufficiency. . . . . . . . . 2110
Craig N. Burkhart, MD, Chris Adigun, MD, &
Claude S. Burton, MD
xi
PART 9 Disease Due to Microbial

Agents, Infestations, Bites, and
Stings
Section 29. Bacterial Disease
175 G
eneral Considerations of Bacterial
Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2121
Noah Craft, MD, PhD, DTMH
Contents
176 S
uperficial Cutaneous Infections
and Pyodermas. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2128
177 G
ram-Positive Infections Associated
with Toxin Production. . . . . . . . . . . . . . . . . . . . . . 2148
Jeffrey B. Travers, MD, PhD &
Nico Mousdicas, MBChB, MD
178 N
on-Necrotizing Infections of the
Dermis and Subcutaneous Fat:
Cellulitis and Erysipelas. . . . . . . . . . . . . . . . . . . . 2160
Adam D. Lipworth, MD,
Arturo P. Saavedra, MD, PhD, MBA,
Arnold N. Weinberg, MD, &
Richard Allen Johnson, MDCM
179 Necrotizing Soft Tissue Infections:
Necrotizing Fasciitis, Gangrenous
Cellulitis, and Myonecrosis . . . . . . . . . . . . . . . . . 2169
Adam D. Lipworth, MD,
Arturo P. Saavedra, MD, PhD, MBA,
Arnold N. Weinberg, MD, &
187 Lyme Borreliosis. . . . . . . . . . . . . . . . . . . . . . . . . . . 2263

Meera Mahalingam, MD, PhD, FRCPath,
Jag Bhawan, MD, Daniel B. Eisen, MD, &
Linden Hu, MD
Section 30. Fungal Diseases

188 Superficial Fungal Infection. . . . . . . . . . . . . . . . . 2277
Stefan M. Schieke, MD & Amit Garg, MD
189 Yeast Infections: Candidiasis,
Tinea (Pityriasis) Versicolor, and
Malassezia (Pityrosporum) Folliculitis. . . . . . . . . . 2298
Roopal V. Kundu, MD & Amit Garg, MD
190 Deep Fungal Infections. . . . . . . . . . . . . . . . . . . . . 2312
Roderick J. Hay, DM, FRCP, FRCPath, FMedSci
SECTION 31. Viral and Rickettsial

Diseases
191 G
eneral Considerations of Viral Diseases. . . . . 2329
L. Katie Morrison, MD, Ammar Ahmed, MD,
Vandana Madkan, MD, Natalia Mendoza, MD, MS,
& Stephen Tyring, MD, PhD
192 E
xanthematous Viral Diseases. . . . . . . . . . . . . . . 2337
Leah T. Belazarian, MD, Mayra E. Lorenzo, MD,
PhD, Andrea L. Pearson, MD,
Susan M. Sweeney, MD, & Karen Wiss, MD
180 Gram-Negative Coccal and Bacillary

Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2178
Myron S. Cohen, MD,
William A. Rutala, BS, MS, PhD, MPH, &
David J. Weber, MD, MPH
193 H
erpes Simplex . . . . . . . . . . . . . . . . . . . . . . . . . . . 2367
Adriana R. Marques, MD & Jeffrey I. Cohen, MD
181 The Skin in Infective Endocarditis,

Sepsis, Septic Shock, and Disseminated
Intravascular Coagulation . . . . . . . . . . . . . . . . . . 2194
Laura Korb Ferris, MD, PhD & Joseph C. English, MD
195 Poxvirus Infections . . . . . . . . . . . . . . . . . . . . . . . . 2402

Caroline Piggott, MD, Sheila Fallon Friedlander, MD,
& Wynnis Tom, MD
182 Bartonellosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2201

Timothy G. Berger, MD & Francisco G. Bravo, MD
183 Miscellaneous Bacterial Infections with
Cutaneous Manifestations. . . . . . . . . . . . . . . . . . 2210
Scott A. Norton, MD, MPH, MS
xii
186 Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2253

Delphine J. Lee, MD, PhD, FAAD,
Thomas H. Rea, & Robert L. Modlin, MD
194 V
aricella and Herpes Zoster. . . . . . . . . . . . . . . . . 2383
Kenneth E. Schmader, MD & Michael N. Oxman, MD
196 Human Papilloma Virus Infections . . . . . . . . . . 2421

Elliot J. Androphy, MD & Reinhard Kirnbauer, MD
197 H
uman T-Lymphotropic Viruses . . . . . . . . . . . . 2434
184 Tuberculosis and Infections with

Atypical Mycobacteria. . . . . . . . . . . . . . . . . . . . . . 2225
Aisha Sethi, MD
198 C
utaneous Manifestations of Human
Immunodeficiency Virus Disease. . . . . . . . . . . . 2439
Lily Changchien Uihlein, MD, JD,
Arturo P. Saavedra, MD, PhD, MBA, &
185 Actinomycosis, Nocardiosis, and

Actinomycetoma . . . . . . . . . . . . . . . . . . . . . . . . . . 2241
Francisco G. Bravo, MD, Roberto Arenas, MD, &
Daniel Asz Sigall, MD
199 T
he Rickettsioses, Ehrlichioses, and
Anaplasmoses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2456
Sandra A. Kopp, MD, Analisa V. Halpern, MD,
Justin J. Green, MD & Warren R. Heymann, MD
SECTION 32. Sexually Transmitted

Diseases
200 S
yphilis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2471
Kenneth A. Katz, MD, MSc, MSCE
201 E
ndemic (Nonvenereal) Treponematoses. . . . . 2493
Nadine Marrouche, MD &
Samer H. Ghosn, MD
202 Chancroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2501
Stephan Lautenschlager, MD
204 Granuloma Inguinale . . . . . . . . . . . . . . . . . . . . . . 2510

Abdul-Ghani Kibbi, MD, FAAD, FACP,
Ruba F. Bahhady, MD, & Myrna El-Shareef, MD
205 G
onorrhea, Mycoplasma, and Vaginosis. . . . . . 2514
Ted Rosen, MD
SECTION 33. Infestations, Bites, and

Stings
206 Leishmaniasis and Other Protozoan
Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2527
Joelle M. Malek, MD & Samer H. Ghosn, MD
207 Helminthic Infections . . . . . . . . . . . . . . . . . . . . . . 2544
Kathryn N. Suh, MD &
Jay S. Keystone, MD, MSc(CTM), FRCPC
208 Scabies, Other Mites, and Pediculosis . . . . . . . . 2569
Craig N. Burkhart, MD &
Craig G. Burkhart, MD, MPH
209 Bites and Stings of Terrestrial and
Aquatic Life. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2578
Jennifer S. Daly, MD &
Mark Jordan Scharf, MD
210 Arthropod Bites and Stings . . . . . . . . . . . . . . . . . 2599
Robert A. Schwartz, MD, MPH &
Christopher J. Steen, MD
PART 10 Occupational Skin

Diseases and Skin Diseases
Due to Biologic Warfare
SECTION 34. Occupational Skin
Diseases
211 O
ccupational Skin Diseases Due to
Irritants and Allergens . . . . . . . . . . . . . . . . . . . . . 2611
Golara Honari, MD,
James S. Taylor, MD, FAAD, & Apra Sood, MD
SECTION 35. The Skin in Bioterrorism

and Biologic Warfare
213 C
utaneous Manifestations of Biologic,
Chemical, and Radiologic Attacks . . . . . . . . . . . 2633
Scott A. Norton, MD, MPH, MSc
PART 11 THERAPEUTICS
Contents
203 Lymphogranuloma Venereum. . . . . . . . . . . . . . . 2505

Rim S. Ishak, MD & Samer H. Ghosn, MD
212 O
ccupational Noneczematous Skin
Diseases Due to Biologic, Physical,
and Chemical Agents: Introduction. . . . . . . . . . 2622
Paul X. Benedetto, MD,
James S. Taylor, MD, FAAD, &
Apra Sood, MD
SECTION 36. Topical Therapy

214 P
rinciples of Topical Therapy . . . . . . . . . . . . . . . 2643
Aieska De Souza, MD, MS &
Bruce E. Strober, MD, PhD
215 P
harmacokinetics and Topical
Applications of Drugs. . . . . . . . . . . . . . . . . . . . . . 2652
Hans Schaefer, PhD, Thomas E. Redelmeier, MD
Gerhard J. Nohynek, PhD, DABT, &
Jrgen Lademann, Prof. Dr. rer. nat. Dr.-Ing. habil.
216 T
opical Corticosteroids. . . . . . . . . . . . . . . . . . . . . 2659
Isabel C. Valencia, MD &
Francisco A. Kerdel, MD
217 Topical Retinoids. . . . . . . . . . . . . . . . . . . . . . . . . . 2665
Anna L. Chien, MD,
John J. Voorhees, MD, FRCP, &
Sewon Kang, MD
218 Topical Antibiotics. . . . . . . . . . . . . . . . . . . . . . . . . 2673
Mark W. Bonner, MD & William D. James, MD
219 Topical Antifungal Agents. . . . . . . . . . . . . . . . . . 2677
Whitney A. High, MD, JD, MEng &
James E. Fitzpatrick, MD
220 T
opical and Intralesional Cytotoxic
Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2685
Aieska De Souza, MD, MS,
Megan M. Moore, MD, & Bruce E. Strober, MD, PhD
221 T
opical Immunomodulators . . . . . . . . . . . . . . . . 2690
Edward M. Esparza, MD, PhD &
Robert Sidbury, MD, MPH
222 O
ther Topical Medications. . . . . . . . . . . . . . . . . . 2697
Craig N. Burkhart, MD &
Kenneth A. Katz, MD, MSc, MSCE
223 Photoprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . 2707
Henry W. Lim, MD
xiii
SECTION 37. Systemic Therapy

224 Systemic Glucocorticoids. . . . . . . . . . . . . . . . . . . 2714
Victoria P. Werth, MD
225 Dapsone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2721
Joni G. Sago, MD & Russell P. Hall III, MD
226 Aminoquinolines. . . . . . . . . . . . . . . . . . . . . . . . . . 2726
Susannah E. McClain, MD, Jeffrey R. LaDuca, MD, PhD
& Anthony A. Gaspari, MD
Contents
227 Cytotoxic and Antimetabolic Agents. . . . . . . . . 2735

Whitney A. High, MD, JD, MEng &
228 Retinoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2759
Anders Vahlquist, MD, PhD &
Jean-Hilaire Saurat, MD
229 Antihistamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2767
Robert A. Wood, MD
230 Antibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2776
Christopher C. Gasbarre, DO, FAAD,
Steven K. Schmitt, MD, &
Kenneth J. Tomecki, MD
231 Antiviral Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . 2787
Dirk M. Elston, MD
232 Oral Antifungal Agents. . . . . . . . . . . . . . . . . . . . . 2796
Reza Jacob, MD & Nellie Konnikov, MD
233 I mmunosuppressive and
Immunomodulatory Drugs. . . . . . . . . . . . . . . . . 2807
Jeffrey P. Callen, MD
234 I mmunobiologicals, Cytokines, and
Growth Factors in Dermatology. . . . . . . . . . . . . 2814
Stephen K. Richardson, MD &
Joel M. Gelfand, MD, MSCE
235 Antiangiogenic Agents. . . . . . . . . . . . . . . . . . . . . 2827
Ricardo L. Berrios, MD, Michael Y. Bonner, BA,
Jonathan Hofmekler, BSc, &
Jack L. Arbiser, MD, PhD
236 Drug Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . 2834
Stephen E. Wolverton, MD
SECTION 38. Physical Treatments

237 Phototherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2841
Jennifer A. Cafardi, MD, Brian P. Pollack, MD, PhD, &
Craig A. Elmets, MD
xiv
238 Photochemotherapy and Photodynamic

Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2851
Herbert Hnigsmann, MD,
Rolf-Markus Szeimies, MD, PhD, &
Robert Knobler, MD
239 Lasers and Flashlamps in Dermatology. . . . . . 2869
Michael Landthaler, MD,
Wolfgang Bumler, PhD, &
Ulrich Hohenleutner, MD
240 Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2890
Roy H. Decker, MD, PhD, &
Lynn D. Wilson, MD, MPH
SECTION 39. Complementary and

Alternative Dermatology
241 C
omplementary and Alternative
Medicine in Dermatology. . . . . . . . . . . . . . . . . . . 2899
Alan Dattner, MD
SECTION 40. Surgery in Dermatology

242 A
natomy and Approach in Dermatologic
Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2905
Sumaira Z. Aasi, MD &
Brent E. Pennington, MD
243 E
xcisional Surgery and Repair, Flaps, and
Grafts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2921
Jessica M. Sheehan, MD, Melanie Kingsley, MD, &
Thomas E. Rohrer, MD
244 M
ohs Micrographic Surgery . . . . . . . . . . . . . . . . 2950
Joseph Alcalay, MD &
Ronen Alkalay, MD, MBA
245 N
ail Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2956
Robert Baran, MD
246 C
ryosurgery and Electrosurgery. . . . . . . . . . . . . 2968
Justin J. Vujevich, MD &
Leonard H. Goldberg, MD, FRCP
247 Surgical Complications. . . . . . . . . . . . . . . . . . . . . 2977
Richard G. Bennett, MD
248 M
echanisms of Wound Repair, Wound
Healing, and Wound Dressing. . . . . . . . . . . . . . 2984
Vincent Falanga, MD, FACP &
Satori Iwamoto, MD, PhD
249 T
reatment for Varicose and Telangiectatic
Leg Veins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2997
Robert A. Weiss, MD & Margaret A. Weiss, MD
SECTION 41. Cosmetic Dermatology

250 C
osmetics and Skin Care in
Dermatology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3009
Leslie Baumann, MD
251 A
blative Lasers, Chemical Peels, and
Dermabrasion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3021
Elizabeth L. Tanzi, MD &
Tina S. Alster, MD
254 S
oft Tissue Augmentation. . . . . . . . . . . . . . . . . . 3044
Lisa M. Donofrio, MD
255 B
otulinum Toxin. . . . . . . . . . . . . . . . . . . . . . . . . . . 3053
Richard G. Glogau, MD
256 H
air Transplantation and Alopecia
Reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3061
Walter P. Unger, MD, Robin H. Unger, MD, &
Mark A. Unger, MD, CCFP
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I-1
Contents
252 C
osmetic Applications of Nonablative
Lasers and Other Light Devices . . . . . . . . . . . . . 3032
Elliot T. Weiss, MD,
Anne M. Chapas, MD, &
Roy G. Geronemus, MD
253 Liposuction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3041

William G. Stebbins, MD, Aimee L. Leonard, MD, &
C. William Hanke, MD, MPH, FACP
xv
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Contributors
Sumaira Z. Aasi, MD
Elliot J. Androphy, MD
Christine Bangert, MD
Chris Adigun, MD
Grant J. Anhalt, MD
Robert Baran, MD
Associate Professor, Department of

Dermatology, Yale University,
New Haven, CT [242]
Department chair Dermatology

at Indiana University School of
Medicine Indianapolis, IN [196]
Department of Dermatology,
Medical University of Vienna,
Vienna, Austria [10]
Professor, Department of
Dermatology and Pathology, Johns
Hopkins University School of
Medicine, Baltimore, MD [55]
Honorary Professor, Department of

Dermatology, Nail Disease Center,
Cannes, France [245]
Jack L. Arbiser, MD, PhD
Dermatology, Emory University
School of Medicine, Atlanta, GA [235]
Chief Executive Officer, Cosmetic

Dermatology, Baumann Cosmetic
and Research Institute, Miami
Beach, FL [250]
Assistant Professor, Department of

Dermatology, University of Texas
Southwestern Medical Center at
Dallas, Dallas, TX [142]
Roberto Arenas, MD
Lisa A. Beck, MD
Ammar Ahmed, MD
Iris K. Aronson, MD
Physician (PGY-3), Department of

Dermatology, UNC-Chapel Hill,
Chapel Hill, NC [174]
Olga K. Afanasiev, BA
University of Washington School
of Medicine, Seattle, WA [120]
Nnenna Agim, MD
Resident Physician, Department of

Southwestern Medical Center,
Dallas, TX [191]
Murad Alam, MD, MSci
Associate Professor, Departments

of Dermatology, Otolaryngology,
and Surgery, Feinberg School of
Medicine, Northwestern University,
Chicago, IL [127]
Dermatology, University of Mexico,
Mexico, DF [185]
Dermatology, University of Illinois
College of Medicine, Chicago, IL
[70]
Daniel Asz-Sigall, MD
Resident, Dermatology, Cutaneous

Oncology and Dermatologic
Surgery, Department of
Dermatology, ABC Hospital, Mexico
City, Mexico [185]
Joseph Alcalay, MD
Monique Aumailley
Ronen Alkalay, MD, MBA
Wolfgang Bumler, PhD
Director, Mohs Surgery Unit, Assuta

Medical Center, Tel Aviv, Israel [244]
Mohs Unit, Assuta Medical Hospital,
Tel Aviv, Israel [244]
Tina S. Alster, MD
Director, Laser Surgery, Washington

Institute of Dermatologic Laser
Surgery, Washington, DC [251]
Antoine Amado, MD
Resident in Dermatology,
Dermatology and Plastic Surgery
Institute, Cleveland Clinic,
Cleveland, OH [48]
Professor, Center for Biochemistry,

Cologne, Germany [63]
Dermatology, University of
Regensburg, Germany [239]
Ruba F. Bahhady, MD
Resident (PGY-4), Department of

Dermatology, American University
of Beirut Medical Center, Beirut,
Lebanon [204]
Evans C. Bailey, MD, PhD
Lecturer, Department of
Michigan, Ann Arbor, MI [124]
Leslie Baumann, MD
Associate Professor of Dermatology

and Medicine, Department of
Dermatology and Medicine,
University of Rochester School of
Medicine, Rochester, NY [31]
Honorary Clinical Lecturer,

Occupational and Environmental
Health Group, University of
Manchester, Manchester, UK [96, 97]
Jrgen C. Becker, MD, PhD
Professor, Division of General

Dermatology, Medical University of
Graz, Graz, Austria [125]
Leah T. Belazarian, MD
Assistant Professor of Medicine and

Pediatrics, Department of Medicine,
Division of Dermatology, University
of Massachusetts Medical School,
Worcester, MA [192]
Donald V. Belsito, MD
Clinical Professor, Medicine

(Dermatology), University of
Missouri, Kansas City, MO [17]
Paul X. Benedetto, MD
Resident Physician, Department

of Dermatology, Cleveland Clinic
Foundation, Cleveland, OH [212]
Richard G. Bennett, MD
Clinical Professor, Dermatology,

University of Southern California,
Los Angeles, CA [247]
Timothy G. Berger, MD
California, San Francisco, San
Francisco, CA [182]
Paul R. Bergstresser, MD
Dallas, TX [91]
Jeffrey D. Bernhard, MD,

FRCP (Edin)
Contributors
Professor Emeritus, University of

Massachusetts Medical School,
Worcester, MA [5]
Ricardo L. Berrios, MD
Post-Doctoral Fellow, Department

of Dermatology, School of Medicine,
Emory University, Atlanta, GA [235]
Marc Beyer, MD
Department of Dermatology and

Allergy, Charit Universittsmedizin
Berlin, Berlin, Germany [145]
Jag Bhawan, MD
Dermatology and Pathology, Boston
University School of Medicine,
Boston, MA [187]
David R. Bickers, MD
Carl Truman Nelson Professor,

Columbia University Medical Center,
New York, NY [132]
Michael Bigby, MD
Associate Professor, Department

of Dermatology, Harvard Medical
School, Boston, MA [2]
Stanca A. Birlea, MD, PhD
Instructor, Dermatology and Human

Medical Genetics Program, School
of Medicine, University of Colorado
Denver, Aurora, CO [74]
Carol M. Black, MD, FRCP,

FMedSci
Professor, Centre for Rheumatology,

University College London, London,
UK [157]
Georgia Dermatology
Warner Robins, GA [218]
Michael Y. Bonner, BA
Research Associate, Department of

Dermatology, School of Medicine,
Laurence M. Boon, MD, PhD
Center for Vascular Anomalies

Division of Plastic Surgery St Luc
University Hospital, Brussels,
Belgium [172]
Barbara Boone, MD, PhD
Dermatologist, Ghent University

Hospital, Ghent, Belgium [75]
Vladimir Botchkarev,
MD, PhD
Professor, Centre for Skin Sciences,

University of Bradford and
Bradford, UK [86]
Gerald S. Braun, MD
Department of Nephrology and

Clinical Immunology, University
Hospital, RWTH University of
Aachen, Aachen, Germany [169]
Francisco G. Bravo, MD
Dermatology, University Hospital
of Dsseldorf, Dsseldorf, Germany
[24]
Leena Bruckner-Tuderman, MD
Dermatology, University Medical
Center Freiburg, Freiburg, Germany
[53]
Lucinda S. Buescher, MD
Associate Professor, Division of

Dermatology, Southern Illinois
University, Springfield, IL [153]
Christopher B. Bunker, MD,

FRCP
Dermatology, University College
London Hospitals, London, UK [77]
Walter H.C. Burgdorf, MD
Lecturer, Department of
Dermatology, Ludwig Maximilian
University, Munich, Germany [43]
Susan Burge, OBE DM FRCP
Consultant Dermatologist, Oxford

University Hospitals, Oxford, UK [51]
Susan Burgin, MD
Alanna F. Bree, MD
Craig G. Burkhart, MD, MPH
Thomas Brenn, MD, PhD,

FRCPath
Craig N. Burkhart, MD
Pediatric Dermatologist,
Dermatology Specialists of Houston,
Bellaire, TX [142]
Consultant Dermatopathologist,
Department of Pathology, Western
General Hospital, Edinburgh, UK
[129]
Lieve Brochez, MD, PhD
Dermatology, Ghent University
Robert T. Brodell, MD
Dermatology, Oregon Health &
Science University, Portland, OR
[29, 42]
Mark Boguniewicz, MD
Katherine L. Brown, MD, MPH
Professor, Department of Pediatrics,

Division of Allergy-Immunology,
National Jewish Health, Denver, CO
[14]
Daniela Bruch-Gerharz, MD

of Pathology, Universidad Peruana
Cayetano Heredia, Lima, Peru
[182, 185]
Professor of Internal Medicine

and Clinical Professor of
Dermatopathology in Pathology,
Department of Internal Medicine
and Pathology, Northeastern Ohio
Universities College of Medicine
and Pharmacy, Rootstown, OH [68]
Andrew Blauvelt, MD
xviii
Mark W. Bonner, MD
Dermatology Resident, Department

of Dermatology, Boston University,
Boston, MA [9]
Assistant Professor, Department

Clinical Professor, Department of
Medicine, College of Medicine,
University of Toledo, Toledo, OH
[208]
of Dermatology, The University
of North Carolina at Chapel Hill,
Chapel Hill, NC [174, 208, 222]
Claude S. Burton, MD
Dermatology, Duke University
School of Medicine, Durham, NC
[174]
Jennifer A. Cafardi, MD

Dermatology, University of Alabama
at Birmingham, Birmingham, AL
[237]
Jeffrey P. Callen, MD
Professor of Medicine
(Dermatology), Department of
Medicine, University of Louisville,
Louisville, KY [233]
John D. Carter, MD

of Internal Medicine, Division of
Rheumatology, University of South
Florida College of Medicine, Tampa,
FL [20]
John A. Carucci, MD, PhD

Dermatology, Weill Cornell Medical
College, New York, NY [115]
Mari Paz Castanedo-Tardan, MD
Lorenzo Cerroni, MD

Veerendra Chadachan, MD
Vascular Medicine Program, Boston

University Medical Center, Boston
MA, USA Consultant, Department of
General Medicine Vascular Medicine
and Hypertension Section, Tan Tock
Seng Hospital, Singapore [173]
Vinod Chandran, MBBS, MD,

DM
Clinical Research Fellow,

Department of Medicine, Division
of Rheumatology, University of
Toronto, Toronto, ON, Canada [19]
Mary Wu Chang, MD
Associate Clinical Professor,

Department of Pediatrics, University
of Connecticut School of Medicine,
Farmington, CT [107]
Anne M. Chapas, MD
Clinical Assistant Professor,

Department of Dermatology, New
York University School of Medicine,
New York, NY [252]
Joel Charrow, MD

Feinberg School of Medicine,
Northwestern University, Chicago,
IL [141]
Mei Chen, PhD
Professor and Director of Research,

University of Southern California,
Los Angeles, CA [60]
Carol E. Cheng, MD
Massachusetts General Hospital,
Boston, MA [16]
Melissa I. Costner, MD
Anna L. Chien, MD
George Cotsarelis, MD
Assistant Professor, Division

of Dermatology, University of
Washington School of Medicine,
Seattle, WA [151]
Dermatology, Johns Hopkins School
of Medicine, Baltimore, MD [217]
Mary-Margaret Chren, MD
Francisco, CA [1]
David H. Chu, MD, PhD
Division of Dermatology and

Cutaneous Surgery, Scripps Clinic
Medical Group, La Jolla, CA [7]
Mon-Li Chu, PhD
Dermatology & Cutaneous Biology,
Thomas Jefferson University,
Philadelphia, PA [63]
Clinical Associate Professor,

University of Texas Southwestern
Medical Center, Dallas, TX [155, 156]
Pennsylvania School of Medicine,
Pierre A. Coulombe, PhD
E.V. McCollum Professor and Chair,

Department of Biochemistry and
Molecular Biology, Johns Hopkins
Bloomberg School of Public Health,
Baltimore, MD [46]
Edward W. Cowen, MD, MHSc
Head, Dermatology Consultation

Service, Dermatology Branch,
National Cancer Institute, National
Institutes of Health, Bethesda,
MD [28]
Joseph Craft, MD
Chief, Medical Virology Section,

Laboratory of Clinical Infectious
Diseases, National Institutes of
Health, Bethesda, MD [193]
Paul B. Beeson Professor of

Medicine and Professor of
Immunobiology, Department of
Internal Medicine, Yale School of
Medicine, Yale University, New
Haven, CT [154]
Myron S. Cohen, MD
Philip R. Cohen, MD
Donna A. Culton, MD, PhD
Chris D. Collins, MD, FAAD
Jennifer S. Daly, MD
Jeffrey I. Cohen, MD
Associate Vice Chancellor and

Professor of Medicine, Microbiology
and Immunology, Departments
of Medicine and Epidemiology,
University of North Carolina,
Clinical Associate Professor,
Department of Dermatology, MD
Anderson Cancer Center, University
of Texas, Houston, TX [32]
Professor of Clinical Dermatology
US Army & Air Force Dermatology
Brooke Army Medical Center,
Wilford Hall Medical Center San
Antonio, TX [22]
Nneka I. Comfere, MD

Medicine, Divisions of Dermatology
and Adult Infectious Disease, Los
Angeles Biomedical Research
Institute at Harbor-UCLA Medical
Center, Torrance, CA [175, 176]
Resident Physician, Department of
Dermatology, University of North
Carolina at Chapel Hill, Chapel Hill,
NC [56]
Professor, Department of Medicine,
University of Massachusetts
Medical School, Worcester, MA [209]
F. William Danby, MD, FRCPC,

FAAD

Dermatology, Mayo Clinic College
of Medicine, Rochester, MN [165]
Adjunct Assistant Professor,

Department of Surgery (Section of
Dermatology), Dartmouth Medical
School, Hanover, NH [78]
Rosamaria Corona, DSc, MD
Stamatina Danielides, MD
Attending Physician, Division

of Immunodermatology, Istituto
Dermopatico dellImmacolata,
Rome, Italy [2]
Contributors
Postdoctoral Research Fellow,

Section of Dermatology, DartmouthHitchcock Medical Center,
Dartmouth Medical School,
Lebanon, NH [13]
Andy J. Chien, MD, PhD
Sjgrens Syndrome Clinic

Gene Therapy and Therapeutics
Branch, National Institute of Dental
and Craniofacial Research
National Institutes of Health
Bethesda, MD [161]
xix
Mazen S. Daoud, MD
Christine A. DeWitt, MD
Daniel B. Eisen, MD
Thomas N. Darling, MD, PhD
Luis A. Diaz, MD
Myrna El Shareef, MD
Alan Dattner, MD
John J. DiGiovanna, MD
James T. Elder, MD, PhD
Private Practice, Dermatology and

Dermatopathology, Advanced
Dermatology Specialties, Fort
Myers, FL [26, 27]
Dermatology, Uniformed Services
University of the Health Sciences,
Bethesda, MD [140]
Contributors
Chief Scientific Officer, Founder and

CEO, www.holisticdermatology.com,
New York, NY [241]
Sofie De Schepper, MD, PhD

Aieska De Souza, MD, MS
Dermatopharmacology
Fellow, Department of Dermatology,
New York University Langone
Medical Center, New York, NY
[214, 220]
Steven M. Dean, DO, FACP,

RPVI
Associate Professor of Internal

Medicine, Department of
Cardiovascular Medicine, The
Ohio State University College of
Medicine, Columbus, OH [173]
Roy H. Decker, MD, PhD

Therapeutic Radiology, Yale School
of Medicine, Yale University, New
Haven, CT [240]
Nicole M. DeLauro, DPM
Associate Physician, Podiatric

Medicine and Surgery, Foot and
Ankle Center of New Jersey,
Plainfield, NJ [98]
Thomas M. DeLauro, DPM
Professor, Departments of Medicine

and Surgery, New York College of
Podiatric Medicine, New York, NY
[98]
Christopher P. Denton, PhD,

FRCP
Professor of Experimental
Rheumatology, Centre for
Rheumatology, University College
London, London, UK [157]
Theresa Schroeder Devere, MD

of Dermatology, Oregon Health &
Science University, Portland, OR [168]
xx

of Dermatology, Georgetown
University Hospital, Washington,
DC [153]
Professor and Chairman,
Staff Clinician, DNA Repair Section,
Dermatology Branch, Center for
Cancer Research, National Cancer
Institute, National Institutes of
Health, Bethesda, MD [49, 139]
Andrzej A. Dlugosz, MD
Poth Professor of Cutaneous

Oncology, Department of
Michigan Medical School, Ann
Arbor, MI [111]
Lisa M. Donofrio, MD

Department of Dermatology, Yale
School of Medicine, Yale University,
New Haven, CT [254]
Daven N. Doshi, MD
Resident, Department of
Dermatology, Albert Einstein
College of Medicine, Bronx, NY [16]
Karynne O. Duncan, MD
Private Practice, Saint Helena, CA

[113]
Jonathan A. Dyer, MD
Assistant Professor, Departments

of Dermatology and Child Health,
School of Medicine, University of
Missouri, Columbia, MO [137]
Robert T. Eberhardt, MD, FACC,

FSVM, RPVI
Medicine, Boston University School
of Medicine, Boston, MA [173]
Benjamin D. Ehst, MD, PhD

of Dermatology, Oregon Health &
Science University, Portland, OR [29]
Lawrence F. Eichenfield, MD
Professor, Departments of Pediatrics

and Medicine (Dermatology),
University of California, San Diego,
San Diego, CA [14]

California, Davis, Sacramento, CA
[187]
American University of Beirut
Medical Center, Beirut, Lebanon
[204]
Michigan Medical School, Ann
Arbor, MI [18]
Craig A. Elmets, MD
Professor and Chair, Department of

Dermatology, University of Alabama
at Birmingham, Birmingham, AL
[237]
Dirk M. Elston, MD
Director, Department of
Dermatology, Geisinger Medical
Center, Danville, PA [99, 231]
Joseph C. English, MD

Pittsburgh, Pittsburgh, PA [181]
Edward M. Esparza, MD, PhD
Resident, Division of Dermatology,

University of Washington, Seattle,
WA [221]
Janet A. Fairley, MD
Professor and Head, Department of

Dermatology, University of Iowa,
Iowa City, IA [138]
Vincent Falanga, MD, FACP
Professor, Departments of
Dermatology and Biochemistry,
Boston University School of
Medicine, Boston, MA [248]
Robert D. Fealey, MD
Consultant, Department of
Neurology, Mayo Clinic College of
Medicine, Rochester, MN [84]
Flavia Fedeles, MD, MS
Intern, Internal Medicine, Hospital

of St Raphael, New Haven, CT [23]
Laura Korb Ferris, MD, PhD

University of Pittsburgh, Pittsburgh,
PA [181]
Patricia M. Fishman, MD

Pathology, University of Illinois at
Chicago, Chicago, IL [70]
Professor and Vice Chair,

University of Colorado, Denver, CO
[219, 227]
Philip Fleckman, MD
Professor, Medicine (Dermatology),

WA [49]
Senior Lecturer (Associate

Professor) and Honorary Consultant
Dermatologist, St Johns Institute of
Dermatology, St Thomass Hospital
and Kings College London,
London, UK [4]
Camille Francs, MD
Dermatology-Allergology, Hpital
Tenon, Paris, France [159]
Jorge Frank, MD, PhD
Dermatology, Maastricht University
Medical Center (MUMC),
Maastricht, The Netherlands [132]
Ilona J. Frieden, MD
Associate Staff Physician, Department

of Dermatology, Cleveland Clinic,
Cleveland, OH [230]
Anthony A. Gaspari, MD
Shapiro Professor, Department

Maryland School of Medicine,
Baltimore, MD [226]
John K. Geisse, MD
Clinical Professor, Department

Francisco, CA [113]
Joel M. Gelfand, MD, MSCE
Assistant Professor of Dermatology

and Epidemiology, Departments
of Dermatology, Epidemiology
and Biostatistics, University of
Carlo Gelmetti, MD
Full Professor, Department of

Anesthesia, Intensive Care and
Dermatologic Sciences, Universit
degli Studi di Milano, Milano, Italy
[147, 148]
Roy G. Geronemus, MD
Director, Dermatology, Laser & Skin

Surgery Center of New York, New
York, NY [252]
Adam B. Glick, PhD
Associate Professor, Center

for Molecular Toxicology and
Carcinogenesis, Department of
Veterinary and Biomedical Sciences,
Hershey Medical Center, The
Pennsylvania State University,
University Park, PA [111]
Richard G. Glogau, MD

Francisco, CA [255]
Raphaela Goldbach-Mansky,
MD, MHS
Acting Chief, National Institute

of Arthritis and Musculoskeletal
and Skin Diseases Intramural
Research Program, Translational
Autoinflammatory Disease Section,
The National Institutes of Health,
Bethesda, MD [134]
Leonard H. Goldberg, MD,

FRCP
Medical Director, DermSurgery

Associates, PA, Houston, TX [246]
Emmy M. Graber, MD
Assistant Professor of Dermatology,

Department of Dermatology, Boston
University Medical Center, Boston,
MA [80]
Samer H. Ghosn, MD
Robin A.C. Graham-Brown,

BSc, MB, FRCP, FRCPCH
Professor, Departments of Pediatrics

and Medicine (Dermatology),
California, San Diego, San Diego,
CA [195]
Lawrence E. Gibson, MD
Jane Margaret Grant-Kels, MD
Ramsay L. Fuleihan, MD

of Pediatrics, Feinberg School of
Chicago, IL [143]
Chair Emerita and Professor of

Dermatology, Department of
Dermatology, Boston University
School of Medicine, Boston, MA
[9, 109]
Abhimanyu Garg, MD
Dafna D. Gladman, MD, FRCPC
Dermatology and Pediatrics,
School of Medicine, University
of California, San Francisco, San
Francisco, CA [126]
Sheila Fallon Friedlander, MD
Professor, Internal Medicine,

Medical Center, Dallas, TX [71]
Amit Garg, MD

of Dermatology, Boston University
[5, 188, 189]

Lebanon [201, 203, 206]
Dermatology, Mayo Clinic College
of Medicine, Rochester, MN [165]
Barbara A. Gilchrest, MD

Division of Rheumatology,
University of Toronto, Toronto, ON,
Canada [19]
Gerald J. Gleich, MD
Professor of Dermatology
and Medicine, Department of
University of Utah, Salt Lake City,
UT [31]
Contributors
Carsten Flohr, BM, BCh (Hons),

MA, Mphil, MRCPCH, MSc, PhD
Christopher C. Gasbarre,
DO, FAAD
Consultant Dermatologist,
University Hospitals of Leicester,
Leicester, UK [150]
Professor and Chair, Department
of Dermatology, University
of Connecticut Health Center,
Farmington, CT [23]
Justin J. Green, MD
Robert Wood Johnson Medical
School, University of Medicine
and Dentistry of New Jersey, Wood
Johnson Medical School, Camden,
NJ [199]
Roy C. Grekin, MD
California, San Francisco School of
Medicine, San Francisco, CA [121]
James M. Grichnik, MD, PhD

Dermatology, Miller School of
Medicine, Miami, FL [122, 123]
xxi
Douglas Grossman, MD, PhD

Dermatology, University of Utah
Health Sciences Center, Salt Lake
City, UT [114]
Johann E. Gudjonsson,
MD, PhD

Bridget C. Hackett, MB BCh,

BAO, MRCPI
Contributors
Department of Dermatology, Mater

Misericordiae University Hospital,
Dublin, Ireland [33]
Russell P. Hall III, MD
J Lamar Callaway Professor and

Chair, Department of Dermatology,
Duke University Medical Center,
Durham, NC [58, 61, 225]
Analisa V. Halpern, MD
Chung-Hong Hu, MD
Warren R. Heymann, MD
Linden Hu, MD
Professor, Hautzentrum Prof.

Hengge, Desseldorf, NRW,
Germany [65]
Professor of Medicine and

Pediatrics, Head, Division of
Dermatology, Robert Wood Johnson
Medical School at Camden,
University of Medicine & Dentistry
of New Jersey, Camden, NJ [199]
Whitney A. High, MD, JD, MEng

Colorado Denver Health Sciences
Center, Denver, CO [219, 227]
Chad Hivnor, MD
Associate Program Director, San

Antonio Uniformed Services
Health Education Consortium, San
Antonio, TX [22]

Medicine, Division of Dermatology,
Cooper University Hospital, Rowan
University, Camden, NJ [199]
Jonathan Hofmekler, BSc
C. William Hanke, MD, MPH, FACP
Ulrich Hohenleutner, MD
Visiting Professor of Dermatology,

University of Iowa Carver College
of Medicine, Iowa City, IA [253]
Christopher B. Hansen, MD

School of Medicine, Salt Lake City,
UT [156]
Philip N. Hawkins, PhD, FRCP,

FRCPath, FMedSci
Professor of Medicine, Centre for

Amyloidosis and Acute Phase
Proteins, University College London
Medical School, London, UK [133]
Roderick J. Hay, DM, FRCP,

FRCPath, FMedSci
Chairman, International Foundation

for Dermatology, London, UK
[3, 190]
Adelaide A. Hebert, MD
Medical School at Houston,
Houston, TX [84]
Stephen E. Helms, MD

of Medicine, Northeastern Ohio
Universities College of Medicine,
Rootstown, OH [68]
xxii
Ulrich R. Hengge, MD, MBA
Associate Researcher, Department

Professor, Klinik und Poliklinik fr
Dermatologie, Universittsklinikum
Regensburg, Regensburg, Germany
[239]
Steven M. Holland, MD
Chief, Laboratory of Clinical

Infectious Diseases, National
Institute of Allergy and Infectious
Diseases, National Institutes of
Golara Honari, MD
Attending Physician, Dermatology

and Plastic Surgery Institute,
Cleveland Clinic, Cleveland, OH,
[211]
Herbert Hnigsmann, MD
Professor of Dermatology,
Emeritus Chairman, Department of
Dermatology, Medical University
of Vienna, Vienna, Austria [32, 35,
238]
Thomas J. Hornyak, MD, PhD
Investigator, Dermatology Branch,

National Cancer Institute, National
Institutes of Health, Bethesda, MD
[73]
Alain Hovnanian, MD, PhD

Departments of Genetics and
Dermatology, University Ren
Descartes, Paris, France [51]
University of Wisconsin
Madison, WI [25]
Medicine, School of Medicine, Tufts
University, Boston, MA [187]
Sam T. Hwang, MD, PhD
Chair and Professor, Department

of Dermatology, Medical College of
Wisconsin, Milwaukee, WI [12]
Sherrif F. Ibrahim, MD, PhD
Procedural Dermatology Fellow,

University of California, San
Francisco, San Francisco, CA [121]
Gabor Illei, MD, PhD, MHS
Head, Sjgrens Syndrome

Clinic, Molecular Physiology and
Therapeutics Branch, National
Institute of Dental and Craniofacial
Research, National Institutes of
Alan D. Irvine, MD, FRCP, FRCPI
Paediatric Dermatology, Our Ladys
Childrens Hospital, Dublin, Ireland
[52]
Rim S. Ishak, MD
Medical Center, Beirut, Lebanon [203]
Peter H. Itin, MD
University of Basel, Basel,
Switzerland [131]
Satori Iwamoto, MD, PhD

of Dermatology and Skin Surgery,
Boston University School of
Medicine, Boston, MA [248]
Reza Jacob, MD
School of Medicine, Boston, MA [232]
Heidi T. Jacobe, MD, MSCS

Dallas, TX [64]
William D. James, MD
Paul R. Gross Professor, Department

University of Pennsylvania,
Melinda Jen, MD
Pediatric Dermatology Fellow,

Division of Pediatric and Adolescent
Dermatology, Rady Childrens
Hospital, University of California,
San Diego, San Diego, CA [130]
Jens-Michael Jensen, MD
Venereology and Allergy, University
of Kiel, Kiel, Germany [47]
Timothy M. Johnson, MD
Graham A. Johnston, MBChB,

FRCP
Consultant, Department of
Dermatology, Leicester Royal
Infirmary, Leicester, Leicestershire,
UK [150]
Marc A. Judson, MD
Professor of Medicine, Division

of Pulmonary and Critical Care
Medicine, Department of Medicine,
Medical University of South
Carolina, Charleston, SC [152]
Andrea A. Kalus, MD

Washington School of Medicine,
Seattle, WA [151]
Insoo Kang, MD
Associate Professor of Medicine,

Department of Internal Medicine,
Yale School of Medicine, Yale
University, New Haven, CT [154]
Sewon Kang, MD
Noxell Professor and Chairman,

Department of Dermatology, Johns
Hopkins University School of
Allen P. Kaplan, MD

Medicine, Medical University of
South Carolina, Charleston, SC [38]
Julie K. Karen, MD

York University Langone School of
Medicine, New York, NY [108]
STD Control Officer and Senior

Physician, Health and Human
Services Agency, County of San
Diego, San Diego, CA [200, 222]
Stephen I. Katz, MD, PhD
Fellow, American Academy of

Dermatology, Schaumburg, IL; Past
President, Society of Investigative
Dermatology, Cleveland, OH;
Director, National Institute of
Arthritis and Musculoskeletal and
Skin Diseases, National Institutes of
Masaoki Kawasumi, MD, PhD

Washington, Seattle, WA [112]
Dean L. Kellogg, Jr., MD, PhD

University of Texas Health Science
Center, San Antonio, TX [93]
Francisco A. Kerdel, MD
Robert Knobler, MD

Vienna, Vienna, Austria [238]
Sandra R. Knowles, BScPhm
Lecturer, Faculty of Pharmacy,

Canada [41]
Christine J. Ko, MD

of Dermatology, Yale School of
Medicine, Yale University, New
Haven, CT [66]
Manuel Koch, PhD
Associate Professor, Institute for

Oral and Musculoskeletal Biology,
Medical Faculty, Center for Dental
Medicine, University of Cologne,
Cologne, Germany [63]
Irene E. Kochevar, PhD
Dermatology, Harvard Medical
Director, Dermatology Inpatient

Unit, Department of Dermatology,
University of Miami Hospital,
Miami, FL [216]
Nellie Konnikov, MD
Helmut Kerl, MD
Sandra A. Kopp, MD
Jay S. Keystone, MD,

MSc(CTM), FRCPC
Chairman Emeritus, Department of

Canada [207]
Abdul-Ghani Kibbi, MD,

FAAD, FACP

Dermatology, Faculty of Medicine,
American University of Beirut,
Beirut, Lebanon [6, 204]
Alexa B. Kimball, MD, MPH
of Dermatology, Robert Wood
Johnson Medical School at Camden,
University of Medicine & Dentistry
of New Jersey, Camden, NJ [199]
Chief, DNA Repair Section,
Dermatology Branch, National
Cancer Institute, Bethesda, MD
[110, 139]
T. Krieg, MD
University of Cologne, Cologne,
Germany [63, 157]
Jean Krutmann, MD

Univ.- Professor Dr. med., Institut

fr Umweltmedizinische Forschung
(IUF), Dsseldorf, NRW, Germany
[90]
Reinhard Kirnbauer, MD
Roopal V. Kundu, MD

of Dermatology, Division of
Immunology, Allergy and Infectious
Diseases (DIAID), Medical University
of Vienna, Vienna, Austria [196]
John H. Klippel, MD
President and Chief Executive

Officer, Arthritis Foundation,
Atlanta, GA [170]
Contributors

School, Boston, MA [105, 178, 179,
198]
Kenneth A. Katz, MD, MSc,

MSCE

Dermatology, Feinberg School of
Chicago, IL [189]
Thomas S. Kupper, MD, FAAD

Thomas B. Fitzpatrick Professor,
Harvard Medical School, Boston,
MA [11]
xxiii
Razelle Kurzrock, MD, FACP
Chair and Professor, Investigational

Cancer Therapeutics, MD Anderson
Cancer Center, University of Texas,
Houston, TX [32]
Helen J. Lachmann, MD, FRCP
Senior Lecturer/Honorary
Consultant, National Amyloidosis
Centre, University College London
Medical School, London, UK [133]
Jeffrey N. Lackey, MD
Contributors
Staff Dermatologist, Kimbrough

Ambulatory Care Center, Fort
George G. Meade, MD [213]
Jrgen Lademann,
Prof. Dr. rer. nat. Dr.-Ing. habil.
Department of Dermatology, Center

of Experimental and Applied
Cutaneous Physiology (CCP),
Charit - Universittsmedizin
Berlin, Berlin, Germany [215]
Jeffrey R. LaDuca, MD, PhD

Reflections Dermatology,
Skaneateles, NY [226]
Jo Lambert, MD, PhD
Michael Landthaler, MD
University of Regensburg,
Regensburg, Germany [239]
Sinad M. Langan, MRCP,

MSc, PhD
Visiting Scholar, Department

Pennsylvania, Philadelphia, PA [4]
Hilde Lapeere, MD, PhD
University Hospital Ghent, Ghent,
Belgium [75]
Anne Laumann, MBChB,

MRCP(UK), FAAD
Associate Professor of Dermatology,

Department of Dermatology, Feinberg
School of Medicine, Northwestern
University, Chicago, IL [101]
Stephan Lautenschlager, MD
Associate Professor, Outpatient

Clinic of Dermatology &
Venereology, City Hospital Triemli,
Zrich, Switzerland [202]
Leslie P. Lawley, MD
xxiv

and Pediatrics, Department of
Chyi-Chia Richard Lee, MD, PhD

Staff Clinician, Laboratory of
Pathology, National Cancer
Institute, National Institutes of
Delphine J. Lee, MD, PhD,

FAAD
Dirks/Dougherty Laboratory
for Cancer Research, Director,
Department of Translational
Immunology, John Wayne Cancer
Institute, Santa Monica, CA [186]
Ken K. Lee, MD

Dermatology, Director of
Dermatologic Surgery, Oregon
Health and Science University,
Portland, OR [118]
Lela A. Lee, MD
Dermatology and Medicine, School
Denver, Denver, CO [37]
David J. Leffell, MD
David Paige Smith Professor

of Dermatology and Surgery,
Chief, Section of Dermatologic
Surgery and Cutaneous Oncology
Department of Dermatology, Yale
New Haven, CT [113, 114, 115]
Kristin M. Leiferman, MD
Dermatology, University of Utah,
Salt Lake City, UT [31, 36]
Yolanda M. Lenzy, MD, MPH

Clinical Dermatologist, Family
Dermatology of Massachusetts,
Brookline, MA [9]
Aimee L. Leonard, MD
Private Practice, New England

Dermatology & Laser Center,
Springfield, MA [253]
Donald Y.M. Leung, MD, PhD

Colorado Denver, Denver, CO [14]
Nikki A. Levin, MD, PhD

Medicine, Division of Dermatology,
Ross M. Levy, MD
Attending Physician, Division of

Dermatology, North Shore University
Health System, Skokie, IL [127]
Bernadette Liegl-Atzwanger,
MD
Institute of Pathology, Medical

University Graz, Graz, Austria [125]
Henry W. Lim, MD
Chairman and C.S. Livingood

Chair, Department of Dermatology,
Henry Ford Hospital, Detroit, MI
[92, 223]
Dan Lipsker, MD, PhD
Dermatology, Universit de
Strasbourg, Facult de Mdecine,
Strasbourg, France [171]
Adam D. Lipworth, MD
Instructor, Department of
School, Harvard University, Boston,
MA [178, 179]
Robert Listernick, MD

Feinberg School of Medicine,
Northwestern University, Chicago,
IL [141]
Rosemarie Liu, MD
Private Practice Skin, Cancer Surgery

Center Fairfax, VA [25]
Zhi Liu, PhD
Dermatology, University of North
Carolina School of Medicine, Chapel
Hill, NC [56]
Robert Loewe, MD

Anke S. Lonsdorf, MD
University Hospital of Heidelberg,
Heidelberg, Germany [12]
Mayra E. Lorenzo, MD, PhD

Instructor, Department of
Thomas A. Luger, MD

University of Mnster, Mnster,
Germany [102]
Calum C. Lyon, MA, FRCP
Department of Dermatology, York

Hospital, York, North Yorkshire, UK
[96, 97]
Catherine Maari, MD
Susannah E. McClain, MD
Daniel Mimouni, MD
Vandana Madkan, MD
John A. McGrath, MD, FRCP
Julia S. Minocha, MD
Meera Mahalingam, MD, PhD,

FRCPath
W. H. Irwin McLean, FRSE,

FMedSci
Paradi Mirmirani, MD

of dermatology, University of
Montreal, Montreal, QC, Canada
[67]
Dermatologist, Center for Clinical
Studies, Dermatological Association
of Texas, Houston, TX [191]
Joelle M. Malek, MD
Chief Resident, Department of

Lebanon [206]
Richard M. Marchell, MD

South Carolina, Charleston, SC [152]
Lynette J. Margesson, MD,

FRCPC
Assistant Professor of Obstetrics

and Gynecology and Medicine
(Dermatology), Section of
Dermatology, Department of
Obstetrics and Gynecology,
Hanover, NH [78]
M. Peter Marinkovich, MD

Dermatology, Stanford University
School of Medicine, Stanford, CA [62]
Adriana R. Marques, MD
National Institute of Allergy and

Infectious Diseases, National
Institutes of Health, Bethesda,
MD [193]
Nadine Marrouche, MD
Medical Center, Beirut, Lebanon
[201]
Erin F. Mathes, MD
University of California, San
Francisco, San Francisco, CA [126]
Theodora M. Mauro, MD
Service Chief, Dermatology, San

Francisco VA Medical Center, San
Francisco, CA [83]
Professor, St Johns Institute of

Dermatology, Guys Campus, Kings
College London, London, UK [8]
Dermatology and Genetic Medicine

University of Dundee, Dundee, UK [8]
Darius R. Mehregan, MD
Associate Professor and Hermann

Pinkus Chair, Department of
Dermatology, Wayne State
University, Detroit, MI [34]
David A. Mehregan, MD

Wayne State University, Detroit,
MI [34]
Atul B. Mehta, MD, FRCP,

FRCPath
Haematology, Royal Free Hospital,
University College London School
of Medicine, London, UK [136]
Natalia Mendoza, MD, MS

of Research and Dermatology,
Universidad El Bosque, Bogot,
Colombia [191]
Peter A. Merkel, MD, MPH
Senior Lecturer, Department of

Dermatology, Beilinson Campus,
Rabin Medical Center, Petah-Tikva,
Israel [55]
Clinical Research Fellow, Department
of Dermatology, Feinberg School of
Chicago, IL [69]
Department of Dermatology, The
Permanente Medical Group, Vallejo,
CA [87]
Robert L. Modlin, MD
Klein Professor of Dermatology,

and Professor of Microbiology,
Immunology and Molecular
Genetics, Department of Medicine,
David Geffen School of Medicine,
University of California, Los
Angeles, Los Angeles, CA [10, 186]
P. Moinzadeh, MD
University of Cologne, Cologne,
Germany [157]
Paul A. Monach, MD, PhD

Medicine, Section of Rheumatology,
Vasculitis Center, Boston University
Megan M. Moore, MD

Permanente Medical Group, Walnut
Creek, CA [220]
Professor of Medicine, Section

of Rheumatology, Clinical
Epidemiology Unit, Boston
Boston, MA [164]
Rebecca J. Morris, PhD
Martin C. Mihm, MD, FACP
L. Katie Morrison, MD
Director, Melanoma Program

in Dermatology, Department
of Dermatology, Brigham and
Womens Hospital, Boston, MA
[6, 124]
Lloyd S. Miller, MD, PhD

of Dermatology, David Geffen
School of Medicine, University
of California, Los Angeles, Los
Angeles, CA [10]
Stanley J. Miller, MD
Associate Professor, Departments of

Dermatology and OtolaryngologyHead and Neck Surgery, Johns
Hopkins Hospital, Baltimore, MD [46]
Contributors
Professor of Dermatology and

Pathology and Laboratory Medicine,
Dermatopathology Section,
Boston, MA [187]
Maryland Medical System,
Baltimore, MD [226]
Professor, Laboratory of Stem Cells

and Cancer, The Hormel Institute,
University of Minnesota, Austin,
MN [45]
University of Texas Health Sciences
Center, Houston, TX [191]
Nico Mousdicas, MBChB, MD

Dermatology, Indiana University,
Indianapolis, IN [177]
Ulrich Mrowietz, MD
Associate Professor, Psoriasis

Center, Department of Dermatology,
Campus Kiel, University Medical
Center Schleswig-Holstein, Kiel,
Germany [21]
xxv
Colin S. Munro, MD, FRCP (Glasg)
Katia Ongenae, MD, PhD
George F. Murphy, MD
Grainne M. ORegan, MRCPI
Professor, Alan Lyell Centre for

Dermatology, Southern General
Hospital, Glasgow, UK [50]
Professor of Pathology, Harvard

Medical School Director, Program in
Dermatopathology, Brigham
and Womens Hospital, Boston
MA [6]
Haley Naik, MD
Contributors
Massachusetts General Hospital,
Boston, MA [105]
Amanda M. Nelson, PhD
College of Medicine, The
Pennsylvania State University,
Hershey, PA [79]
Isaac M. Neuhaus, MD

Francisco, CA [121]

of Medicine and Dermatology,
WA [112, 120]
Gerhard J. Nohynek,
PhD, DABT
Scientific Director, Worldwide Safety

Department, LOreal R&D, Asnires,
France [215]
David A. Norris, MD

Department of Dermatology, School
Denver, Denver, CO [74]
Scott A. Norton, MD,

MPH, MSc
Professor of Dermatology, Division

of Dermatology, Department of
Medicine, Georgetown University
Hospital, Washington, DC [183,
213]
Lillian Odo, MD

Santo Amaro, So Paulo, SP, Brazil
[100]
John E. Olerud, MD
Professor, Medicine, Division

Washington, Seattle, WA [151]
xxvi
Dermatology, University Hospital
Ghent, Ghent, Belgium [75]
Department of Paediatric
Dermatology, Our Ladys Childrens
Hospital, Dublin, Ireland [52]
Anthony E. Oro, MD, PhD
Andrea L. Pearson, MD

Worcester, MA [192]
Michelle T. Pelle, MD
Attending Physician, Department of

Medicine, Scripps Mercy Hospital,
San Diego, CA [81]
Associate Professor, Program

in Epithelial Biology, School of
Medicine, Stanford University,
Stanford, CA [116]
Brent E. Pennington, MD
Catherine H. Orteu, MBBS, BSc,

MD, FRCP
Department of Dermatology, Mayo

Clinic, Rochester, MN [36]
Department of Dermatology, Royal
Free Hospital, London, UK [136]
Nina Otberg, MD
Hair Clinic, Skin and Laser Center

Berlin, Potsdam, Germany [88]
Michael N. Oxman, MD
Professor of Medicine and

Pathology, University Of California,
San Diego, San Diego, CA [194]
Amy S. Paller, MD
Walter J. Hamlin Professor and

Chair of Dermatology, Professor
of Pediatrics, Feinberg School of
Chicago, IL [143]
Hee-Young Park, PhD

of Dermatology, Boston University
Sareeta R.S. Parker, MD

Department of Dermatology, School
of Medicine, Emory University,
Atlanta, GA [82]
Nashville Skin & Cancer, Nashville,

TN [242]
Margot S. Peters, MD
Julia S. Pettersen, MD
Yale School of Medicine
New Haven, CT [115]
Peter Petzelbauer, MD
Professor of Microvascular Research,

Medical University of Vienna,
Vienna, Austria [162]
Tania J. Phillips, MD, FRCP,

FRCPC
Boston University School of Medicine,
Boston, MA [100]
Grald E. Pirard, MD, PhD
Chief, Dermatopathology Service,

University Hospital of Lige, Lige,
Belgium [94]
Claudine Pirard-Franchimont,
MD, PhD
Dermatopathology, University
Hospital of Lige, Lige, Belgium [94]
Anisha B. Patel, MD
Tejesh S. Patel, MBBS (Lon),

BSc (Hons)
Caroline Piggott, MD
Resident, Department of Dermatology,

Oregon Health & Science University,
Portland, OR [168]
Dermatology Resident,
Tennessee Health Science Center,
Memphis, TN [103]
Aimee S. Payne, MD, PhD

Pennsylvania, Philadelphia, PA
[53, 54]
Chair, Division of Dermatology,

John H. Stroger Jr. Hospital of Cook
County, Chicago, IL [144, 160]
CA [195]
Bianca Maria Piraccini, MD, PhD
Researcher, Department of
Dermatology, University of Bologna,
Bologna, Italy [89]
Dermatology and Biochemistry and
Molecular Biology, Mayo Clinic
College of Medicine, Mayo Medical
School, Rochester, MN [26, 27, 158]
Jordan S. Pober, MD, PhD
Professor and Vice Chair,

Department of Immunobiology, Yale
New Haven, CT [162]
Brian P. Pollack, MD, PhD
Miriam Keltz Pomeranz, MD

of Dermatology, Duke University,
Durham, NC [58]
Thomas H. Rea, MD
Emeritus Professor, Department

of Dermatology, Keck School of
Medicine, University of Southern
California, Los Angeles, CA [186]
Kavitha K. Reddy, MD
Thomas E. Redelmeier, MD
Dermatology Department
Charite Hospital/Humboldt
University, Berlin, Berlin, Germany
[215]
Jean-Claude Roujeau, MD
Hpital Henri Mondor
Universit Paris XII Crteil
Paris, France [39, 40]
Anne H. Rowley, MD
Pediatrics, and Microbiology
Immunology, Feinberg School of
Chicago, IL [167]
Thomas M. Rnger, MD, PhD

Pathology, Department of
[110, 139]
William A. Rutala, BS, MS, PhD,

MPH

York University School of Medicine,
New York, NY [108]
Arthur R. Rhodes, MD, MPH
Frank C. Powell, FRCPI, FAAD
Stephen K. Richardson, MD
Thomas Ruzicka, Prof. Dr. med.

Dr. h.c.
Evan Rieder, MD
Arturo P. Saavedra, MD, PhD,

MBA

Dermatology, University College
Dublin, Dublin, Ireland [33]
Julie Powell, MD, FRCPC
Associate Clinical Professor, and

Director of Pediatric Dermatology,
Department of Pediatrics, Division
of Dermatology, CHU Sainte-Justine
University of Montreal, Montreal,
QC, Canada [67]
Jennifer G. Powers, MD
Julie S. Prendiville, MB, FRCPC

Pediatrics, University of British
Columbia, Vancouver, British
Columbia, Canada [44]
Howard B. Pride, MD
Associate, Departments of
Dermatology and Pediatrics,
Geisinger Medical Center, Danville,
PA [106]
Ehrhardt Proksch, MD, PhD
Dermatology, University of Kiel,
Kiel, Germany [47]
Pascale Quatresooz, MD, PhD
Lecturer Senior Registrar,

Department of Dermatopathology,
University Hospital of Lige, Lige,
Belgium [94]
Dermatology, Rush Medical College,
Rush University, Chicago, IL [122]
Florida State College of Medicine,
Tallahassee, FL [234]
Department of Psychiatry, New York
University School of Medicine, New
York, NY [104]
Maureen Rogers, MBBS, FACD

Head and Professor, Department

of Dermatolgy and Allergology,
Ludwig Maximilian University,
Munich, Germany [24]

School, Boston, MA [178, 179, 198]
Emeritus Consultant, Department

of Dermatology, Royal Alexandra
Hospital for Children, Sydney,
Australia [87]
Joni G. Sago, MD
Thomas E. Rohrer, MD
Director, Lipid Clinic, Heart

Institute (InCor), University of So
Paulo Medical School Hospital, So
Paulo, Brazil [135]
Clinical Associate Professor of

Dermatology, Brown University,
Alpert School of Medicine,
Providence, RI [243]
Arash Ronaghy, MD, PhD
Dermatology Associates of
Kingsport, Kingsport, TN [225]
Raul D. Santos, MD, PhD
Jean-Hilaire Saurat, MD
Research Associate, Department

of Dermatology, Duke University,
Durham, NC [61]
Professor, Swiss Center for

Human Applied Toxicology,
University Medical Center, Geneva,
Switzerland [228]
Ted Rosen, MD
Stephanie Saxton-Daniels, MD
Marti J. Rothe, MD
Ernst J. Schaefer, MD
Dermatology, Baylor College of
Medicine, Houston, TX [205]
Associate Professor of Dermatology,
University of Connecticut Health
Center, Farmington, CT [23]
Contributors

and Pathology/Laboratory
Medicine, Emory University,
Winship Cancer Institute and the
Atlanta VA Medical Center, Atlanta,
GA [237]
Caroline L. Rao, MD

Medical Center, Dallas, TX [64]
Senior Scientist and Director

Lipid Metabolism Laboratory
Jean Mayer USDA HNRCA at Tufts
University, Boston, MA [135]
xxvii
Hans Schaefer, PhD
Professor, Retired [215]
Mark Jordan Scharf, MD
Clinical Professor of Medicine,

of Massachusetts Medical School,
Worcester, MA [209]
Stefan M. Schieke, MD
Robert L. Sheridan, MD

Surgery, Harvard Medical School,
Boston, MA [95]
Jeff K. Shornick, MD, MHA

Private Practice [59]
Robert Sidbury, MD, MPH

Boston, MA [188]

Pediatrics, Division of Dermatology,
Seattle Childrens Hospital, Seattle,
WA [221]
Bethanee J. Schlosser, MD, PhD
Nicholas R. Snavely, MD
Contributors

Dermatology, Feinberg School of
Chicago, IL [69]
Kenneth E. Schmader, MD
Professor and Chief, Department

of Medicine-Geriatrics, Division of
Geriatrics, Duke University Medical
School, Durham, NC [194]
Holger Schmid, MD, MSc PD
Department of Internal Medicine,

Ludwig Maximilian University,
Munich, Germany [169]
Steven K. Schmitt, MD
Head, Section of Bone and

Joint Infections, Department of
Infectious Disease, Cleveland Clinic,
Cleveland, OH [230]
Oregon Health & Science University
Portland, OR [118]
Arthur J. Sober, MD
School, Boston, MA [122, 124]
Richard D. Sontheimer, MD
School of Medicine, Salt Lake City,
UT [155, 156]
Apra Sood, MD
Associate Staff, Department of

Dermatology, Cleveland Clinic,
Cleveland, OH [48, 211, 212]
Nicholas A. Soter, MD
Professor and Head, Department of

Dermatology, New Jersey Medical
School, Newark, NJ [210]
Professor of Dermatology, Ronald

O. Perelman Department of
Dermatology, New York University
School of Medicine, New York, NY
[163]
Aisha Sethi, MD
Richard A. Spritz, MD
Robert A. Schwartz, MD, MPH

Dermatology, University of Chicago,
Chicago, IL [184]
Jerry Shapiro, MD, FRCPC,

FAAD

Dermatology and Skin Science,
University of British Columbia,
Vancouver, Canada [88]
Neil H. Shear, MD, FRCPC
Dermatology & Pharmacology,
Canada [41]
Jessica M. Sheehan, MD
Mohs Surgeon and Dermatologist,

Northshore Center for Medical
Aesthetics, Northbrook, IL [243]
Director, Human Medical Genetics

Program, School of Medicine,
University of Colorado Denver,
Aurora, CO [74]
Divya Srivastava, MD

Dallas, TX [119]
John R. Stanley, MD
William G. Stebbins, MD
Department of Dermatology, Laser

and Skin Surgery Center of Indiana,
Carmel, IN [253]
Christopher J. Steen, MD
xxviii
Private Practice, Portland, ME [210]
Martin Steinhoff, MD, PhD

Full Professor, Department of
Francisco, CA [102]
Wolfram Sterry, Prof. Dr.

Venereology and Allergology,
Charit Universittsmedizin Berlin,
Berlin, Germany [145]
Georg Stingl, MD
Dermatology, Division of
Immunology, Allergy and Infectious
Diseases, Medical University of
Stephen P. Stone, MD
Professor, Division of Dermatology,

Southern Illinois University School
of Medicine, Springfield, IL [153]
Bruce E. Strober, MD, PhD
Assistant Professor, Ronald

O. Perelman Department of
Dermatology, New York University
School of Medicine, New York, NY
[214, 220]
Kathryn N. Suh, MD
Assistant Professor, Medicine and

Pediatrics, University of Ottawa,
Ottawa, ON, Canada [207]
Tung-Tien Sun, PhD
Professor, Departments of Cell

Biology, Pharmacology and Urology,
School of Medicine, New York
University, New York, NY [46]
Neil A. Swanson, MD

Dermatology, Oregon Health and
Science University Portland, OR
[118]
Susan M. Sweeney, MD

Worcester, MA [192]
Virginia P. Sybert, MD

of Medicine, Division of Medical
Genetics, University of Washington
School of Medicine, Seattle, WA
[142]
Rolf-Markus Szeimies, MD, PhD

and Allergology, Klinikum Vest
Academic Teaching Hospital,
Recklinghausen, Germany [238]
Moyses Szklo, MD, MPH, DrPH

Epidemiology and Medicine, Johns
Hopkins Schools of Public Health
and Medicine, Baltimore, MD [2]
Jean Y. Tang, MD, PhD
Assistant Professor, Dermatology,

Stanford University, Redwood City,
CA [116]
Elizabeth L. Tanzi, MD
Co-Director, Washington Institute

of Dermatologic Laser Surgery,
Washington, DC [251]
Rochester, Rochester, NY [104]
Charles R. Taylor, MD

James S. Taylor, MD, FAAD
Dermatology and Plastic Surgery
Institute, Cleveland Clinic,
Cleveland, OH [48, 211, 212]
R. Stan Taylor, MD
Southwestern, Dallas, TX [119]
Andrew R. Tegeder, MS

of Washington School of Medicine,
Seattle, WA [120]
Michael D. Tharp, MD
The Clark W. Finnerud, MD

of Dermatology, Rush University
Medical Center, Chicago, IL [149]
Diane M. Thiboutot, MD
Dermatology, College of Medicine,
The Pennsylvania State University,
Hershey, PA [79, 80]
Bruce H. Thiers, MD

Department of Dermatology and
Dermatologic Surgery, Medical
University of South Carolina,
Charleston, SC [152]
Valencia D. Thomas, MD

of Dermatology, Section of
Dermatologic Surgery & Cutaneous
Oncology, Yale University School of
Medicine, New Haven, CT [118]
Assistant Professor, Departments

of Pediatrics and Medicine
(Dermatology), University of
CA [195]
Kenneth J. Tomecki, MD
Lily Changchien Uihlein,

MD, JD
Jouni Uitto, MD, PhD
Vice Chairman, Department of

Dermatology, Cleveland Clinic,
Cleveland, OH [230]

of Dermatology and Cutaneous
Biology, Jefferson Medical College,
Antonella Tosti, MD
Mark A. Unger, MD, CCFP
Dermatology & Cutaneous
Surgery, Miller School of Medicine,
University of Miami, Miami, FL [89]
Franz Trautinger, MD
Professor and Head, Department

of Dermatology and Venereology,
Landesklinikum St. Poelten St.
Poelten, Austria [35]
Jeffrey B. Travers, MD, PhD
Pharmacology and Toxicology,
Departments of Dermatology,
Pharmacology and Toxicology,
Indiana University School of
Medicine, Indianapolis, IN [177]
Hensin Tsao, MD, PhD

Fragkiski Tsatsou, MD,

MSc, BSc
Dermatology Resident, Departments

of Dermatology, Venereology,
Allergology and Immunology,
Dessau Medical Center, Dessau,
Germany [85]
Private Practice, Toronto, ON,

Canada [256]
Robin H. Unger, MD

Dermatology, Mount Sinai School of
Walter P. Unger, MD

Dermatology, Mt. Sinai School of
Anders Vahlquist, MD, PhD
Professor, Department of Medical

Sciences, Uppsala University,
Uppsala, Sweden [228]
Isabel C. Valencia, MD
Dermatopathology, Dermpath
Diagnostics Bay Area, Tampa,
FL [216]
L. Valeyrie-Allanore, MD
Universit Paris XII, Cedex, France
[40]
Nanja van Geel, MD, PhD

Venereology, Department of
Vienna, Vienna, Austria [128, 197]
Mireille Van Gele, PhD
Margaret A. Tucker, MD
Maurice A.M. van Steensel,

MD, PhD
Director, Human Genetics Program,

Division of Cancer Epidemiology
and Genetics, National Cancer
Institute, Bethesda, MD [123]
Department of Dermatology, Ghent

University Hospital, Ghent, Belgium
[75]
Professor, Dermatology, Maastricht

University Medical Center,
Maastricht, The Netherlands [50]
Stephen Tyring, MD, PhD
Travis W. Vandergriff, MD
Selma Ugurel, MD
Evelien Verhaeghe, MD

Health Science Center, Houston, TX
[191]
Wrzburg, Wrzburg, Germany
[125]
Contributors
Francisco A. Tausk, MD
Wynnis Tom, MD
Chief Resident, Department of

Dallas, TX [91]
Department of Dermatology, Ghent
University Hospital, Ghent, Belgium
[75]
xxix
Miikka Vikkula, MD, PhD
Lucile E. White, MD
Sophie M. Worobec, MD, FAAD
John J. Voorhees, MD, FRCP
Hywel C. Williams, MSc,

PhD, FRCP
Mina Yaar, MD
Maitre de Recherces du F.N.R.S.

Human Molecular Genetics (GEHU)
Christian de Duve Institute,
Universit catholique de Louvain,
Brussels, Belgium [172]
Justin J. Vujevich, MD
Contributors
Director, Mohs Surgery, Vujevich

Dermatology Associates, PC,
Pittsburgh, PA [246]
Daniel Wallach, MD
Senior Lecturer, Department of

Dermatology, Hpital TarnierCochin, Paris, France [33]
David J. Weber, MD, MPH
Professor of Medicine, Pediatrics, and

Epidemiology, University of North
Carolina, Chapel Hill, NC [180]
Roger H. Weenig, MD, MPH

Adjunct Assistant Professor,
University of Minnesota,
Minneapolis, MN [158]
Arnold N. Weinberg, MD
Professor, Infectious Disease Unit,

Department of Medicine, Harvard
Medical School, Boston, MA
[178, 179]
Martin A. Weinstock, MD, PhD

Dermatology and Community
Health, Brown University,
Providence, RI [1]
Elliot T. Weiss, MD
Laser & Skin Surgery Center of New

York, New York and Southampton,
NY [252]
Margaret A. Weiss, MD
Johns Hopkins University School of
Robert A. Weiss, MD
Professor of Dermato-Epidemiology,
Centre of Evidence-Based
Nottingham, Nottingham, UK [4]
Ifor R. Williams, MD, PhD

of Pathology, School of Medicine,
Lynn D. Wilson, MD, MPH
Professor, Vice Chairman and

Clinical Director, Therapeutic
Radiology, Yale School of medicine,
Yale University, New Haven, CT [240]
Karen Wiss, MD
Professor, Department of Medicine

(Dermatology) and Pediatrics,
Klaus Wolff, MD, FRCP
Chairman Emeritus, Department of
Stephen E. Wolverton, MD
Theodore Arlook Professor of

Clinical Dermatology, Department
of Dermatology, Indiana University
School of Medicine, Indianapolis,
IN [236]
Sook-Bin Woo, DMD

of Oral Medicine, Infection and
Immunology, Harvard School of
Dental Medicine, Boston, MA [76]
Gary S. Wood, MD
Johnson Professor and Chairman,

University of Wisconsin School
of Medicine and Public Health,
Madison, WI [25, 146]

of Dermatology, Johns Hopkins
Baltimore, MD [249]
Robert A. Wood, MD
Victoria P. Werth, MD
David T. Woodley, MD
xxx
Pearland Dermatology and

DermSurgery Associates, The
Methodist Hospital, Houston, TX
[127]

Johns Hopkins University School
of Medicine, Baltimore, MD [229]
Dermatology, The Keck School of
Medicine, University of Southern
California, Los Angeles, CA [60]

of Dermatology, Chicago School
of Medicine, University of Illinois,
Chicago, IL [70]
[72, 109]
Albert C. Yan, MD

of Pediatrics and Dermatology,
Pennsylvania, Philadelphia, PA
[130]
Kim B. Yancey, MD

Dallas, TX [57]
Gil Yosipovitch, MD
Dermatology, Wake Forest
Winston Salem, NC [103]
Andrea L. Zaenglein, MD
Associate Professor, Departments of

Dermatology and Pediatrics, Penn
State Milton S. Hershey Medical
Center, Hershey, PA [80]
Mozheh Zamiri, BSc (Hons),

MBChB, MRCP, MD
Specialist Registrar, Alan Lyell

Centre for Dermatology, Southern
General Hospital, Glasgow, Scotland
[50]
Christos C. Zouboulis, MD, PhD
Professor and Director, Departments

of Dermatology, Venereology,
Allergology and Immunology,
Dessau Medical Center, Dessau,
Germany [85, 166]
Kathryn A. Zug, MD
Professor, Section of Dermatology,

Hanover, NH [13]
Melanie Kingsley, MD
Assistant Professor of Dermatology,

Director of Cosmetic Dermatology
and Laser Surgery, Department of
Dermatology, Indiana University
School of Medicine, Indianapolis,
IN [243]
PREFACE
New knowledge drives medical progress and improves

patient care. The rapid growth of this knowledge in
skin diseases and skin biology makes publication of
the eighth edition of Fitzpatricks Dermatology in General
Medicine (DIGM) particularly timely. Forty years
ago, the first edition of Fitz was a critical textbook
devoted to providing a comprehensive knowledge
of dermatology. The relevance of dermatology to
general medicine and the basic science foundations
of the specialty were defining elements of the new
text. This edition, more than ever, reinforces those
earlier goals and is designed to be easily accessible
to those interested in the clinical and basic science of
dermatology. This reference text also highlights the
relevance of dermatology to general internal medicine
and other disciplines of medicine and surgery. It is
written for experienced clinicians and skin biologists
worldwide as well as for those in training.
The online edition adds further textual and
illustrative detail to almost all chapters and provides
extensive and robust literature citations, many with
online links, which are especially useful for those who
seek an in-depth understanding of a particular topic.
The accompanying CD-ROM contains the figures from
the print edition in an easily downloaded format for
slide production.
Because of the explosion of new knowledge relevant
to dermatology and cutaneous biology, chapters have
been extensively revised and new chapters have been
added on global dermatologic health, ethnic, and racial

considerations for normal and diseased skin, and stem
cell science. Medical and surgical therapeutics sections
have been greatly expanded to reflect the increased
importance of procedural dermatology.
Twenty percent of the chapters have new authorship,
drawing from expertise around the world. These
authors provide new perspectives and guarantee that
the content of the book remains fresh and vital.
Schematic diagrams of clinical and basic science
mechanisms and clinical care algorithms have been
revised to allow rapid intuitive guidance while retaining
accuracy and critical detail. This edition is enhanced with
additional clinical figures and new tables that permit a
quick look at key points in each chapter. Finally, the
Parts of the book are designated with different colors,
thus allowing the reader to easily find sections of interest.
Validated, well-synthesized, and critically interpreted
information is essential to improve the care of patients,
to prevent skin disease, and to advance cutaneous
biology. The current editors of DIGM have striven to
fulfill these goals of the original text.
Lowell A. Goldsmith
Stephen I. Katz
Barbara A. Gilchrest
Amy S. Paller
David J. Leffell
Klaus Wolff
ACKNOWLEDGMENTS
We thank and salute the nearly 500 authors who

contributed to the creation of this new and vibrant
eighth edition of Fitzpatricks Dermatology in General
Medicine (DIGM). The eighth edition of this classic
text reflects the amazing growth in new knowledge
in basic and clinical sciences related to the skin and
to its relationship with other organ systems. The
authors have worked assiduously to integrate this
new information within the context of established
knowledge. The authors, all respected experts in
their disciplines, wrote some of the most extensively
referenced chapters available either in print or online.
We are deeply grateful to them and their staff for
their commitment to this text. Their expertise
has created chapters that continue to define the
comprehensiveness of this textbook.
We are deeply grateful to our families, who
appreciated the importance and immensity of our
task. They recognized and accepted that editing this
textbook demanded many hours of time and evenings
spent with a computer screen rather than with them. We
thank them for their support during this all-consuming
effort.
The editors were supported by talented and dedicated
staff, Renate Kosma, Jacy Bernal, Jaime Zagami, Nilda
Reyes, and Grace Camire, each of whom handled the
correspondence with over 50 authors. The debt that we

owe to these individuals cannot be calculated. Many
readers of previous editions and dermatology residents
from several training programs painstakingly reviewed
and critiqued the seventh edition and provided
extremely useful advice on improving the content and
the presentation for this new edition.
The staff at McGraw-Hill Medical made this text
their highest priority. They were led by our ever vigilant
and talented editor, Anne M. Sydor, and our project
manager for manuscript production and completion,
Sarah M. Granlund; and a most professional production
team led by Robert Pancotti and Sherri Souffrance in
New York and by Sandhya Joshi in India.
A major hallmark and the fresh look for this eighth
edition are the hundreds of new figures that required
meticulous attention by authors and a creative design and
art team at Dragonfly Media Group. For their talented
and effective partnership we are forever grateful.
Lowell A. Goldsmith
Stephen I. Katz
Barbara A. Gilchrest
Amy S. Paller
David J. Leffell
Klaus Wolff
Introduction
PA RT
General Considerations
Chapter 1 :: T
he Epidemiology and Burden
of Skin Disease

:: Martin A. Weinstock &
Mary-Margaret Chren
Scientists in health-related fields focus on phenomena
at different levels. For laboratory scientists, the focus
is at the molecular, cellular, or organ system level; for
clinical scientists, the focus is on the patient; and for
public health practitioners, the focus is on the population. Epidemiology is the basic science of public health.
Epidemiology has many subdivisions and offshoots.
Often the epidemiology of a disease in a clinical review
refers primarily to its frequency and distribution in the
population and estimates of its morbidity and mortality. These data are derived by descriptive epidemiology. Case-control, cohort, and cross-sectional studies
may seek to identify risk factors and causes of disease
and form the core of analytical epidemiology. Evaluations of public health interventions (experimental
epidemiology) constitute the third major branch of
classic epidemiology. The basic principles of epidemiology have found broad application in many areas,
including understanding the public health implications of naturally occurring and synthetic compounds
(molecular epidemiology), the complex interactions of
genetic and environmental factors in disease (genetic
epidemiology), the formulation of better diagnostic
and treatment strategies for patients based on available evidence (clinical epidemiology), and the structuring of health care delivery for better outcomes and
greater efficiency (health services research). The reader
is referred to other sources for a more detailed discussion of various topics in dermatoepidemiology.13
TYPES OF
EPIDEMIOLOGIC STUDIES
Three of the many types of epidemiologic studies are
mentioned here because of their prominence in epidemiologic research. The randomized, controlled trial is
a particularly rigorous type of study appropriate to the
evaluation of public health interventions. In general,
the intervention is performed on a random sample of
the study population, and the entire study population
is then observed for the occurrence of the outcome
in question. The random assignment of intervention
allows the more rigorous application of many statistical techniques and reduces the potential for bias. Elimination of biases permits these studies to evaluate the
efficacy and impact of an intervention more accurately
than trials that do not assign the intervention randomly. Standards for reporting have been published4
(http://www.consort-statement.org, accessed Jul 7,
2010) and adopted by leading dermatology journals to
improve assessment of their validity and their use in
subsequent systematic reviews5 (see Chapter 2).
When evaluating risk factors for disease, it is frequently impossible to assign the risk factor randomly.
Hence, inference is based on observational studies.
In classical cohort studies, a group with exposure to
the risk factor and a group without are chosen and
observed over time. Occurrences of the study outcome
Section 1
::
are counted and compared between groups. Although

more vulnerable to bias than randomized trials, cohort
studies, in which exposure to the risk factor is known
well before the study outcome is knowable, avoid
some potentially serious biases. In a cohort study,
the incidence of the study outcome can be measured
directly in each group, and the relative risk can be measured directly as the ratio of the incidence between the
two groups.
Cohort studies often are quite expensive to conduct
because they require following a large population over
time and may be impossible if the outcome being studied is uncommon. Hence, observational studies often
use the case-control approach, in which cases with
the outcome being studied and appropriate controls
are investigated to determine their past exposure to
the risk factor. Relative risks can be estimated by this
approach, although incidence of the disorder cannot.
Readers are referred to standard texts for more detail
regarding epidemiologic study designs.6 Case-control
and cohort study methods in dermatology also have
been reviewed.79
BIAS AND CONFOUNDING

The problem with inference from observational studies
is that one may be led to draw erroneous conclusions.
In particular, an association that is found between an
exposure and a disease may be an artifact due to one
or more of the many forms of bias or confounding.
Proper inference regarding cause and effect requires
understanding these possible artifacts and their potential impacts.10
Selection bias occurs when factors that lead to selection of the study population affect the likelihood of the
outcomes or exposures evaluated. For example, a casecontrol study of cutaneous lymphoma may recruit its
cases from sources that typically include a high proportion of referred patients. If controls are recruited from
a local clinic population, their socioeconomic status
and location of residence may be substantially different from those of the cases simply due to the method
of recruitment. Under these circumstances, an association of cutaneous lymphoma with occupation may
be noted. It then becomes important to note that the
observed association may be due not to a carcinogenic
chemical in the workplace but rather to the method
by which cases and controls were selected. Similarly,
if one were conducting a cohort study of the effect of
breast-feeding on the risk of atopic dermatitis, it would
be important to select breast-fed and bottle-fed infants
from similar environments.
Information bias occurs when the assessment of exposure or outcome may differ between the groups being
compared. People who were exposed to a publicized
environmental toxin may be more likely to seek care
for minor symptoms or signs (and hence be more
likely to be diagnosed and treated) than those who
were not so exposed, even if the exposure had no biologic effect. Similarly, people who are diagnosed with
a disease may be more likely to recall past exposures
than healthy controls.
Confounding occurs when an observed association (or

lack thereof) between exposure and disease is due to
the influence of a third factor on both the exposure and
the disease. For example, people who use sunscreens
may have more intense sun exposure than those who
do not, and intense sun exposure is one cause of melanoma. Hence, observational studies may mistakenly
conclude that sunscreen use is a cause of melanoma
when the observed association is due to sunscreen use
serving as an indicator of a lifestyle involving intense
sun exposure.
CAUSAL INFERENCE
Key issues in the public health arena often must rely
on observational data for inferring cause and effect; in
these situations, the validity and generalizability of the
individual studies and of the totality of the evidence
must be carefully examined. The following criteria
generally are applied for causal inference when an
association is found. Although they are described for
inferring causality between an exposure and a disease,
they are more generally applicable to epidemiologic
causal inference.
TIME SEQUENCE
The exposure must precede the disease. This concept is
simple and obvious in the abstract but sometimes difficult to establish in practice because the onset of disease
may precede the diagnosis of disease by years, and the
timing of exposure is often not well defined.
CONSISTENCY ON REPLICATION
Replication of the observed association is key and
provides the strongest evidence if the replications are
many and diverse and with consistent results. The
diversity of the replications refers to varied contexts as
well as to study designs with different potential weaknesses and strengths.
STRENGTH OF ASSOCIATION
True causal relationships may be strong (i.e., high
relative risk) or weak, but artifactual associations are
unlikely to have a high relative risk. If the association between factors x and y is due to the association
of both with confounding variable z, the magnitude
of the association between x and y always will be less
than the magnitude of the association of either with z.
GRADED ASSOCIATION
Also described as biologic gradient, this criterion refers
to an association of the degree of exposure with occurrence of disease, in addition to an overall association of
presence of exposure with disease. This dose-response
relation may take many forms, as degree of exposure
may, for example, refer to intensity, duration, frequency, or latency of exposure.
COHERENCE
INVESTIGATION OF
DISEASE OUTBREAKS
Although outbreaks of disease vary tremendously, use
of a standard framework for investigation is important to address the public health issues efficiently (see
Chapter 4). The Centers for Disease Control and Prevention has outlined this framework as a series of ten
steps, which are described in more detail at http://
www.cdc.gov.
1. Preparation. Before initiating fieldwork,
background information on the disease must be

gathered, and appropriate interinstitutional and
interpersonal contacts should be made.
2. Confirm the outbreak. Publicity, population
changes, or other circumstances may lead to
an inaccurate perception that more cases than
expected have occurred. Hence, local or regional
data should be sought to confirm the existence
of an increased frequency of disease.
3. Confirm the diagnosis. Symptoms and signs of
persons affected should be determined and
laboratory findings confirmed, perhaps with the
assistance of reference laboratories.
4. Establish a case definition, and find cases. Careful
epidemiologic investigation will involve precise
and simple case definitions that can be applied
in the field. Efforts to find and count additional
DESCRIPTIONS OF DISEASE
IN POPULATIONS: MEASURES
OF DISEASE BURDEN
The Epidemiology and Burden of Skin Disease
Experimental support is critical when feasible. As

noted in Section Types of Epidemiologic Studies, the
strongest inferences derive from results of randomized
trials, although other experimental designs and quasiexperimental designs may contribute useful evidence.
More detailed discussions of these issues are available.11,12
::
EXPERIMENT
Chapter 1
Coherence refers to plausibility based on evidence

other than the existence of an association between this
exposure and this disease in epidemiologic studies.
Coherence with existing epidemiologic knowledge of
the disease in question (e.g., other risk factors for the
disease and population trends in its occurrence) and
other disorders (including but not limited to related
disorders) supports inference. Coherence with existing knowledge from other fields, particularly those
relevant to pathogenesis, is critically important when
those fields are well developed. It may involve direct
links, which are preferred, or analogy. Just as observations in the laboratory assume greater significance
when their relevance is supported by epidemiologic
data, the reverse is equally true.
cases beyond those reported initially are key to

defining the scope of the outbreak.
5. Establish the descriptive epidemiology. The cases
can now be characterized in terms of time,
including development of an epidemic curve
that describes the changes in magnitude
of the outbreak; place, including mapping
the distribution of cases; and person, the
demographic and potential exposure
characteristics of cases.
6. Develop hypotheses. On the basis of the data
gathered in steps 1 through 5 and the input
of other individuals, plausible hypotheses
about causality can be developed for further
evaluation.
7. Conduct analytical epidemiologic investigations.
If the data gathered do not yet clearly
prove a hypothesis, cohort and case-control
investigations can be conducted to verify or
disprove the hypotheses.
8. Revise hypotheses and obtain additional evidence as
needed. Steps 6 and 7 are repeated, each building
on prior iterations, to establish the causal chain
of events.
9. Implement control measures. As soon as the causal
chain of events is understood, prevention and
control measures are initiated.
10. Communicate results. An outbreak investigation
is not complete until the results have been
appropriately communicated to the relevant
communities.
No single number can completely describe the burden

of skin disease because that burden has many dimensions and because the term skin disease itself is rather
ambiguous. Many disorders with substantial morbidity or mortality, such as melanoma or lupus erythematosus, affect multiple organ systems. The degree
of skin involvement may vary widely from patient to
patient and within the same patient from time to time.
Diseases not typically treated by dermatologists, such
as thermal burns, often are excluded from estimates of
the burden of skin disease even though they primarily involve the skin. In addition, some diseases treated
most often by dermatologists may be classified in a
different category by funding agencies or others [e.g.,
melanoma is classified as an oncologic disorder as
opposed to a disease of the skin by the National Institutes of Health and by the International Classification of
Diseases, (http://www.who.int/classifications/apps/
icd/icd10online/, accessed Jul 7, 2010) even though it
almost always arises in the skin]. Organ systems are
interrelated, and the overlap is sufficiently great that
any definition of skin disease is necessarily arbitrary,
and any global estimate of the public health burden of
these diseases is therefore open to challenge. Typical
measures of disease burden are discussed in the following sections.
MORTALITY
Section 1
::
Mortality is a critical measure of disease impact. Death

certification is universal in the United States, and
the International Classification of Diseases code of the
underlying cause of each death is recorded. For the
year 2006, there were 16,163 deaths reported as due
to skin disease in the United States, of which most
were due to melanoma (Table 1-1). Additional major
causes included other skin cancers (primarily keratinocyte carcinomas), infections of the skin, and skin ulcers
(primarily decubitus ulcers). Bullous disorders represented less than 2% of these deaths. The total number
of skin disease deaths, of course, depends critically
on the definition of skin disease, as noted in Section
Descriptions of Disease in Populations: Measures of
Disease Burden.
In addition to the total number of deaths, mortality
typically is expressed as an age-adjusted rate to facilitate comparisons among populations with different
age distributions. Statements of age-adjusted rates of
mortality (or other results standardized by age) should
be accompanied by an indication of the standard used
in the adjustment to avoid potentially misleading
inferences. For example, when 1998 melanoma mortality rates are estimated using the 2000 US population
standard, the result is 50% higher than when the 1940
US standard population is used (1.8 vs. 1.2 per 100,000
per year for women and 4.1 vs. 2.7 per 100,000 per year
for men). Similarly, when years of potential life lost are
reported, the reader must be wary of different definitions that may be applied. In one analysis, a decline in
years lost from melanoma was noted by one definition
that was not observed with another.13
TABLE 1-1
Skin Disease Deaths, United States, 2006

Disease
Deaths (n)
Cancers
Melanoma
Genital
Lymphoma
Other cancers
12,301
8,441
1,126
91a
2,643a (primarily basal and
squamous cell carcinoma)
Ulcers
1,496
Infections
1,793
Bullous disorders
269
Other causes
304
Total
a
16,163
We estimate that approximately one-half of keratinocyte carcinoma deaths are misclassified squamous cell carcinomas arising
from mucosal surfaces in the head and neck16 and that cutaneous
lymphoma deaths are underestimated by a factor of 2 (see text).
[Adapted from http://wonder.cdc.gov/ (verified Apr 27, 2010).]
Careful analyses of mortality include assessment of

the validity of the data. Melanoma mortality statistics
appear to be reasonably accurate.14,15 However, deaths
from keratinocyte carcinomas are overestimated by a
factor of 2 (mostly due to the erroneous inclusion of
mucosal squamous cell carcinomas of the head and
neck region),16,17 and conventional estimates of deaths
from cutaneous lymphoma miss about half of the
actual deaths.18
INCIDENCE
Incidence refers to the number of new cases of a disorder. Mortality is low for most skin diseases; hence,
incidence may be a more useful measure for the
assessment of burden of skin disease. However, many
features of skin diseases make their incidence difficult to measure. For example, for many skin disorders, there are no diagnostic laboratory tests, and, in
fact, some disorders may evade physician diagnosis
(e.g., allergic reactions). Incidence for reportable communicable diseases in the United States is published
periodically based on reports to health departments,
although underreporting of skin diseases due to failure to present for medical care or to misdiagnosis is
a concern (Table 1-2). Incidences of melanoma and
cutaneous lymphoma have been published based on
data from a system of nationwide cancer registries,
yet underreporting remains a potential concern with
these data.19,20 Special surveys have been conducted
and administrative datasets analyzed to estimate
incidence of other disorders, such as keratinocyte
carcinomas, although a system of sentinel registries
would improve nationwide assessment.21,22 For some
diseases unlikely to evade medical detection due to
their severity, such as toxic epidermal necrolysis,
efforts to estimate incidence have met with considerable success.23,24 Specific contexts that permit more
accurate incidence estimates include the workplace;
for example, where occupational skin disease is a
prevalent problem.25
COHORT PATTERNS
Cohort patterns of changes in mortality or incidence
typically are observed when exposures determined
in childhood predict frequency of disease throughout
the life span. A classic example is melanoma mortality,
for which sun exposure in childhood is an important
determinant. A birth cohort is defined as the group
of individuals born within a defined (e.g., 10-year)
period. Melanoma mortality generally increases as
a power function of age within a birth cohort. Until
recent decades, each successive birth cohort had higher
risk than its predecessor; hence, the curves of mortality versus age were shifted upward. Thus, the crosssectional relationship of mortality versus age and the
increase in mortality risk during most of the twentieth
century followed a cohort pattern. For many countries
in the past several decades a decline in melanoma
mortality has been observed in younger age groups
TABLE 1-2
New Cases of Selected Reportable Diseases in the United States

1940
1950
1960
1970
1980
Anthrax
76
49
23
Congenital rubella
77
Congenital syphilis
Diphtheria
15,536
5,796
918
Gonorrhea
175,841
286,746
44
291,162
Hansen disease
Lyme disease
Measles
41,595
40,758
39,202
50
11
3,865
529
227
435
258,933
600,072
1,004,029
690,169
358,995
229,315
54
129
223
198
91
72
17,730
26,739
319,124
441,703
47,351
13,506
27,786
86
132
13
18
457
464
204
380
1,163
651
495
2,276
Syphilis (primary and

secondary)
23,939
16,145
21,982
27,204
50,223
5,979
12,195
Toxic shock
syndrome
322
135
66
102,984c
121,742c
55,494
37,137
27,749
25,701
16,377
9,795
132
151
179
203
227
249
281
304
Rocky Mountain
spotted fever
Tuberculosisb
US population
(millions)
a
NA = data not available.

Reporting criteria changed in 1975.
c
Data include newly reported active and inactive cases.
Adapted from Weinstock MA, Boyle MM: Statistics of interest to the dermatologist. In: The Year Book of Dermatology and Dermatologic Surgery,
2009, edited by B Theirs, PG Lang. Philadelphia, Elsevier Mosby, 2009, p. 53-68.
b
despite an increase in older age groups, suggesting a

lower baseline in these mortality-versus-age curves
for recent cohorts and hence a likely future decline in
overall melanoma mortality.
PREVALENCE
Prevalence refers to the proportion of the population
affected by a disorder. Because many skin diseases
are nonlethal yet chronic, prevalence is a particularly
important measure of frequency in dermatology.
Population-based data on prevalence of skin disease
for the United States were obtained in the first Health
and Nutrition Examination Survey, which was conducted in the early 1970s.26 Despite its limitations, this
study was notable because the sample was representative of the general US population, the number surveyed was large (over 20,000), and the entire surveyed
population was examined by physicians (primarily
dermatology residents), so the resulting estimates
were not dependent on patients ability or inclination
to seek medical care. Indeed, one of the findings of the
survey was that nearly one-third of those examined
Plague
2008
::
NAa
2000
Chapter 1
Acquired
immunodeficiency
syndrome
1990
had one or more skin conditions judged to be significant enough to merit a visit to a physician. The most
common conditions and their age- and gender-specific prevalence are indicated in Table 1-3 and Fig. 1-1.
A similar survey in the United Kingdom of over 2,000
Londoners in 1975 noted that almost one-quarter of
adults had a skin condition serious enough to warrant
medical care.27 Other efforts have focused on obtaining prevalence estimates of specific conditions with
special surveys.28,29
LIFETIME RISK
Lifetime risks for certain disorders are quoted commonly, although their validity can be questioned.
Lifetime risk can be measured only in retrospect, and
even then it reflects competing causes of mortality in
addition to incidence. It is commonly quoted for disorders such as cutaneous malignancies that are changing substantially in incidence, yet those changes are
frequently ignored in its calculation, and, in any case,
projections of future changes are quite speculative and
may be misleading.30
Prevalence rates for the four leading types of

significant skin pathology
TABLE 1-3
Prevalence of Skin ConditionsUnited States,

19711974a
Section 1
::
Female
Dermatophytosis
131
34
81
Acne (vulgaris and cystic)
74
66
70
Seborrheic dermatitis
30
26
28
Atopic dermatitis/eczema
20
18
19
Verruca vulgaris
Malignant tumors
Psoriasis
Vitiligo
Herpes simplex
Cases per 1,000 population.

From Skin conditions and related need for medical care among persons 174 years, United States, 19711974. Vital Health Stat [11], No.
212, US Department of Health, Education, and Welfare, November
1978.
NUMBER OF PHYSICIAN VISITS

Number of physician visits for a condition is one practical measure of its frequency that may reflect its incidence, prevalence, and severity, as well as access to
health care. Table 1-4 lists frequencies of dermatologist
and other physician outpatient visits for some of the
Diseases of sebaceous glands

Dermatophytoses
250
Rate per 1000 persons
Male
Both
Sexes
300
Tumors
200
150
100
50
0
10
20
30
40
Age in years
50
60
70
Figure 1-1 Prevalence rates for the four leading types of

significant skin pathology among persons 174 years, by
age, in the United States, 19711974.
most common skin conditions. A feature of this measure of disease frequency is its direct relation to expenditures for care of the disease.
OTHER MEASURES OF MORBIDITY:

CONCEPTUAL ISSUES
The consequences of skin disease for a population (or
the burden of disease) are complex; a practical conceptu-
TABLE 1-4
Visits to Non-Federal Office-Based Physicians in the United States, 2006a

Type of Physician
Diagnosis
All Physicians
b
2,217 (8.8%)
Eczematous dermatitis
3,183 (12.6%)
5,377 (0.6%)
8,560 (1.0%)
Warts
1,041 (4.1%)
1,361 (0.2%)
2,401 (0.3%)
Skin cancer
2,672 (10.6%)
928 (0.1%)
3,599 (0.4%)
Fungal infections
Hair disorders
Actinic keratosis
Benign neoplasm of the skin
All disorders
692 (2.7%)
b
1,759 (0.2%)
3,274 (0.4%)
737 (0.1%)
2,002 (0.2%)
741 (2.9%)
1,571 (0.2%)
2,432 (9.6%)
2,717 (0.3%)
1,293 (5.1%)
25,256 (100%)
876,698 (100%)
2,170 (0.2%)
901,954 (100%)
Estimates in thousands.
Figure does not meet standard of precision.
Note: Percentage of total visits is in parentheses.
Adapted from Weinstock MA, Boyle MM: Statistics of interest to the dermatologist. In: The Year Book of Dermatology and Dermatologic Surgery,
2009, edited by B Theirs, PG Lang. Philadelphia, Elsevier Mosby, 2009, p. 53-68.
Other
Acne vulgaris
Psoriasis
Dermatologistb
Components of burden of disease
Effects on Health
Costs
Mortality
Effect on
well-being
Direct
Impairment
Disability
Handicap
Indirect
Like all assays, measures of the nonfatal consequences

of diseases must be accurate. For example, they must
be reliable in that the variability in results among sub-
OTHER MEASURES OF MORBIDITY:

ISSUES IN QUANTIFICATION
A significant challenge for the development of clinimetric measures is developing a consensus among
clinicians about the specific features of an individual
disease that are important to include in such measures. Substantial progress in the empiric derivation
of these features has been made for disease severity
measures in certain skin diseases.34,35 The extent to
which a specific skin disease disrupts the skin itself
is related both to the percentage of body surface area
involved and to physical signs of the eruption, such as
the amount of induration and the degree of scale. Given
the pleomorphism of skin eruptions, most dermatologic
severity-of-disease measures are disease-specific, and
for common skin conditions, multiple instruments are
often available. Among the most studied instruments
to measure clinical severity of disease are the Psoriasis Area and Severity Index (PASI)36 and the Severity
Scoring of Atopic Dermatitis (SCORAD) index.37 With
the PASI, severity of disease is assessed by judgment
of the degree of involvement of four body regions
with signs of erythema, induration, and desquamation. The SCORAD index combines an assessment of
disease area with six clinical signs of disease intensity
(scales to measure pruritus and sleep loss also can be
included). Standardized reviews of severity measures
can be helpful for informing a consensus as well as
focusing futures studies; such reviews have recently
been published of 20 measures of atopic dermatitis38
and 53 measures of psoriasis.39
::
alization is contained in Fig. 1-2. Broadly, components

of burden of skin disease are those related to effects on
health or costs. Aspects of health include mortality and
effects on well-being, including those related to the
impairment, disability, or handicap a disease causes.
For example, a patient with psoriasis may have thickening and scaling of the palms (a bodily impairment),
which may cause disability (e.g., use of the hands),
dysfunction (role at work), and effects on quality of
life. Costs are either direct (for which funds can be
paid) or indirect (for which charges are not routinely
assigned, such as lost income because of disease).31
The measurement of burden of skin disease is challenging, in part because these conditions typically do
not cause mortality and do not result in changes in
easily measured laboratory tests. The most important
gauges of skin disease status and progression (i.e., the
physical examination and patients reports) can be difficult to measure and compile; in most cases patients
reports of the effects of skin disease on their activities
and well-being are crucial for determining the overall
consequences of those diseases. The measurement challenges are heightened because people understand and
value these aspects of health quite differently due to age,
gender, cultural conceptions, or access to health care.
The measurement of nonfatal consequences of disease is the subject of much international scientific and
political attention (http://www.who.int/healthinfo/
global_burden_disease/en/, accessed Mar 5, 2010,
and Chapter 3). An important point for dermatology is that patients experiences of illness may not be
adequately assessed with global measures that focus
on single aspects of health, or which were developed
without substantial input from patients.32 For example,
skin diseases that are visible and affect appearance
may result in social stigma and mood changes, which
would not be measured with metrics that are based on
dysfunction.
CLINICAL SEVERITY OF DISEASE
Chapter 1
Figure 1-2 Components of burden of disease.
jects who truly differ should be greater than the variability when a stable subject is examined repeatedly.
The measures must have evidence of validity, which
refers to the extent to which an instrument measures
what it is supposed to measure and does not measure
something else. Health outcome measures also must
demonstrate responsiveness, the ability to detect clinical
change. Furthermore, even when an accurate instrument exists, the clinical significance or interpretability
of scores or changes in scores often cannot be judged
until the tool is used widely and scores are available
for many patients with disease of varying severity.33
PATIENT-REPORTED OUTCOMES
As noted above, patients reports of their experiences of
disease and health care are particularly important for
assessing the course of chronic diseases (like most skin
diseases). Table 1-5 includes typical aspects of patients
experience that are measured in health care research.
The effects of disease on patients quality of life can
be assessed with generic instruments (which permit
comparisons of effects in patients with different diseases), skin-specific instruments (which permit comparisons of patients with different skin diseases), and,
more uncommonly, condition-specific instruments
(which permit comparisons of patients with the same
skin disease). Although more specific instruments may
assess aspects of a disease that would be missed with
TABLE 1-5
Typical Instruments Used to Measure Patient Reports

Domain
Typical Instrument(s)
Comment
Overall quality of life
Medical Outcomes Study Short-Form instruments

(SF-36)40 and (SF-12)41
36 or 12 items; commonly used in clinical

research; interpretable scores
Skin-related quality of life
Dermatology Life-Quality Index42
10 items, most commonly used, focuses on

functioning
29 or 16 items, focuses on emotional
effects, symptoms, and functioning
Skindex-2943, Skindex-1644
Section 1
Patient-Oriented Eczema Measure (POEM)45, SelfAdministered Psoriasis Area and Severity Index
(SAPASI)46
Correlate well with clinician measures
Symptoms: pruritus
Itch Severity Scale47, Pruritus-Specific Quality-of-Life

Instrument48
Demonstrate promising measurement

properties
Patient satisfaction
Consumer Assessment of Healthcare Providers and

Systems (CAHPS) survey49
Correlates with adherence, quality of life,

and quality of care
Patient preferences
Utilities50, Willingness to Pay51
Correlations among different measures of

preferences can be weak
::
Disease-specific severity
generic tools, both generic and specific tools contribute

unique information to a snapshot of a patients overall health-related quality of life. Substantial progress has
been made in the development and testing of patients
reports of the effects of their skin diseases on their activities and quality of life. Although quality of life is the
patient-reported outcome most often measured, patients
reports of symptoms, satisfaction with health care, and
preferences for health states are other examples. Data continue to be accumulated about the performance of these
instruments (including the use of sophisticated psychometric methods and the interpretation of their scores52).
On a national level, to develop a core set of questions and
metrics and to create item banks and repositories of items
that perform well using modern analytic techniques,
the National Institutes of Health has recently initiated
the Patient-Reported Measurement Information System
(PROMIS, http://www.nihpromis.org/).
A utility is a numeric measure of the value a patient
places on a given health state compared with other
health states. In the measurement of utilities, a variety
of procedures are used (such as visual analog scales
and time tradeoff exercises) to assign a numerical
value (or utility) to health states. This value reflects
patients preferences for the health states, in which
1.0 represents perfect health and 0.0 represents death.
Utilities are advantageous because they permit the
incorporation of patient preferences into medical care
decisions. Also, because they describe improvements
in morbidity with a single weighted metric, utilities
are used for the evaluation of complex tradeoffs such
as the calculation of cost-effectiveness, in which the
costs of treatments are compared with the values of
the health states they make possible. However, utilities are controversial because they can be difficult to
measure and can vary among patients in unpredictable
ways. An increasing number of studies exist that formally measure utilities of patients with skin diseases.50
COSTS
Costs of skin disease depend on the perspective from
which they are measured, because the costs to insurers
and patients may be quite different from the overall
cost to society. Because most skin diseases are chronic
and are cared for in the outpatient setting, estimation
of both their monetary and intangible costs is difficult.
Costs for individual skin conditions have been calculated53, and therapies have been evaluated in relation
to their benefits and effectiveness.54 In addition, overall
direct and indirect cost to payers, patients, and society
of 22 skin diseases have been reported.55
QUALITY OF CARE IN
DERMATOLOGY
Health services research uses many scientific methods from epidemiology, clinical epidemiology, and
the quantitative social sciences to study and improve
the quality of health care. From the perspective of
health services research, access to care, the processes
involved in the provision of care, the particular therapeutic interventions, as well as patient and provider
characteristics, are all determinants of the quality of
care. Studies of both the effectiveness of care (i.e., outcomes of health care as it is usually practiced) and the
efficacy of interventions (i.e., the results of interventions implemented in the idealized circumstances of
a randomized clinical trial) are important. Many of
the examples cited earlier demonstrate a sharpened
focus in dermatology on accurate measurement of
the clinical encounter. This capacity to measure the
progress of chronic diseases and their care will permit
rigorous efforts to evaluate and improve the quality
of that care.
KEY REFERENCES
Full reference list available at www.DIGM8.com
DVD contains references and additional content
1. Barzilai DA et al: Dermatoepidemiology. J Am Acad Der
matol 52:559, quiz 574, 2005
10. Sackett DL: Bias in analytic research. J Chron Dis 32:51,
1979
12. Hill AB: Environment and disease: Association or causation? Proc R Soc Med 58:295, 1965
38. Schmitt J, Langan S, Williams HC: What are the best outcome measurements for atopic eczema? A systematic review. J Allergy Clin Immunol 120(6):1389-1398, 2007
39. Spuls PI et al: How good are clinical severity and outcome
measures for psoriasis?: Quantitative evaluation in a systematic review. J Invest Dermatol 130(4):933-943, 2010
52. Both H et al: Critical review of generic and dermatologyspecific health-related quality of life instruments. J Invest
Dermatol 127(12):2726-2739, 2007
55. Bickers DR et al: The burden of skin diseases: 2004 a joint
project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J
Am Acad Dermatol 55(3):490-500, 2006
EBM is predicated on asking clinical

questions, finding the best evidence to
answer the questions, critically appraising
the evidence, applying the evidence to the
treatment of specific patients, and saving the
critically appraised evidence.
The EBM approach is most appropriate for
frequently encountered conditions.
Results from well-designed clinical studies
involving intact patients are at the pinnacle
of the hierarchy of evidence used to practice
EBM.
Recommendations about treatment,
diagnosis, and avoidance of harm should take
into account the validity, magnitude of effect,
precision, and applicability of the evidence on
which they are based.
WHAT IS THE BEST EVIDENCE?

The acceptance of evidence-based medicine (EBM)
in the specialty of dermatology has been slow and
reluctant. The term and principles are understood by
few and misunderstood by many. EBM is perceived
as an attempt to cut costs, impose rigid standards of
Evidence-Based Dermatology
Evidence-based medicine (EBM) is the use of

the best current evidence in making decisions
about the care of individual patients.
care, and restrict dermatologists freedom to exercise

individual judgment. Practicing EBM in dermatology is hampered by the continued belief among dermatologists that clinical decisions can be guided by
an understanding of the pathophysiology of disease,
logic, trial and error, and nonsystematic observation.7,8
It is hampered also by a lack of sufficient data in many
areas. As with EBM in general, therapy is often primarily emphasized; however, evidence-based approaches
to diagnosis and avoidance or evaluation of harm are
also important considerations.
Practicing EBM is predicated on finding and using
the best evidence. Potential sources of evidence include
knowledge regarding the etiology and pathophysiology of disease, logic, personal experience, the opinions
of colleagues or experts, textbooks, articles published
in journals, and systematic reviews. An important
principle of EBM is that the quality (strength) of evidence is based on a hierarchy. The precise hierarchy of
evidence depends on the type of question being asked
(Table 2-1).9 This hierarchy consists of results of welldesigned studies (especially if the studies have findings of similar magnitude and direction, and if there
is statistical homogeneity among studies), results of
case series, expert opinion, and personal experience,
in descending order.6,8 The hierarchy was created to
encourage the use of the evidence that is most likely to
be accurate and useful in clinical decision-making. The
ordering in this hierarchy has been widely discussed,
actively debated, and sometimes hotly contested.10
A systematic review is an overview that answers a
specific clinical question; contains a thorough, unbiased search of the relevant literature; uses explicit criteria for assessing studies; and provides a structured
presentation of the results. A systematic review that
uses quantitative methods to summarize results is a
meta-analysis.11,12 A meta-analysis provides an objective and quantitative summary of evidence that is
::
EVIDENCE-BASED MEDICINE
AT A GLANCE
Chapter 2
Chapter 2 :: Evidence-Based Dermatology

:: Michael Bigby, Rosamaria Corona, &
Moyses Szklo
Table 2-1
Grades of Evidencea,b
Grade
Level of Evidence
Therapy/Harm
Diagnosis
1a
Systematic review (with

homogeneityc) of RCTs
1b
Individual RCT (with narrow

confidence intervals)
1c
All or noned
Systematic review (with homogeneity) of level 1 (see

column 2) diagnostic studies, or a CPG validated on a test
set.
Independent blind comparison of an appropriate
spectrum of consecutive patients, all of whom have been
evaluated by both the diagnostic test and the reference
standard.
Very high sensitivity or specificity.
Section 1
2a
2b

homogeneity) of cohort studies
Individual cohort study [including
low-quality RCT (e.g., <80%
follow-up)]
::
B
2c
3a
3b
Outcomes researche
homogeneity) of case-control
studies
Individual case-control study
Systematic review (with homogeneity) of level 2 or

better (see column 2) diagnostic studies.
Independent blind comparison but either in
nonconsecutive patients or confined to a narrow
spectrum of study individuals (or both), all of whom
have been evaluated by both the diagnostic test and the
reference standard or a diagnostic CPG not validated in
a test set.
Systemic review (with homogeneity) of 3b (see column 2)
and better studies.
Independent blind comparison of an appropriate
spectrum, but the reference standard was not applied to
all study patients.
Case series (and poor-quality

cohort and case-control studies)
Reference standard was not applied independently or

not applied blindly.
Expert opinion without explicit critical appraisal, or based on physiology, bench research, or
logical deduction.
CPG = clinical practice guideline, a systematically developed statement designed to help practitioners and patients make decisions about
appropriate health care for specific clinical circumstances; RCT = randomized controlled clinical trial.
a
These levels were generated in a series of iterations among members of the NHS R&D Centre for Evidence-Based Medicine (Chris Ball, Dave
Sackett, Bob Phillips, Brian Haynes, and Sharon Straus). For details see Levels of Evidence and Grades of Recommendation, http://www.cebm.net/
levels_of_evidence.asp, accessed May 2001.
b
Recommendations based on this approach apply to average patients and may need to be modified in light of an individual patients unique
biology (e.g., risk, responsiveness) and preferences about the care he or she receives.
c
Homogeneity means lacking variation in the direction and magnitude of results of individual studies.
d
All or none means interventions that produced dramatic increases in survival or outcome, such as the use of streptomycin to treat tubercular
meningitis.
e
Outcomes research includes cost-benefit, cost-effectiveness, and cost-utility analyses.
10
amenable to statistical analysis.11 Meta-analysis is credited with allowing the recognition of important treatment effects by combining the results of small trials that
individually lacked the power to demonstrate differences among treatments. For example, the benefits of
intravenous streptokinase in treating acute myocardial
infarction were recognized by means of a cumulative
meta-analysis of smaller trials at least a decade before
this treatment was recommended by experts and before
it was demonstrated to be efficacious in large clinical
trials.13,14 Meta-analysis has been criticized because
of the discrepancies between the results of metaanalysis and those of large clinical trials.1417 For example, results of a meta-analysis of 14 small studies of the
use of calcium to treat preeclampsia showed a benefit
to treatment, whereas a large trial failed to show a
treatment effect.14 The frequency of such discrepancies
ranges from 10% to 23%.14 Discrepancies can often be

explained by differences in treatment protocols, heterogeneity of study populations, or changes that occur
over time.14
Publication bias is an important concern regarding systematic reviews. It results when factors other
than the quality of the study are allowed to influence
its acceptability for publication. Several studies have
shown that factors such as sample size, direction and
statistical significance of findings, and investigators
perceptions of whether the findings are interesting
are related to the likelihood of publication.18,19
For example, in a study by Dickersin et al, the reasons given by investigators that results of completed
studies were not published included negative results
(28%), lack of interest (12%), and sample size problems (11%).18 Results of studies with small samples are
personal experience and describe several of these pitfalls.37 These include the following:
Overemphasis on vivid anecdotal occurrences and
underemphasis on significant statistically strong
evidence
Bias in recognizing, remembering, and recalling
evidence that supports preexisting knowledge
structures (e.g., ideas about disease etiology and
pathogenesis) and parallel failure to recognize,
remember, and recall evidence that is more valid
Failure to accurately characterize population
data because of ignorance of statistical principles,
including sample size, sample selection bias, and
regression to the mean
Inability to detect and distinguish statistical association and causality
Persistence of beliefs in spite of overwhelming
contrary evidence
Chapter 2
::
FINDING THE BEST EVIDENCE

The ability to find the best evidence to answer clinical questions is crucial for the practice of EBM. Finding evidence requires access to electronic search tools,
searching skills, and availability of relevant data. Evidence about therapy is the easiest to find. The most
useful sources for locating the best evidence about
treatment include the following:

The Cochrane Library

The MEDLINE (Medical Literature Analysis and
Retrieval System OnLine) and EMBASE (Exerpta
Medica Database) databases
Primary journals
Secondary journals
Evidence-based dermatology and EBM books
The National Guideline Clearing-house
(http://www.guideline.gov/)
The National Institute for Health and Clinical
Excellence (http://www.nice.org.uk)
less likely to be published, especially if they have negative results.18,19 This type of publication bias jeopardizes
one of the main goals of meta-analysis (i.e., an increase
in power through pooling of the results of small studies). Creation of study registers and advance publication of research designs have been proposed as ways
to prevent publication bias.20,21 Publication bias can be
detected by using a simple graphic test (funnel plot) or
by several other statistical methods.22,23 In addition, for
many diseases, the studies published are dominated
by drug company-sponsored trials of new, expensive
treatments. The need for studies to answer the clinical questions of most concern to practitioners is not
addressed because sources of funding are inadequate.
Not all systematic reviews and meta-analyses are
equal. A systematic review can be only as good as the
clinical trials that it encompasses. The criteria for critically appraising systematic reviews and meta-analyses
are shown in eTable 2-1.1 in online edition. Detailed
explanations of each criterion are available.11,24
The type of clinical study that constitutes best evidence is determined by the category of question being
asked. Questions about therapy and prevention are
best addressed by RCT.11,2426 Questions about diagnosis are best addressed by cohort studies.11,24,27,28
Cohort studies, case-control studies, and postmarketing surveillance studies best address questions about
harm.11,24,29 RCT are a good source of evidence about
the harmful effects of interventions for adverse events
that occur frequently but not for rare adverse events.
Case reports are often the first line of evidence regarding rare adverse events, and sometimes they are the
only evidence. Methods for assessing the quality of
each type of evidence are available.11,24
With regard to questions about therapy and prevention, the RCT has become the gold standard for
determining treatment efficacy. Thousands of RCT
have been conducted. Studies have demonstrated that
failure to use randomization or to provide adequate
concealment of allocation resulted in larger estimates
of treatment effects, caused predominantly by a poorer
prognosis in nonrandomly selected control groups
than in randomly selected control groups.30 However,
studies comparing randomized and nonrandomized
clinical trials of the same interventions have reached
disparate and controversial results.3032 Some found
that observational studies reported stronger treatment effects than RCT.30 Others found that the results
of well-designed observational studies (with either a
cohort or a case-control design) do not systematically
overestimate the magnitude of the effects of treatment
compared with RCT on the same topic.31,32 Examining
the details of the controversy leads to the following
limited conclusions. Trials using historical controls
do yield larger estimates of treatment effects than do
RCT. Large, inclusive, fully blinded RCT are likely to
provide the best possible evidence about effectiveness.10,33,34
Although personal experience is an invaluable part
of becoming a competent physician, the pitfalls of
relying too heavily on personal experience have been
widely documented.3,35,36 Nisbett and Ross extensively
reviewed peoples ability to draw inferences from
The Cochrane Library contains the Cochrane Database of Systematic Reviews, the Database of Abstracts
of Reviews of Effectiveness, the Cochrane Central
Register of Controlled Trials, and the Health Technology Assessment Database, among other databases
(http://www.thecochranelibrary.com/view/0/index.
html). Volunteers write the systematic reviews in the
Cochrane Library according to strict guidelines developed by the Cochrane Collaboration. Issue 1, 2010, of
the Cochrane Library contained 6,153 completed systematic reviews. The number of reviews of dermatologic topics is steadily increasing.
CRITICALLY APPRAISING
THE EVIDENCE
After evidence is found, the next step in practicing
EBM is critically appraising the quality of the evidence and determining the magnitude of effects and
11
the precision of the evidence. The criteria for critically appraising papers about treatment, diagnostic
tests, and harmful effects of exposures are shown in
eTables 2-1.2, 2-1.3, and 2-1.4 in online edition, respectively.11,24 Papers that meet these criteria are more likely
to provide information that is accurate and useful in
the care of patients.11,24 Critically appraising evidence
consists in determining whether the results are:

Section 1
::
Determining the validity of evidence centers on

ascertaining whether the evidence was produced in a
manner most likely to eliminate and avoid bias. The
critical questions to ask to determine the validity of
papers about therapy, diagnostic tests, and harmful
effects are shown at the tops of eTables 2-1.2, 2-1.3, and
2-1.4 in online edition, respectively.
EVIDENCE ABOUT THERAPY

AND PREVENTION
Studies of therapy should randomly assign patients
to treatment groups (using a table of random numbers or pseudorandom numbers generated by computer) and ensure concealed allocation (e.g., by using
opaque envelopes) so that the treating physician cannot know or anticipate to which treatment group the
patient has been assigned. In addition, there should be
nearly complete follow-up of all patients entered into
the study; intention-to-treat analysis of results; masking of investigators, patients, and statisticians where
possible; equal treatment of groups; and similarity
between treatment groups with regard to the distributions of prognostic variables. These criteria represent
only a small subset of the features of a well-designed
and well-reported clinical trial.35 A more complete set
of criteria has been published and recently updated,
and adherence to these criteria is required by many of
the leading medical journals.47,48
Important terms and concepts that must be understood to determine whether the results of a paper about
therapy are clinically important include the following:

12
valid (i.e., they are as unbiased as possible);

clinically important; and
applicable to the specific patient being seen.
The magnitude of the treatment effect

The precision of this value
The difference in response rates
Its reciprocal, the number needed to treat (NNT)
The confidence interval
In evaluating a clinical trial, the physician should

look for clinical outcome measures that are clear-cut
and clinically meaningful to the physician and his or
her patients.35 For example, in a study of a systemic
treatment for warts, complete disappearance of warts
is a meaningful outcome, whereas a decrease in the volume of warts is not. Historically, two principal methods have been used to determine patient outcomes in
dermatologic clinical trials. The first involves examining the patient before, during, and at the conclusion of
treatment and reporting how the patient appears at the

various time points. The second involves determining
the degree of improvement during treatment.49 A third
method, determining the impact of therapy on the
quality of the patients life, is being increasingly used
in dermatologic trials.35
An example of the first method is commonly
encountered in therapeutic trials of psoriasis. A common practice is to assign numerical values to (1) the
amount of erythema, (2) the amount of scaling, (3) the
degree of infiltration, and (4) the body surface area
involved, and to formulate an index by calculating a
derivative of some product of these four numbers.50,51
The overall condition of the patient can then be represented by this index. A common index is the psoriasis
area and severity index, which ranges from 0 to 72.50
The major problem with indices is that they confound
area of involvement with severity of disease.49 For
instance, a patient with thick plaque-type psoriasis
of the knees, elbows, and scalp may have the same
index as a patient with diffuse but minimal psoriasis
of the trunk and arms. Whereas the former condition
is notoriously difficult to treat, the latter will generally
respond rapidly and easily to many forms of therapy.49
The second problem with indices is that they lend an
air of precision to the analysis and presentation of data
that is not warranted.49 For instance, Tiling-Grosse and
Rees demonstrated that physicians and medical students were poor at estimating the area of involvement
of skin disease, and therefore some of the components
that make up indices may be inaccurate.52 Finally, calculations of the means, differences in means, and percentages of change in indices in response to treatment
often do not convey an accurate clinical picture of the
changes that have occurred.49
The second method of assessment groups patients
according to their degree of improvement. Treatments
are then compared in terms of their ability to move
patients into categories representing higher degrees
of improvement. There are two major problems with
this form of assessment. The first is that the categories
of improvement are often not well defined. The second problem is that the categories are not additive.49
That is, 60% to 80% improvement is often assumed to
be twice as good as 20% to 40% improvement, but no
such numerical relationship exists between these subjectively defined categories.
To be most useful, the outcome variables to be measured must be clearly defined, must be as objective as
possible, and must have clinical and biologic significance.35,49 The best indices and scales are the ones that
accurately reflect the state of the disease and the ones
whose validity and reliability have been verified by
previous work.35,49,53 The development of scales and
indices for assessing cutaneous diseases and the testing of their validity, reproducibility, and responsiveness have been inadequate.35,49,54 Therefore, a lack of
clearly defined and useful outcome variables remains
a major problem in interpreting dermatologic clinical
trials.
Until better scales are developed, trials with the
simplest and most objective outcome variables are
::
their validity must have been demonstrated in prior

studies.
Once sound, clinically relevant outcome measures
are chosen, the magnitude of the difference between
the treatment groups in achieving these meaningful
outcomes should be determined. The precision of the
estimate of the differences among treatments should
be assessed. Useful measures of the magnitude of the
treatment effect are the difference in response rate and
its reciprocal, the NNT.11,24,41 The NNT represents the
number of patients one would need to treat to achieve
one additional cure or clinically relevant improvement.
The confidence interval provides a useful measure
of the precision of the treatment effect.11,24,41,56,57 The
calculation and interpretation of confidence intervals
have been extensively described.58 In simple terms,
the reported result (known as the point estimate) provides the best estimate of the treatment effect. Values
become less and less likely as they move away from
the reported result within the confidence interval.11,24,41
The confidence interval provides a range of values in
which the population or true response to treatment
is likely to lie.
Examples of the application of the concepts of NNT
and confidence interval are given in a paper identified
through a search of the Cochrane Library that reported
the results of a RCT the use of a placebo, acyclovir,
prednisone, and acyclovir plus prednisone in the treatment of herpes zoster.59 At day 30 of the trial, 48 of 52
patients treated with acyclovir experienced total healing compared with 22 of 52 patients who received a
placebo. The response rates for acyclovir and placebo
were 0.92 and 0.42, respectively, and the difference in
response rates was 0.5. The NNT was 2 (1/0.5). This
result means that for every two patients treated with
acyclovir instead of placebo, one additional patient
would show total healing by day 30. The 95% confidence interval for the difference in response rates is
0.35 to 0.65, and the 95% confidence interval for the
NNT is 2 to 3.
What does it actually mean that the confidence interval for the difference in response rates in the foregoing example is 0.35 to 0.65? If the investigators in this
study had the opportunity to repeat the study many
times using the same design and procedures, sampling variability would prevent obtaining the same
results in each study. Repeated trials were simulated
using resampling (resampling is a computer-intensive
method that uses the reported results of a trial to simulate the results that would be obtained if the trial were
repeated a number of times).41,60 The results when the
trial was repeated 10 and 1,000 times are shown in
eFigs. 2-0.1A and 2-0.1B in online edition, respectively.
A 95% confidence interval of 0.35 to 0.65 means that
if the trial is repeated many times and a confidence
interval is calculated for each trial, the true result or
response to treatment will be included in 95% of the
confidence intervals so produced. Alternatively, if the
trial were repeated multiple times, the results would
lie within that interval (0.35 to 0.65) 95% of the time.
The population or true response to treatment
will most likely lie near the middle of the confidence
Chapter 2
the best. They lead to the least amount of confusion

and support the strongest conclusions. Thus, trials in
which a comparison is made between death and survival, recurrence of disease and no recurrence, or cure
and lack of cure are studies whose outcome variables
are easily understood and verified. For trials in which
the outcomes are less clear-cut and more subjective, a
simple ordinal scale is probably the best choice.49 The
best ordinal scales involve a minimum of human judgment, have a precision that is much smaller than the
differences being sought, and are sufficiently standardized so that they can be used by others and produce similar results.36
In addition to being clearly defined, outcome variables should have clinical and biologic significance.25,26
For example, in a therapeutic trial of patients with
severe acne, treatment was associated with a decrease
in lesion count from a mean of 40 to a mean of 35. This
numerical difference may be of statistical significance,
but it does not convey the biologic significance of the
change in lesion number.49 This result may mean that
some patients with severe acne experienced complete
clearance, whereas in others the acne remained the
same or got worse. It could also mean that in most
patients the acne got slightly better. Furthermore, does
an individual patient look better when the lesion number has been reduced from 40 to 35? Is there less scarring and fewer complications?
To strengthen clinical trials and help validate their
conclusions, investigators should select only a few
outcome variables and should choose them before initiation of the study. Measurement of many outcome
variables increases the likelihood that spurious, chance
differences will be detected. An ineffective treatment
may be found efficacious when tested using poorly
designed outcome assessment tools. Conversely, an
effective therapy may be found ineffective when an
insensitive scale is used.
Special precautions are recommended to recognize
and remain skeptical of substitute or surrogate endpoints, especially when no differences are detected in
clinically important outcomes.26,55 Examples of such
endpoints include CD4/CD8 ratios instead of survival
rates in studies of treatments for acquired immunodeficiency syndrome, antinuclear antibody levels or sedimentation rates instead of clinical measures of disease
activity in lupus erythematosus, and volume of warts
instead of proportion of patients cleared of warts. The
use of carefully chosen and validated surrogate endpoints often allows studies to provide answers to questions that would typically require much larger or longer trials if the targeted clinical endpoint were used.
For example, a well-designed short clinical trial may
be sufficient to demonstrate that a new drug effectively
lowers serum cholesterol level or that a given drug is
effective in controlling hypertension. In both cases,
much longer and larger studies would be required to
demonstrate that the cholesterol-lowering drug and
the antihypertensive drug reduced morbidity and
mortality from atherosclerotic and hypertensive cardiovascular diseases, respectively. However, surrogate
endpoints must correlate with clinical outcomes and
13
Section 1
::
14
interval and will rarely be found at or near the ends

of the interval. The population or true response to
treatment has only a 1 in 20 chance of being outside of
the 95% confidence interval. Unless a given patient is
very different from the patients included in the study,
his or her response will most likely lie near the middle of the confidence interval. If the 95% confidence
interval of the difference in response rates excludes
zero difference, one can reject the null hypothesis
that the two treatments are the same.24,41,56,57
Misinterpreting trials that fail to show statistically
significant differences among treatments is a common error in dermatologic clinical trials. It is important
to remember that not statistically significant means
that a difference has a reasonably high probability of
having been due to chance; it does not mean that there
is no difference or that treatment is necessarily ineffective.35 Significant differences in treatment effects
in comparison trials may be missed if the number of
subjects tested is small. For example, in a 1978 survey
of 71 published trials with negative results, Freiman
et al found that a 25% or 50% improvement in outcome
might have been missed in 57 (80%) and 34 (48%) of the
studies, respectively.61 A follow-up study conducted by
Moher, Dulberg, Wells in 1994 indicated that a 25% or
50% improvement in outcome might have been missed
in 84% and 64%, respectively, of 102 studies with negative
results.62 The sample sizes of many dermatologic trials are
often inadequate to detect clinically important differences.
The acceptance of a significance level of .05 as the
cutoff for rejecting the null hypothesis is a tradition based on quality control standards and is not an
absolute truth. At times (e.g., when treatments have
substantial side effects) more stringent standards are
required, and paradoxically, results that do not meet
the p = 0.05 standard sometimes may be clinically significant. For example, consider a hypothetical trial of
a new chemotherapeutic agent involving 30 patients
with metastatic melanoma randomly assigned to treatment groups that produced a 5-year survival rate of 7
of 15 among patients treated with the new agent and
3 of 15 among control patients treated with conventional surgery, chemotherapy, and radiation. Whereas
the result does not achieve statistical significance when
analyzed by g 2 testing (Yates corrected g 2 = 1.35; p =
0.25), the result is nonetheless potentially significant.
If the therapy is beneficial and the estimated difference in response rates is the true difference in response
rates, it may result in the saving of 2,880 lives annually (based on 8,650 deaths from melanoma annually
and the improvement in survival in this hypothetical
example). Because of the biologic and clinical importance of the results suggested by the trial, the treatment
should be investigated in a study that uses a larger
patient group and has more power to detect a significant difference if one exists.35
The potential benefit of the treatment may be further revealed by the use of confidence intervals. To
determine whether a treatment effect may have been
missed in a study reporting negative (not statistically
significant) results, one should look at the upper
boundary of the 95% confidence interval. If this
value would be clinically important if it were the true
response, then an important treatment effect may

have been missed in the study. Consider our hypothetical new treatment for metastatic melanoma. The
cure rates for the new treatment and the conventional
treatment were 47% and 20%, respectively, and the
difference between them was thus 27%. The 95% confidence interval for the difference in cure rates was
10% to 51%. The upper boundary of the difference
in cure rates was 51%. This difference would clearly
have a significant impact on the treatment of patients
with metastatic melanoma (the NNT is 2!), and therefore a significant treatment advance may have been
missed in this study. Also note that the 95% confidence interval of the difference in cure rates includes
zero difference; therefore, we cannot conclude with
a high degree of confidence that the response rates
of the two treatments are different. However, when
zero is included as one of the values in the confidence
interval, the inference that the therapy is not efficacious fails to consider the fact that the best estimate
of effect is the point estimate (e.g., the observed difference in cure rates of 27% in our hypothetical example).63 In other words, the values contained in the
confidence interval are not equally likely and become
less and less likely as they move away from the point
estimate. Thus, in the example, a difference of 25%
(close to the observed 27%) is much more likely than
a difference of 5% (far from the observed 27%).35
APPLYING EVIDENCE TO
SPECIFIC PATIENTS
Applying the evidence to treatment of specific patients
involves determining whether the evidence from studies is applicable to a given patient. This decision is
based on the patients condition and values. It involves
asking a series of questions that are specific to the type
of evidence being considered (see eTables 2-1.22-1.4 in
online edition). When faced with the task of determining whether the results of a particular study are applicable to specific patients, physicians should determine
whether there are any compelling reasons that the result
should not be applied.35 Applying evidence to specific
patients always involves physicians judgment.
KEY REFERENCES
2. Sackett DL et al: Evidence based medicine: What it is and
what it isnt. BMJ 312:71, 1996
6. Cochrane A: Effectiveness and Efficiency. London, Royal Society of Medicine Press, 1999
7. Sackett DL et al: Clinical Epidemiology: A Basic Science for Clini
cal Medicine. Boston, Little, Brown and Company, 1991, p. 441
13. Greenhalgh T: How to Read a Paper: The Basics of Evidence
Based Medicine. London, BMJ Publishing Group, 4th edition,
BMJ books, 2010
26. Sackett D et al: Evidence-Based Medicine: How to Practice and
Teach EBM. Edinburgh, Churchill Livingstone, 1996, p. 250
37. Bigby M, Gadenne AS: Understanding and evaluating clinical trials. J Am Acad Dermatol 34:555, 1996
39. Nisbett R, Ross L: Human Inference: Strategies and Short
comings of Social Judgment. Englewood Cliffs, New Jersey,
Prentice-Hall, 1980, p. 330
49. PubMed clinical queries using research methodology
filters: http://www.ncbi.nlm.nih.gov/entrez/query/static/
clinicaltable.html, accessed August 26, 2011.
52. Higgins JPT, Green S, eds.: Cochrane handbook for systematic reviews of interventions 5.1.0 [updated March
2011]. The Cochrane Collaboration. 2011. Available
form www.cochrane-handbook.org, accessed August
26, 2011
63. Gardner MJ, Altman DG, eds.: Statistics with Confidence,
2nd edition. London, BMJ, 2005
The rational basis for this idea is simple as no nation

or region is a complete island in terms of health; what
affects one country may well, in time, affect another.
The most obvious examples of this concept from past
history involve the spread of infections. At present,
there is a concerted effort to follow the international
spread of HIV or avian influenza. Both present global
risks to health, which is the reason why their current
distributions are tracked regularly and with accuracy.1
Spread of these diseases has occurred and will continue to occur through a combination of both social and
economic factors and the movement of populations
and individuals. Yet historically, infectious diseases
that have spread rapidly to cause maximum chaos
have often resulted from a relatively minor, and often
unrecognized, episode rather than a large movement
of individuals. For instance, the impact that a localized
outbreak of bubonic plague had on medieval Europe
when the besieged Genoese garrison in Caffa, in the
Crimea, fled by ship bringing the rat host with them
was not foreseen.2 The subsequent epidemic, caused
by Yersinia pestis, known as the Black Death, reduced
the population of Europe by a third over the following 2 years. In addition to the mortality and distress, it
resulted in profound social and economic changes that
Global Health in Dermatology
HEALTH AND GLOBAL

INTERDEPENDENCE
long outlived the epidemic itself. Predicting and tracking the international course of infections is now a key
element of global surveillance.
However, global health problems and disease are
not limited to infections, although the propensity to
spread is more demonstrable in this group; chronic
noninfectious conditions are also global. The relentless
increase in the prevalence of diabetes mellitus type 2
in aging populations is such an example. Global health
is affected by other factors that include the impact of
social, economic, and environmental change on populations. This reflects the fact that human populations
are no more isolated socially than they are geographically, but manifest a measure of interdependence
where what happens in Kazakhstan may be reflected,
in time, in New York City. In the case of diabetes, the
causes of changes in health status are different; the
international dissemination and adoption of Western
dietary behaviors are, at least partly, responsible for
this. Health-determining trends such as diet, lifestyles,
or global warming are all examples of noninfective risk
factors that may affect global health. The international
spread of risks to health may follow different routes,
often simultaneously.
In many parts of Europe and the United States, the
decline of tuberculosis was a marker of economic progress in the twentieth century,3 the main reduction in disease incidence, and subsequently mortality, preceding
by many years the development of new specific treatments such as streptomycin or the introduction of BCG
immunization. This health improvement reflected the
huge social changes made during this era, such as the
provision of sustainable and affordable water supplies
and drainage, heating schemes, better housing, and
nutrition. While the increasing prosperity and subsequent social reforms that affected the industrialized
Western nations in the late nineteenth and early twentieth centuries had a huge impact, mainly for the good,
in promoting better health, in international terms the
benefits were relatively restricted and not global in
their reach; large areas of the world did not benefit
from this change. In the recent report by Michael Marmot,4 the continuing influence of social and economic
conditions on both national and global health are
::
The word global describing something that is worldwide is not a concept that is difficult to understand,
whereas the term health is frequently misused on
the assumption that it simply means freedom from
disease. However, health and disease are not merely
examples of the converse, a point that is captured by
the mission statement of the World Health Organization (WHO), whose objective is to promote health. The
WHO definition of health, which is widely used as
the definitive descriptor of health, says that health is
a state of complete physical, mental, and social wellbeing and not merely the absence of disease or infirmity.
Therefore, global health implies a worldwide mission
to promote complete well-being.
Chapter 3
Chapter 3 :: Global Health in Dermatology

:: Roderick J. Hay
15
Section 1
::
clearly demonstrated and poor social and economic

status linked closely to poor health indicators such as
high maternal and infant mortality. He cites Sweden
as an example of a country that has adopted a policy
where the creation of appropriate social conditions
would ensure the health of the nation. Much of this
health initiative concentrates on social initiatives such
as improvement of participation, economic security,
and healthy working. This type of policy has been supported in both rich and poor countries. For instance,
the Mexican initiative, Programa de Educacion, Salud
y Alimentacion (Progresa), which provides financial
incentives for families to adopt measures that will
ensure social improvements leading to better health, is
a good example.5 While this may seem oversimplistic,
poor health is often an indicator of social ills and vice
versa; the two are interdependent. Health can make a
significant impact on both micro- and macroeconomics;
conversely economic performance has a direct impact
on health. The WHO report on macroeconomics and
health6 asserted the view that the investment of both
time and money on health improvement had multiple
benefits through reduction of mortality and increase
in the healthy employed, measures that would lead to
improvement in both family and national economics.
By ensuring good health of their populations nations
would improve economic performance and social conditions, which, in turn, would improve health status of
their peoples. So good health is an important facet of
social and economic development, just as poor health
is an indicator of poor performance in both domains.
Therefore, global health becomes an important social
aspiration in a world where international collaboration and interdependence as well as increasing global
industry are slowly replacing, or at any rate adding
another dimension to, the nation state.7
GLOBAL BURDEN OF
DISEASE PROJECT
16
In order to determine the impact of global health, a

consortium of international bodies such as the World
Bank in 1990 commissioned a report on the global
burden of disease (GBD); a project that has now gone
through several iterations involving other organizations, including WHO and an international group of
universities.8 In doing this work, there were two key
objectives, namely: (1) to provide up-to-date information on the incidence of disease states in all the regions
of the globe and (2) to assess their impact on mortality and disability. In carrying out this work, the interdependence of health and social and economic wellbeing was clearly recognized. These large surveys of
global disease have had to draw on the availability of
studies that can provide the necessary information. A
subsequent development from GBD, aimed at health
in developing countries, was the Disease Control Priorities Project (DCPP), an international report focusing on sustainable measures of disease elimination or
control.9 The latest GBD round of studies is incomplete
at the time of writing.8 However, it differs from other
studies in that much of the work of collecting data is

the task of specialist groups, including one for dermatology. The target is to provide data covering diseases and risk factors (such as consumption of alcohol
or atmospheric pollution) in the WHO designated
regions and, where this is missing, to provide robust
means of adducing the data using defined mathematical models. The study aims to target disease incidence
at two time points(1) 1990 and (2) 2005. It will also
provide measures of mortality as well as disability.
The methods used to assess the latter is more refined
than previously in that lay panels (i.e., patients) will be
asked to assign the weighting that determines the disability that accompanies disease states.
GLOBAL HEALTH AND THE SKIN

Within this international perspective, there is a similar connection between global health, dermatology,
and the spread of skin disease. Dermatology is subject
to the same factors that regulate the spread of other
diseases and determine its control; infection, social,
and economic factors are all important in determining the prevalence and impact of skin disease.10 Skin
infections are very common in all societies; tinea pedis
(athletes foot), onychomycosis, scabies and childhood
pyoderma, viral warts, and recurrent human herpes
virus (HHV1) are all examples of everyday skin infections that affect many people. There are also examples
to show that this spread is mediated by human contact and, where there is facility for this to occur, for
instance, in a swimming pool in the case of human
papilloma virus infections of the feet and tinea pedis,
there is a higher incidence of disease.11 Likewise,
movements of numbers of individuals through travel,
migration, or war increase the chance of global spread
of these infections. For instance, the world diffusion
of infection due to Trichophyton rubrum is said to have
followed the displacements of populations and the
movement of soldiers in the 19141918 and 19391945
wars.12 More recently, the spread of Staphylococcus
aureus bearing the PantonValentin leukocidin (PVL)
virulence gene causing furunculosis has been tracked,
in some cases, to international travel.13 Despite this, in
some parts of the world there are still unique and geographically localized skin infections, largely because
these occur in remote areas. The lower limb infection
of children and young adults seen in remote regions
of the developing world where there is a high rainfall, tropical ulcer (Fig. 3-1), is an example of a condition that has remained relatively isolated14; the fungal infection of the skin, tinea imbricata, is a further
example.15 However, even where there is relative isolation, changes over time such as migration can lead
to epidemic spread of previously endemic disease.
Tinea capitis has undergone a remarkable transformation in the Western hemisphere in the past 50 years.
It has seen the introduction of an effective treatment
regimen with griseofulvin initially and subsequent
decline in infection rates followed by the relentless
spread of one dermatophyte fungus, Trichophyton
tonsurans, initially from a zone of endemic disease in
Figure 3-2 Actinic cheilitis. Mexico, Guerrero State.
::
Mexico, where it still remains as a stable infection of

moderate incidence, to reach epidemic proportions in
children in inner cities, initially in the United States,
but subsequently in Canada, Europe, the West Indies,
and Latin America.16 The spread appears to follow an
increased susceptibility to infection of children with
African Caribbean hair type; in recent years it has
begun to spread in Africa as well.
In a similar way, noninfectious skin disease, as with
other illnesses, is also affected by those social and economic changes that are international in dimension. The
complex history of the medical reaction to the fashion
for sun exposure was formed initially by the recognition of the health promoting, and then health limiting,
effects of sun and ultraviolet (UV) light.17 The current
concern over excessive exposure to both natural sun
or UV exposure, for instance, in sunbed parlors, or as
part of UV therapies, is an important stage in an exercise that started as genuine attempt at health promotion. The ancient Greeks, for instance, promoted sun
exposure or heliotherapy as beneficial for a number of
medical problems.3 While largely ignored for the best
part of two millennia the revolution in medical ideas
in the nineteenth century led to sun exposure being
adopted as a health-giving practice with the discovery of Vitamin D and the award of the Nobel Prize to
Finsen for light therapy. Health-giving sun exposure
was adopted widely and became a fashion that was the
rage of the health conscious, delivered in spa environments such as William Kelloggs Battle Creek clinic.18
However, the habit, perhaps fueled by the recognition
that exposure to natural light was in some ways health
giving, led inevitably to one of the consequences, the
sun tan. It is not certain if the recognition of the suntanned skin as fashionable can all be laid at the door
of Coco Chanel, who is said to have been overexposed
to the sun during a holiday in Cap Antibes in France.
The resulting effect on her skin color was soon to be
Chapter 3
Figure 3-1 Tropical ulcer. (From CDC/K. Mae Lennon,

Tulane Medical School; Clement Benjamin.)
adopted by the fashionable and white wherever they

lived.19 Soon it became a global trend in fashion. The
recognition that sun exposure also led to a rising incidence of skin cancer followed more slowly, but perhaps with greater speed than that concerned with the
connection between smoking and lung cancer. Protection against sun exposure has become a major global
focus of preventive measures of public health medicine, from public education to the risks involved to
early detection of melanoma and nonmelanoma skin
cancers. Dermatological organizations have reacted
with admirable speed to the recognition of the risk of
UV exposure. This has been accomplished through
seminars, magazine articles, public health campaigns,
and training camps. The introduction of educational
programs in schools has been a welcome addition.
The trend to the opposite, skin lightening, in women
of color has been an equally global trend where the
use of skin bleaching products has been adopted by
different cultures throughout the world. The common agents in use include hydroquinone- or steroidcontaining creamswith a resulting risk of the development of skin disease such as ochronosis and more
general medical problems, including low birth weight
infants in pregnant women using topical corticosteroids to achieve lightening.20 As with infections, there
are also examples of skin diseases that are caused by
social customs or economic conditions that remain geographically localized. Erythema ab igne of the forearms
is almost unknown in most parts of the world but is
associated with the cooking of tortillas (enfermedad de
las tortilleras)so it is only seen where the tortilla is a
staple of diet; oral submucous fibrosis occurs where the
Betel nut is chewed is another example. However, some
noninfective skin conditions occur in isolated communities for a different reason, genetic susceptibility, such
as actinic dermatitis seen in native American communities in North and South America (Fig. 3-2). These are
not the only examples of the relation between noninfectious skin disease as an international concern and social
and economic factors. One of the earliest public health
campaigns that crossed national boundaries stemmed
from the recognition that industrial workers exposed
to oil during the operation of large-scale spinning were
17
Section 1
::
18
susceptible to skin cancer and the ingestion of arsenic at work or as a medication was also potentially
harmful through the development of skin cancer.21
Recently, much international interest has focused on
the changing face of atopic dermatitis and although
the evidence suggests that this is a condition associated with societies enjoying improved socioeconomic
status,22 the quest for modifiable risks whose resolution may, in turn, provide benefit to children with this
condition is now the subject of a global initiative (the
ISAAC study).
So skin disease is subject to different, but nonetheless global influences, compared with other illnesses
and in the pursuit of skin health there is a great need
to promote international cooperation. This objective is
identified, not just in order to share learning experiences, but also because the burden of skin disease is
spread unequally around the world and many of the
poorest nations face the greatest problems.9 Here,
the social and economic factors plus uncontrolled or
poorly controlled infection play key roles in determining the pattern of disease.
SKIN DISEASE IN RESOURCE

POOR ENVIRONMENTS
In the poorest countries skin disease usually ranks as
one of the first three common disorders encountered in
frontline medical facilities, i.e., the first point of call for
a patient seeking treatment. Whereas in the developed
countries many of the problems facing dermatologists
and primary care practitioners are noninfectious skin
diseases, the opposite is true in developing countries
where infections dominate the pattern of presentation.23
Where infections occur in the industrialized countries,
the general public have widespread access to treatment
through pharmacies or primary care doctors as well as
specialists. Access to treatment is limited by a number
of factors that range from poor training of health care
workers to the need to journey considerable distances in
order to obtain help.24 Likewise in the poorest communities ready access to cash is more limited, with a large part
of household economics depending on self-sufficiency
in growing food or creating housing from local materials. Cash is necessary for some things such as clothing
and for additional food. Treatment of even the simplest
of conditions such as scabies or pyoderma presents a
competing call on the available household cash income
(Fig. 3-3); poor or ineffective treatment is a drain on
resources that would otherwise be spent on food. The
exact sums are small but their impact is large.25
The burden of skin disease is often unrecognized at
national or international level as it is perceived to come
low in the global league table of illnesses and, compared
with diseases that carry a significant mortality such as
HIV, community acquired pneumonias and tuberculosis, skin disease-related mortality is low. However, as
skin problems are generally found to be amongst the
most common presentations of diseases seen in a primary care setting in tropical9 and nontropical10 areas,
in some regions, where transmissible diseases such
Cost of ineffective medicines for skin disease

40
Cayaco
35
Sta Maria
30
Total cost (dollars)
25
20
15
10
Sc
Py
Hp
AF
Figure 3-3 Cost of ineffective medicines for skin disease

in two rural communities, Mexico. Sc = scabies; Py = pyoderma; Hp = hypopigmentation; AF = expected cost of
additional food during the same period.
as tinea imbricata or onchocerciasis are endemic, they

are the commonest reason for an individual to present themselves for treatment. The GBD estimates for
2001 indicated that skin disease was associated with
mortality rates of 20,000 in Sub-Saharan Africa.8 This
was comparable to mortality rates attributed to meningitis and hepatitis B, obstructed labor, and rheumatic
heart disease in the same region. The disability rate
calculated as disability adjusted life years (DALYs) in
the same report showed an estimated total of 896,000
DALYs recorded for the region in the same year; this
was comparable to that attributed to gout, endocrine
disease, panic disorders, and war-related injury. While,
as described before, these figures are currently being
reassessed, it suggests that the burden of disease due
to skin-related illness is high. Many of the international
studies that have focused on the impact of illness on
individuals utilize disability scores. Those interested in
skin disease frequently use patient-focused measures
Quality of Life (QOL) scales.26 While these may be less
objective they do, by concentrating on the impact of
disease on personal values and performances, provide,
according to many interested in the impact of disease,
a more realistic measure of how patients are likely
to use health services. Assessing the impact of skin
disease on quality of life in comparison with other

chronic nondermatological diseases is difficult. However, the decline in QOL for patients with the common
skin disease, acne, is similar to that experienced by
patients with chronic disorders such as asthma, diabetes, and arthritis; all showed comparable deficits in
objective measurements of life quality.26 Skin disease
related to HIV, which constitutes an important skin disease burden, particularly in Sub-Saharan Africa, leads
to a similar diminution of QOL compared with nonHIV related skin problems, although the use of antiretroviral therapy produces a significant improvement.27
In Western societies there have been few studies aimed

at estimating disease prevalence or risk, a necessary
prelude to health intervention. However, a study in
Lambeth, South London in 1976 using a questionnairebased population-centered approach, backed by random examination, revealed an overall 52% prevalence
of skin disease of which just over half the cases were
judged by the investigators to require treatment.35 The
NHANES study in the United States36 produced very
similar figures. More recent studies of skin disease burden in the United States and the United Kingdom confirm these earlier investigations. Studies from developing countries have generally been conducted through
systematic community-based surveys backed by clinical
examination. Published figures for skin disease prevalence in developing countries range from 20% to 80%.9
From these studies it became clear that different populations have different levels of awareness of illness. For
instance, in a study in Ethiopia between 47% and 53%
of members of two rural communities claimed to have
skin disease.30 However, when they were examined 67%
of those who denied having a skin problem were found
to have a treatable skin condition; the majority of these
were infections. Tinea capitis, which is equally common in the same population may be ignored because
it is common knowledge that this follows a benign and
asymptomatic course in many patients, although in
those communities where the clinical form of tinea capitis, favus, occurs, the local populations recognize that
this type of infection is associated with permanent scalp
scarring and so present for treatment.
The main risk factors associated with skin disease
in developing countries are largely socioeconomic;
the most important of these appears to be household
overcrowding estimated by person per room in living
accommodation. For instance, in Tanzania, Gibbs found
that 27% of patients had treatable skin disease in surveying two village communities; once again infections
were the most common diseases found.37 Overcrowding
was a major risk factor in this latter survey. What also
IDENTIFYING RISK
::
Despite the unequal comparison of mortality rates with

other diseases, there are a number of important and relevant reasons why the needs of the populace for effective remedies or control policies for skin conditions
should be in place. Firstly, the diseases are very common and patients present in very large numbers in primary care settings. In some cases more than 60% of the
population has at least one skin disease.23 Even though
significant numbers never seek treatment for a variety
of reasons, including lack of awareness that treatments
are available, the workload generated by patients presenting with skin problems at primary care level can be
huge. This is a problem in all countries but particularly
in those with the lowest gross domestic product.28 Children and the elderly, in particular, are affected, adding
to the burden of disease in already vulnerable groups.
Secondly, the morbidity can cause significant disability
through disfigurement or restriction of movement. For
instance, the effects of elephantiasis secondary to lymphatic filariasis last for years after the elimination of
the filarial parasites. As stated previously, the relative
economic cost of treating even trivial skin complaints in
families in poor regions reduces the capacity of families
to contribute to their local economies as their disposable
cash is exchanged for poor medicine rather than other
goods.25 The skin is often the site where changes of a
number of other neglected tropical diseases are present. Leprosy, onchocerciasis, guinea worm, HIV/AIDS,
tuberculosis, yaws, and Buruli ulcer are all examples.29
A shortage of elementary skills in the recognition and
management of disease that present with skin abnormalities reduces the capacity for surveillance of these
important diseases. In truth, skin disease in the tropics
is a neglected problem that should be added to the list
of neglected tropical diseases.
Globally, one of the current problems highlighted
in a number of studies has been the management of
skin disease in primary care settings. In the developing world high treatment failure rates of over 70% are
common in frontline health posts.30 The same may be
true in settings in industrialized nations where lack
of recognition of some skin problems at primary care
level is a factor limiting effective treatment. This situation is compounded by changes to the undergraduate
medical curriculum where, in many countries, the fac-
Chapter 3
PRACTICAL PROBLEMS
IN SKIN CARE
tual and academic content, such as knowledge of skin

or eye disease, has been reduced to allow students to
assimilate greater patient-oriented skills such as communication; the gap in learning for those not intending to follow a career in subjects, such as dermatology,
yet who have some responsibility for managing skin
problems, has not yet been plugged satisfactorily. One
way forward in streamlining the capacity to cope with
common diseases, such as skin disease, has been to prioritize treatment options. For instance, in the developing world a small number of common skin diseases,
mainly infections, account for the vast majority of the
disease burden. Therefore, implementation of effective
treatment targeted on these conditions confers significant gains to both personal and public health. Two
prime examples are scabies31,32 and pyoderma.33 In the
industrialized nations concerted efforts to prevent or
diagnose skin cancer at an early stage have formed key
elements of public health strategy.34
19
seems to influence the overall prevalence and pattern of

skin conditions is the existence of a number of common
contagious diseases, notably scabies and pyoderma, in
certain areas. Hot and humid climatic conditions may
also predispose to certain skin infections such as pyoderma, thereby affecting the distribution of disease.
SKIN DISEASETHE PATTERN

AT COMMUNITY LEVEL AND
INTERNATIONAL INITIATIVES
Section 1
::
Using the World Bank figures (World Development

Indicators 2002) for low-income populations in 2000,
the estimated numbers of individuals infected with
pyoderma and scabies based on the highest prevalence
figures from community surveys in the developing
world are 400 and 600 million, those based on the lowest prevalence figures are 40 and 50 million. For tinea
capitis the estimated number of cases based on the
highest estimates of prevalence for Sub-Saharan Africa
alone is 78 million.9
Overall these data suggest that significant improvements could be made in reducing the burden of skin
disease by focusing on the small group of conditions,
particularly infections, which comprise the majority of
the community caseload. This may be accomplished
by community control programs (see Chapter 4). The
examples of scabies and skin cancer have already been
cited. There are now a number of different bodies that
understand the need to prioritize and have started, at
first individually but increasingly in collaboration, to
try to improve this situation.
The main focus of these efforts has been the identification of the health needs for skin disease in poor
countries, the simplest methods of dealing with the
majority and the development of programs to cope
with these. In most cases, the key elements necessary
to deliver an effective program are as follows:
a. Data on skin disease and current resources that
could be mobilized to deal with the problem.

b. Education of those charged with improving skin
health.
c. Evidence of the efficacy of each project.
DATA ON SKIN DISEASE
20
Data on the global epidemiology of skin disease are

inadequate, not just because current estimates of global
health are subject to enormous variations. In skin disease a major and recurrent problem has been the very
small number of studies that document the prevalence
or incidence of disease at population level. The reasons are not difficult to identify. Firstly, because skin
disease is not associated with significant mortality, the
first international indicators of disease activity, death
rates, have not triggered a demand at governmental or
even regional levels for comprehensive epidemiological
surveys. Secondly, and allied to the first point, the disability associated with skin disease is often thought to
be minoranother reason why there has been few central calls for further investigation. There are also practical reasons why studies of this nature have been few
until recently. Because the diagnosis of changes in the
skin depends on a visual assessment, whose accuracy
is largely based on experience, it becomes very difficult
to teach those without the relevant experience to assign
diagnostic labels. It is only comparatively recently that
attempts have been made to simplify and validate
diagnostic criteria for use in large population studies
and those originating from the international studies of
allergy now provide a global picture of the prevalence
of atopic dermatitis.38 However, this is but one example
and there have been a few similar initiatives in other
areas of dermatology, for example, classification of skin
changes in lymphatic filariasis.39 The upshot has been
that skin disease has remained a subject where epidemiological studies have relied on the diagnosis of a trained
observer, usually a dermatologist. The large studies of
global disease have had to draw on the availability of a
few surveys that can provide the necessary information.
Most of these are the fruits of a comparatively small
number of dermatologists who have taken on the task of
investigating the impact of skin disease and developing
measures for assessing disease prevalence and quality
of life. Yet there are examples where disease presenting
in the skin has attracted more global attention. Yaws,
for instance, was one of the first examples of an infectious disease that was targeted by WHO for elimination
through mass penicillin therapy.40 In the first few years,
the campaign made extraordinary advances with massive reductions in the numbers of new cases. As with
other diseases lack of resources and major disruption,
such as human conflict, have ensured that there are still
pockets of yaws that have yet to be brought under control. The recognition of the risk of skin cancer has stimulated regional and national initiates in areas such as
Australia34; but there are still few cancer registries that
collect data on nonmelanoma skin cancer.
EDUCATION AND TRAINING

More effort has gone into education to improve knowledge of skin disease and its management and the
examples of initiatives established by departments and
national and international dermatology societies are
important to recognize. These range from the national
programs of skin cancer prevention to Web sites that
promote public awareness. These often also include
training for other health professionals, such as pharmacists, who may encounter skin disease. In the developing world the International Foundation for Dermatology has established a number of such programs.41,42 The
first of these, the Regional Dermatology Training Centre
(RDTC) in Moshi, Tanzania was set up as collaboration
between the International Foundation for Dermatology;
The Ministry of Health and the Good Samaritan Foundation is an example of a training initiative that affects
many countries. The Centre trains clinical officers with
regional responsibility for skin disease, sexually transmitted infection, and leprosy, and more recently it has
established an international dermatology residency-
training program for Sub-Saharan Africa. Other programs of training or assistance established in Mexico,43
Mali,44 Ethiopia,45 Haiti,46 Fiji,47 and Cambodia amongst
others are all examples of international collaboration to
improve skin health in poorer countries.
HOW EFFECTIVE ARE THESE

INITIATIVES?

5. Levine R and the What Works Working Group: Millions
Saved. Proven Successes in Global Health. Washington DC,
Center for Global Development, 2004
9. World Health Organization: Global Burden of Disease for the
Year 2001 by World Bank Region. Disease Control Priorities
Project, http://www.fic.nih.gov/dcpp, 2005
23. Mahe A: Epidemiology and Management of Common Skin Dis
eases in Children in Developing Countries. WHO 2005, whqlibdoc.who.int/hq/2005/WHO_FCH_CAH_05.12_eng.pdf
32. Lawrence G et al: Control of scabies, skin sores and haematuria in children in the Solomon Islands: Another role
for ivermectin. Bull WHO 83:34, 2003
42. Hay R, Marks R: The International Foundation for Dermatology: An exemplar of the increasingly diverse activities
of the International League of Dermatological Societies.
Br J Dermatol 150:747, 2004
Public Health in Dermatology
In summary, the global incidence of disease affecting

the skin is very large; the disability related to it is less,
but is nonetheless significant. Managing this burden
remains the responsibility of those specially trained in
the field. Increasingly, dermatologists and dermatological nurses have turned their attention to adopting measures that benefit a wider group of individuals than the
KEY REFERENCES
::
SUMMARY
Chapter 4
These initiatives have been less successful in the provision of evidence that the campaigns have worked.
There are some data from the sun protection programs
that the incidence of advanced melanoma is improved
by early screening measures.48 However, measuring
the impact of education on disease incidence is difficult, but it is clearly needed in order to justify the outlay of time and expense.
patient sitting on the other side of the consulting desk.

To do so means setting up partnerships and alliances
both nationally and internationally. Whether developing or assisting local or global public health schemes to
control, eliminate, or improve skin problems through
education or community initiatives is realistic is a matter for debate. What is certain, though, is that intervention to improve the health of those with skin problems
within communities improves both the health of the
people as well as the image of the profession.
Chapter 4 :: Public Health in Dermatology

:: Hywel C. Williams, Sinad M. Langan, &
Carsten Flohr
PUBLIC HEALTH IN DERMATOLOGY AT A GLANCE
Public health dermatology promotes skin health.
Modern public health dermatology is still
relatively underdeveloped.
Doctors help individual patients but have little
influence on the health of entire populations.
Conversely, the impact of large population
interventions is rarely appreciated by individuals.
Prevention is often more logical than only
treating sick individuals.
A low-risk approach of reducing risk in the
whole population for diseases such as melanoma
may achieve more than a high-risk approach of

targeting just those who have skin cancer or who are
at higher risk of developing skin cancer.
When entire populations are considered, a little
bit of harm affecting a lot of people can add up to
more than a lot of harm affecting a few people.
Modern public health dermatology has had some
success in the reduction of skin cancer incidence
and control of infectious diseases.
Low-technology educational interventions directed
at entire communities can result in more benefit
than high-technology drugs targeted at a few ill
individuals.
21
WHAT IS PUBLIC HEALTH

MEDICINE ALL ABOUT?
DEFINITION
Section 1
The World Health Organization defines health as a

state of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity.1 The key message of this definition is that health
is a holistic measure that is influenced by socioeconomic factors and inequality. Public health is a discipline in which the level of focus is on the health of
populations as opposed to that of individuals, as is the
case in clinical medicine. A useful definition of public
health is as follows:
::
Public health is the science and the art of prevent

ing disease, prolonging life, and promoting physi
cal health and mental health and efficiency through
organized community efforts toward a sanitary
environment, the control of community infections, the
education of the individual in principles of personal
hygiene, the organization of medical and nursing ser
vice for the early diagnosis and treatment of disease
and the development of the social machinery to ensure
to every individual in the community a standard of
living adequate for the maintenance of health.2
This definition articulates some of the roles of
public health practitioners in relation to society and
health. It also highlights the four key areas of public health action: (1) preventing disease and promoting health, (2) improving medical care, (3) promoting
health-enhancing behavior, and (4) modifying the
environment.3
HISTORICAL PERSPECTIVES
22
As early as in the fifth century bc, Hippocrates suggested a clear link between environmental factors and
disease states. In more recent centuries, the physician John Snow helped to establish the field of public
health during the 1854 London cholera epidemic.4 By
carefully counting the number of deaths from cholera
according to population denominators in specific London districts, he was able to establish that household
water supply might be the key common factor leading to cholera deaths. Snow hypothesized that cholera
was a water-borne disease, and he was able to trace
the origin of the epidemic to a contaminated water
pump in Broad Street, Soho. Consequently, he ordered
removal of the pump handle, which was followed by a
dramatic reduction in cholera deaths. Thus, Snow first
made detailed planned observations, then analyzed
the data, formulated a hypothesis, tested this hypothesis through experiment, and finally mounted a campaign to prevent further disease. This led to a widespread political campaigning for clean water from
which millions have benefited worldwide ever since.
What is intriguing about Snows work on the causal
relationship between water and cholera is that it pre-
ceded the discovery of the Vibrio cholerae organism by

Koch a third of a century later.
Public health has played a key role in the prevention and treatment of dermatologic diseases. One of
the first historical examples is scurvy. In 1746, James
Lind discovered through observation, analysis, and
performance of a controlled trial that scurvy in sailors
was a dietary disease that could be cured by administration of oranges and lemons5 (see eFigs. 4-0.1 and
4-0.2 in online edition). Linds treatise preceded the
discovery of vitamin C by more than a century. In
1775, Percivall Pott was the first to describe an occupationally induced cancer by noting that the mortality from scrotal cancer was 200 times higher in chimney sweeps than in other workers.6 He attributed the
excess mortality to tar and soot exposure in combination with poor personal hygiene. The first carcinogenic
polycyclic aromatic hydrocarbon was not discovered
until 1933. In the early twentieth century, pellagra
was a major public health problem (see eFig. 4-0.3 in
online edition). There were 100,000 deaths from the
disease in a 40-year period and over 3 million sufferers
in the United States at that time. In 1914, Dr. Joseph
Goldberger noticed that inmates at the Georgia State
Sanatorium developed high rates of pellagra whereas
the nurses and attendants did not, and concluded that
the origin of pellagra was probably a disease caused by
a dietary deficiency. He confirmed his hypothesis with
controlled clinical trials.7 The deficient dietary factor,
niacin, was discovered in 1937.
Collectively, these examples illustrate the importance and potential power of public health in the prevention of disease. These examples also highlight the
fact that knowledge of disease pathophysiology (i.e.,
mechanisms) is not always a prerequisite to determining the cause or risk factors for a disease and the potential for effective public health interventions.
HIGH-RISK AND LOW-RISK

APPROACHES TO PUBLIC HEALTH
Traditionally, dermatology, like other branches of specialist medicine, has concentrated on the treatment of
those who have fallen ill, those who believe they are
ill, or people at high risk of developing disease. For
instance, we prescribe topical corticosteroids for those
with atopic dermatitis, and we may give advice on sun
protection to patients who previously had a malignant
melanoma. We may see such melanoma patients on a
regular basis in skin cancer follow-up clinics to monitor treatment success and to be able to detect recurrences or new early second melanomas. Doctors and
patients alike tend to be highly motivated when such
an approach is used. The potential benefits seem obvious, and although there may be adverse effects associated with the prescribed treatment, such as skin thinning with prolonged use of topical corticosteroids, or a
scar from excision of a melanoma, many patients will
accept such risks, because appropriate treatment leads
to a tangible and significant improvement of symptoms and improved quality of life or survival. Such an
% of population
Before implementation
30
20
0
Personal UV radiation exposure
Figure 4-1 Distribution of ultraviolet (UV) radiation exposure before (solid line) and after (dashed line) implementation of a population strategy to reduce personal UV radiation exposure.
After implementation
::
Distribution of ultraviolet (UV) radiation
tection. The state of Victoria, Australia, has the most

comprehensive population-based primary prevention
campaign against skin cancer in the world (SunSmart
campaign, http://www.sunsmart.com.au/), and it has
been reported that this programs public investment
was worthwhile. Not only has it resulted in a significant reduction in skin cancer incidence and mortality,
but the returns from savings on skin cancer treatments
have also exceeded the overall costs of the SunSmart
campaign.9
In view of the above, it seems obvious that upstream
prevention is more desirable than treating sick individuals who come for treatment downstream after a
long chain of pathologic events, some of which may
be irreversible. However, it is generally more difficult
to persuade healthy individuals to protect themselves
against prolonged sun exposure than to persuade those
who have already had a malignant melanoma excised.
Partly because of this, funding for population prevention strategies is often difficult to obtain, yet the whole
population will potentially benefit, as long as such
interventions are evidence based and sustainable. It is
also worth pointing out that although a public health
intervention such as vaccination against measles has
dramatically reduced the incidence of disease at a population level, it is impossible to say which individuals
have been helped by such a population intervention
a phenomenon known as the prevention paradox.
A population strategy is not suitable for trying to
control all skin diseases at present, because such a
strategy depends on the knowledge of modifiable risk
factors. In the many cases for which exposures that
predispose to a particular skin condition are unknown,
prevention through avoidance is not possible, and the
only option available is treatment of disease rather
than primary disease prevention.
Chapter 4
approach to tackling disease has often been referred

to in the literature as the high-risk approach, because it
focuses on the treatment and detection of those at high
risk of developing disease and those who have already
fallen ill.8
In contrast to the high-risk approach, the ultimate
aim of public health medicine and public health dermatology is to prevent the development of disease in
the first place whenever possible, not only by forestalling it in those identified as being at high risk (e.g.,
because of a strong family history), but by shifting the
entire distribution of a certain exposure in a healthier
direction for the whole population (population strategy). Such a low-risk approach can be implemented
through large-scale public health education campaigns
aimed at fundamentally changing the entire populations behavior and lifestyle. For example, based on
the data of the Framingham study one can extrapolate that a reduction of everybodys blood pressure by
10 mm Hg would result in an overall reduction in mortality from heart disease of around 30%.8 In dermatology, a good example of a such a population strategy
is attempts to change the general populations sun
exposure behavior to reduce exposure to ultraviolet
light and ultimately skin cancer incidence and mortality through public health education campaigns that
are national (e.g., Australia) or international (e.g., the
World Health Organizations INTERSUN program,
http://www.who.int/uv/intersunprogramme/en/)
in scope (Fig. 4-1). This makes sense particularly in
a country like Australia, because a strong association between ultraviolet radiation and melanocytic
and nonmelanocytic skin cancer is well established,
and such risk is distributed widely through the predominantly fair-skinned population. Skin cancer is
an important cause of death in economically active
younger people, and treatments for all forms of skin
cancer pose an important burden on many countries
health care resources. Simple measures, such as avoiding sun exposure during peak hours of radiation and
wearing suitable clothing, can provide adequate pro-
BALANCING BENEFIT AND HARM

Making the conceptual jump from thinking about individual patients to thinking about entire populations
can be challenging for practicing dermatologists, especially because such jumps can come up with some surprising results. For example, a dermatologist with an
interest in contact dermatitis might see a case of severe
hand dermatitis in a printer caused by allergic contact
dermatitis from a chemical and then publicize such a
case in a respected journal.10 Another dermatologist
reading such a case report might come to the conclusion that allergic contact dermatitis is an important
cause of hand dermatitis in printers. Yet when this dermatologist visits the workplace to conduct a survey of
all cases of hand eczema in printers, it becomes apparent that true allergic contact dermatitis is probably
quite rare, and by far the most common cause of hand
eczema is constant low-grade exposure to soap and
water from repeated washing and friction from paper
and dirt.11 Thus, it is possible that a little bit of harm
affecting a lot of individuals can add up to much more
in absolute terms (the realm of the public health/occupational health physician) than a lot of harm affecting
one or two workers (the realm of the dermatologist).
23
Section 1
::
24
Another well-known example of such a phenomenon

is the effects of smoking on reduction in cardiovascular
disease. Even though the association between tobacco
smoking and lung cancer (relative risk of 14.0) is much
stronger than that between smoking and cardiovascular disease (relative risk of 1.6), strategies for smoking
cessation save around twice as many lives from cardiovascular disease than from lung cancer simply because
heart disease is much more common than lung cancer.12 Therefore, from a public health perspective the
population-attributable risk (the proportion of the disease that may be attributable to a particular risk factor)
is more important than other traditional measures of
risk, such as the relative risk (whose magnitude may
tell us something about the strength of a particular
association). In a study of risk factors for psoriasis in
Italy, Naldi et al found that smoking accounted for up
to 26% of all cases.13 In individuals with psoriasis who
smoked and who also had a family history of psoriasis,
an increased body mass index might accounted for up
to 48% of disease.13 The fact that smoking and obesity
are modifiable risk factors suggests that psoriasis is
preventable, at least to some degree, in this population.
PUBLIC HEALTH APPROACHES

IN DERMATOLOGY
So far, we have illustrated the public health approach
in dermatology using mainly historical examples. Yet
although current dermatologic research is still relatively dominated by the pursuit of studies in which the
unit of analysis is at a cellular or subcellular level, there
are some good examples of public health dermatology
in action.
One of the classic studies illustrating the public
health approach in action for infectious skin disease
was that conducted by Taplin and colleagues concerning scabies among Kuna Indians on the San Blas Archipelago.14 These islands off the coast of Panama were
plagued by very high rates of scabies in children in
the 1980s, which led to misery and secondary bacterial
infections. Despite the use of the best treatments available to combat the problem, the population burden of
scabies remained largely unchanged. Only after the
adoption of a public health approach in which everyone in defined areas was treated did the prevalence of
scabies fall dramatically from approximately 33% to
approximately 1%. Similar dramatic decreases in scabies prevalence (from 25% to 1%) and in associated pyoderma and possibly poststreptococcal nephritis have
been observed through the use of population-based
treatment with ivermectin in the Solomon Islands.15
Another example is the Global Alliance to Eliminate
Lymphatic Filariasis (GAELF; http://www.filariasis.
org/), an alliance between the World Health Organization, ministries of health, and the private sector aimed
at the worldwide eradication of this devastating disease by 2020. GAELF is probably the biggest public
health program ever and involves mass treatment of
around 750 million people in 48 countries with antifilarial drugs and also includes public health education
and advice on skin care of lymphedematous legs to

prevent further morbidity. Public health interventions
are not restricted to administration of pharmaceutical
drugs but can also include educational interventions
such as the public education campaigns for reducing
skin cancer through reduction in ultraviolet light exposure. One such successful program has been the introduction of basic dermatologic care in Mali through the
development of a training program for general health
care workers on the management of common skin diseases.16 The proportion of patients with skin disease
with a clear diagnosis increased from 42% before the
training to 81% after it. Although such dramatic effects
might be overestimated in a simple before-and-after
study, the effects were sustained for up to 18 months
after training. Paradoxically, these improvements in
care were associated with a 25% reduction in prescription costs, which suggests that inappropriate empirical
prescribing was a source of unnecessary expenditure
before the training. Other researchers have also documented how scarce family income can be wasted on
inappropriate treatment for skin diseases such as pyoderma and scabies in Mexico.17 Ryan has described the
role of educational clinics in the prevention of skin cancers as well as the management of early lesions in the
albino population of 170,000 in Tanzania.18 The principles of community dermatology in the face of mobile
populations are also discussed elsewhere.19
Three further points in relation to public health dermatology are worth noting. The first is that although
dermatologists are best placed to provide an accurate
diagnosis of skin diseases, such provision may not be
realistic for interventions on a public health scale in
poorer countries, where there is a strong argument for
embedding dermatological skills into primary health
care services as has been done successfully in training health care workers in the diagnosis of leprosy in
Mali.20 The second is that public health interventions,
like drug treatments, are not without their potential
drawbacks. For example, limiting sun exposure in
order to reduce the incidence of skin cancer may be
associated with drawbacks including depression and
less skin synthesis of vitamin D, deficiency of which
may be associated with a range of diseases such as cancer, bone disease, and heart disease.21 Yet recent studies of seasonal variations in vitamin D levels suggest
that the commonly held view that 10 to 20 minutes sun
exposure during the summer is enough to boost overall 25 hydroxy Vitamin D levels is wrong, and that sufficient sun exposure for a worthwhile benefit would be
countered by an unacceptable burden of skin cancer.22
Therefore, fortifying foods with Vitamin D seems a
safer public health option than increasing sun exposure
for maintaining adequate vitamin D levels.23 Balancing
benefits and harms requires special consideration in
public health simply because they affect so many people. Whilst some public health interventions, such as
immunization or advice on reduction of sun exposure,
allow some degree of choice for individuals to heed or
ignore as they choose, others, such as fluoridation of
water or addition of iodine to salt, are less amenable
to personal modification. Third is that although many
public health interventions may not sound as high
tech as drugs targeted at specific biologic receptors,

they may be more effective and appropriate for sick
populations. The concept that a little bit of harm affecting a lot of people can add up to more than a lot of
harm affecting a few people was developed earlier,
but a similar maxim also holds true: sometimes a lowtechnology beneficial intervention that can be applied
to a large population can add up to far greater benefit
in population terms than a high-technology solution
that will benefit only a few.

2. Winslow CEA: The untilled field of public health. Mod
Med 2:183, 1920
7. Goldberger J, Wheeler GA, Syndenstricker E: A study
of the diet of nonpellagrous and pellagrous households.
JAMA 71:944, 1918
8. Rose G: Sick individuals and sick populations. Int J Epide
miol 14:32, 1985
9. Carter R, Marks R, Hill D: Could a national skin cancer
primary prevention campaign in Australia be worthwhile?
An economic perspective. Health Promot Int 14:73, 1999
14. Taplin D et al: Community control of scabies: A model
based on use of permethrin cream. Lancet 337:1016, 1991
16. Mah A et al: Integration of basic dermatological care into
primary health care services in Mali. Bull World Health Or
gan 83:935, 2005
18. Ryan TJ: Healthy skin for all. Int J Dermatol 33:829, 1994
KEY REFERENCES
::
Some dermatologists, rather than just viewing the

world of skin disease from within the narrow confines
of a private practice or hospital-based practice, have
already conducted population-based needs assessments for dermatologic care, followed by organization of the appropriate services at a population level. A
health care needs assessment conducted in the United
Kingdom found that skin diseases are one of the commonest reasons why people consult their family doctor where training was paradoxically the least.24 New
data from the World Health Organization project on
the Global Burden of Diseases will include important information on the comparative burden of skin
diseases compared with other skin diseases (http://
www.who.int/healthinfo/global_burden_disease/
en/). New methods of communication such as social
networking Internet sites have become an increasingly
important source of public health information.25
There are increasing international collaborations to
try to prevent and reduce the burden of skin diseases
at a global level through health care planning and
focused interventions. These are carried out through
organizations such as the International Foundation
for Dermatology (http://www.ifd.org/) in conjunction
with the International League of Dermatological Societ-
Chapter 4
FUTURE OF PUBLIC HEALTH

IN DERMATOLOGY
ies (http://web.ilds.org/). The International League of

Dermatological Societies is working to improve community dermatologic programs in developing countries, focusing on better diagnosis and clear evidencebased guidance for the management of common dermatoses. Training courses have been established, such
as those at the Regional Dermatology Training Centre
in Moshi, Tanzania (http://www.global-campus.org/
rdtc) and short courses in Guerrero, Mexico, and Mali.
One of the key aims of these programs is to educate at
the primary care level, with the idea that the trainees
will then multiply such knowledge by training others in their own countries. As Weinstock points out in
Chapter 1, the burden of skin diseases is high. Many
skin diseases such as infections, cancer, and atopic
eczema can already benefit from a public health
approach. What is needed to redress the relative paucity of public health dermatology is to understand the
concept that populations are as important as individuals and to build on the sort of collaboration championed by the International Foundation for Dermatology.
25
Approach to Dermatologic Diagnosis
Chapter 5 :: S
tructure of Skin Lesions and
Fundamentals of Clinical Diagnosis

:: Amit Garg, Nikki A. Levin, & Jeffrey D. Bernhard
You see, but you do not observe
Holmes to Watson in Scandal in Bohemia,
by Arthur Conan Doyle, 1892
SKIN LESIONS AND DIAGNOSIS

AT A GLANCE
A patient and thorough approach to the
evaluation decreases the risk of making an
incorrect diagnosis or overlooking another
diagnosis.
Knowledge and appropriate use of
dermatological terminology are fundamental.
Recognition of disease patterns requires
repeated patient encounters.
The history is indispensable in elucidating
complex diagnoses.
The entire mucocutaneous surface, as well
as the hair and nails, should be examined
whenever reasonable.
Morphologic characteristics derived
from cell type in skin must be carefully
scrutinized.
Diseases have characteristic morphology and
distribution.
Common pitfalls in dermatologic diagnosis
exist and can be avoided.
THE ART AND SCIENCE OF

DERMATOLOGIC DIAGNOSIS
The diagnosis and treatment of diseases that affect
the skin rest on the physicians ability to use the lan-
guage of dermatology, to recognize the primary and

sequential lesions of the skin, and to recognize the
various patterns in which they occur. In this chapter,
we discuss a fundamental approach to the patient
presenting with a skin problem. We introduce the
technical vocabulary of dermatologic description, the
dermatology lexicon. It is important to know and
use this standard terminology, as it is the first step
in generating a differential diagnosis. Once a lesion
has been described as a pearly, flesh-colored, telangiectatic, ulcerated nodule, the experienced physician
puts basal cell carcinoma at the top of the differential
diagnosis. It is also important to use standard dermatologic terminology for consistency in clinical documentation, in research, and in communication with
other physicians.
The process of examining and describing skin
lesions may be likened to that of viewing a painting.
First, one stands back and takes in the whole canvas,
viewing the patient from a few feet away, at which
distance an overall assessment of the patients general
and cutaneous health may be made. One may note
such findings as skin color and turgor, presence of pallor or jaundice, degree of sun damage, and the overall
number and location of lesions. Next, one looks more
closely at the trees or mountains that make up the
landscape, describing and categorizing the specific
lesions on the patient. Finally, one may closely examine the details of the canvas, taking in the texture and
brush-strokes, using magnification to see the borders
of a nevus or compressing a lesion to see if it blanches.
Just as a knowledgeable viewer of art may recognize
a work of Georges Seurat by its tiny, dot-like brush
strokes, an experienced observer of the skin can recognize a melanoma by its asymmetry, irregular borders,
and multiple colors.
APPROACH TO THE PATIENT

HISTORY
Dermatology is a visual specialty and some skin
lesions may be diagnosed at a glance. Nonetheless, the
history is important and in complex cases, such as the
patient with rash and fever or the patient with generalized pruritus, history may be crucial. Dermatologists
vary in whether they prefer to take a history prior to,
during, or after performing a physical examination. In
practice, many take a brief history, perform a physical
examination, then undertake more detailed questioning based on the differential diagnosis that the examination suggests.
For the following reasons, it is often useful to at least
briefly examine the patient before taking a lengthy history:

EXAMINATION OF THE
DERMATOLOGIC PATIENT
SCOPE OF THE COMPLETE CUTANEOUS
EXAMINATION. The complete cutaneous exami-
nation includes inspection of the entire skin surface,

including often-overlooked areas such as the scalp,
eyelids, ears, genitals, buttocks, perineal area, and
interdigital spaces; the hair; the nails; and the mucus
membranes of the mouth, eyes, anus, and genitals. In
routine clinical practice, not all of these areas are examined unless there is a specific reason to do so, such as
a history of melanoma or a particular localizing complaint. A guide to performing the physical examination
of the patient presenting with a skin problem is presented in Box 5-2.
Identification of potentially harmful lesions (e.g.,

skin cancers) of which the patient is unaware; any
patient with a history of skin cancer or a chief
complaint of a new growth deserves a full skin
examination.
Identification of benign lesions (e.g., seborrheic
keratoses, angiokeratomas) that the patient was
concerned about but reluctant to mention, thereby
enabling the physician to provide reassurance.
Finding hidden clues to diagnosis (e.g., scabies
lesions on the penis, psoriatic plaques on the buttocks, Wickham striae of lichen planus on the buccal
mucosa, nail pitting in alopecia areata).
Opportunity for patient education (e.g., lentigines
are a sign of sun damage and suggest the need for
improved sun protection).
Opportunity to convey the physicians concern about
the patients skin health as a whole. Patients appreciate this and also regard the physician as thorough.
BARRIERS TO PERFORMING A COMPLETE

SKIN EXAMINATION. Despite the advantages
of performing a full cutaneous examination, numerous barriers exist that may prevent the dermatologist
from performing such an evaluation for every patient.
Understandably, patients may decline a full examination when their chief complaint is relatively minor or
localized, such as a wart or acne. In other cases, patients
may express resistance to disrobing for a full examination due to embarrassment, especially when the physician is of the opposite gender. Sometimes the physician
is uncomfortable performing a complete skin examination with the concern that a patient may misinterpret
the examination as improper. In many instances, time
constraints and lack of personnel to serve as chaperones limit the ability to perform full skin examination.
IDEAL CONDITIONS FOR THE COMPLETE

SKIN EXAMINATION. A complete skin examina-
tion is most effective when performed under ideal conditions. It is most important to have excellent lighting,
preferably bright, even light that simulates the solar
spectrum. Without good lighting, subtle but important details may be missed. The patient should be fully
undressed, wearing only a gown that is easily moved
aside, with a sheet over the legs, if desired. Underwear,
socks, and shoes should be removed, as should any
makeup or eyeglasses. The examining table should
be at a comfortable height, with a head that reclines,
an extendable footrest, and gynecologic stirrups. The
examining room should be at a comfortable temperature for the lightly dressed patient. It should contain a
sink for hand washing and disinfecting hand foam, as
patients are reassured by seeing their physician wash
hands before the examination. If the patient and physician are of opposite genders, having a chaperone in
Structure of Skin Lesions and Fundamentals of Clinical Diagnosis
In taking a history from a patient presenting with a

new skin complaint, the physicians primary goal is to
establish a diagnosis, with a secondary goal of evaluating the patient as a candidate for therapy. In patients
whose diagnosis is already established, the physicians
goals are to reevaluate the original diagnosis, monitor
disease progress and complications, and modify treatment accordingly.
Box 5-1 presents a suggested approach to obtaining
the history in a patient presenting with a skin problem.
Clearly, not all of the questions are necessary for every
patient. The physician will need to tailor the history
depending on whether the chief complaint is a growth
or an eruption, a nail or hair disorder, or another condition, and whether it is a new problem or a follow-up
visit for an ongoing condition.
it is not always essential or practical to perform a complete skin examination, there are many advantages to
doing so, especially for new patients and challenging
cases:
::
Chapter 5
Certain skin conditions, such as classic plaquetype psoriasis or molluscum contagiosum, for
example, present with such distinctive morphologies that the diagnosis may be immediately
obvious, rendering extensive history taking
unnecessary.
A patients history may contain red herrings,
which lead the physician away from, rather
than toward, the correct diagnosis. Examination
of the patient before taking a history may yield
a more complete and unbiased differential
diagnosis.
In certain situations, such as the evaluation of
alopecia, initial examination of the patient to determine what type of hair loss is present allows the
physician to pursue a line of questions pertinent to
that type of alopecia.
ADVANTAGES TO PERFORMING A COMPLETE CUTANEOUS EXAMINATION. Although
27
BOX 5-1 History Taking in Dermatologic Diagnosis
Section 2
CHIEF COMPLAINT AND HISTORY OF THE PRESENT ILLNESS

Duration: When the condition was first noted and dates of any recurrences or remissions
Periodicity: For example, constant, waxing and waning, worst at night, worst in winter
Evolution: How the condition has spread or developed over time; often useful to ask patient whether lesion always
looked this way, or if not, how it looked when it first started
Location: Where lesions were first noted and how they have spread, if applicable
Symptoms: For example, pruritus, pain, bleeding, nonhealing, change of preexisting moles
Severity: Especially for painful or pruritic conditions, it can be useful to ask patient to rate severity on a ten-point
scale in order to follow severity over time
Ameliorating and Exacerbating Factors: Relation to sun exposure, heat, cold, wind, trauma, and exposure to chemicals, topical products, plants, perfumes or metals, relation to menses or pregnancy
Preceding illness, new medications, new topical products, or exposures
Therapies tried, including over-the-counter or home remedies, and response to therapy
Prior similar problems, prior diagnosis, results of biopsies or other studies performed
::
PAST MEDICAL HISTORY

A history of all chronic illnesses, particularly those that may manifest in the skin, (diabetes, renal and hepatic disease,
infection with HIV or hepatitis viruses, polycystic ovarian syndrome, lupus, thyroid disease) and those that are associated with skin disease (asthma, allergies)
History of surgical procedures, including organ transplantation and bariatric surgery
Immunosuppression: Either iatrogenic, infectious, genetic
Pregnancies
Psychiatric disease
History of blistering sunburns, exposure to arsenic or ionizing radiation
Medication History: A detailed history with particular attention to those medications started recently
Prescription
Over-the-counter medications
Vitamins and dietary supplements
Herbal remedies
Allergies: To medications, foods, environmental antigens, and contactants
Social History: Occupation, hobbies and leisure activities, alcohol and tobacco use, illicit drug use, sexual history
(including high-risk activities for sexually transmitted diseases), dietary history, bathing habits, pets, living conditions (e.g., alone, with family, homeless, in an institution), history of travel or residence in endemic areas for infectious diseases, ethnicity, religious practices
Family History: Of skin disease, atopy (atopic dermatitis, asthma, hay fever) or skin cancer
Review of Systems: Constitutional symptoms (fatigue, weight loss, fever, chills, night sweats), acute illness symptoms (headache, photophobia, stiff neck, nausea, vomiting, cough, rhinorrhea, sneezing, myalgias, arthralgias),
symptoms of conditions such as hypothyroidism (cold intolerance, weight gain, constipation) or psoriatic arthritis
(joint pain, swelling and stiffness), which may accompany a dermatologic condition
the room can make the examination more comfortable

for both.
RECOMMENDED TOOLS FOR THE COMPLETE SKIN EXAMINATION. Although the phy-
sicians eyes and hands are the only essential tools for
examination of the skin, the following are often useful
and highly recommended:

28
A magnifying tool such as a loupe, magnifying

glass, and/or dermatoscope.
A bright focused light such as a flashlight or penlight to sidelight lesions.
Glass slides or a hand magnifier for diascopy.
Alcohol pads to remove scale or surface oil.

Gauze pads or tissues with water for removing
makeup.
Gloves to be used for examination when scabies
or another highly infectious condition (secondary syphilis) is suspected, when examining mucus
membranes, and vulvar and genital areas, and
when performing any procedure.
A ruler for measuring lesions.
Number 15 and number 11 scalpel blades for scraping and incising lesions, respectively.
A camera for photographic documentation.
A Woods lamp (365 nm) for highlighting subtle
pigmentary changes.
BOX 5-2 Physical Examination in Dermatologic Diagnosis
GENERAL IMPRESSION OF THE PATIENT

Well or ill
Obese, cachectic, or normal weight
Skin Color: Degree of pigmentation, pallor (anemia), carotenemia, jaundice
Skin Temperature: For example, warm, cool, and clammy
Skin Surface Characteristics: Xerosis (dryness), seborrhea (excessive oil), turgor, hyper- or hypohidrosis (excessive
or decreased sweating), and texture
Degree of Photoaging: Lentigines, actinic purpura, rhytides
PRIMARY LESIONS
Superficial (e.g., scaly, rough, smooth)

Deep (e.g., firm, rubbery, mobile)
ASPECTS OF GENERAL PHYSICAL EXAMINATION THAT MAY BE HELPFUL

Vital signs
Abdominal examination for hepatosplenomegaly
Pulses
Lymph node examination (especially in cases of suspected infection and malignancy)
TECHNIQUE OF THE DERMATOLOGIC

PHYSICAL EXAMINATION. Just as there is no one
correct way to perform a general physical examination,

each physician approaches the complete skin examination with his or her own style. A common thread to
effective styles of skin examination is consistency in the
order of examining different body areas to ensure that
no areas are overlooked. One approach to the complete
skin examination is presented here. First, observe the
patient at a distance for general impressions (e.g., asymmetry due to a stroke, obesity, pallor, fatigue, jaundice).
Next, examine the patient in a systematic way, usually from head to toe, uncovering one area at a time to
preserve patient modesty. Move the patient (e.g., from
sitting to lying) and the illumination as needed for the
best view of each body area. Palpate growths to determine whether they are soft, fleshy, firm, tender, or fluidfilled. Use of the hands to stretch the skin is especially
useful in diagnosis of basal cell carcinoma, in which
stretching skin reveals a pearly quality often not seen
on routine inspection. A magnifier worn on the head
leaves both hands free for palpation of lesions. Certain lesions, such as porokeratosis, are best examined
with side lighting that reveals depth and the details of
borders. During the examination, patients often find
it reassuring for the physician to name and demystify
benign lesions as they are encountered.
Special examination techniques for hair disorders
are discussed in Chapter 88; these include having the
patient sit in a chair so that the entire scalp is easily

examined, parting the patients hair at the front and
occiput, and gently tugging on hairs to determine the
fraction of loose (telogen) hairs. Examination of the
nails is discussed in Chapter 89.
After completing the examination, it is important
to document the skin findings, including the type of
lesions and their locations, either descriptively or on
a body map. Careful documentation is particularly
important for suspicious lesions that are to be biopsied, so that the exact location may be found and
definitively treated at a later date. Instant or digital
photography is a useful adjunct for documentation.
PALPATION
::
Define their type (e.g., papule, plaque, bulla)

Describe their shape (e.g., arcuate, annular, linear)
Describe any secondary changes (e.g., crusting, excoriations)
Chapter 5
Describe the Distribution of Lesions: Localized (isolated), grouped, regional, generalized, universal, symmetrical, sunexposed, flexural, extensor extremities, acral, intertriginous, dermatomal, follicular
INTRODUCTION TO MORPHOLOGY
Siemens (18911969) wrote, he who studies skin diseases and fails to study the lesion first will never learn
dermatology. His statement reinforces the notion that
the primary skin lesion, or the evolution thereof, is the
essential element on which clinical diagnosis rests.
Joseph Jakob von Plencks (17381807) and Robert
Willans (17571812) work in defining basic morphologic terminology have laid the foundation for the
description and comparison of fundamental lesions,
thereby facilitating characterization and recognition of
skin disease as, Wolff and Johnson state, to read words,
one must recognize letters; to read the skin, one must
29
Section 2
::
recognize the basic lesions. To understand a paragraph, one must know how words are put together; to
arrive at a differential diagnosis, one must know what
the basic lesions represent, how they evolve, and how
they are arranged and distributed.
Variation and ambiguity in the morphologic terms
generally accepted by the international dermatology
community have engendered barriers to communication among physicians of all disciplines, including dermatologists. In dermatologic textbooks, the papule, for
example, has been described as no greater than 1 cm
in size, less than 0.5 cm, or ranging from the size of a
pinhead to that of a split pea. Thus, in forming a mental image of a lesion or eruption after hearing its morphologic description, physicians sometimes remain
irresolute. The mission of the Dermatology Lexicon
Project has been to create a universally accepted and
comprehensive glossary of descriptive terms to support research, medical informatics, and patient care.
Morphologic definitions in this chapter parallel and
amplify those of the Dermatology Lexicon Project.
Table 5-1 contains a summary of the lesions discussed.
RAISED LESIONS
PAPULE.
A papule is a solid, elevated lesion less

than 0.5 cm in size in which a significant portion projects above the plane of the surrounding skin. Papules
surmounted with scale are referred to as papulosquamous lesions. Sessile, pedunculated, dome-shaped, flattopped, rough, smooth, filiform, mammillated, acuminate, and umbilicated constitute some common shapes
and surfaces of papules. A clinical example is lichen planus (Fig. 5-1; see Chapter 26).
PLAQUE. A plaque is a solid plateau-like elevation

that occupies a relatively large surface area in comparison with its height above the normal skin level and has
a diameter larger than 0.5 cm. Plaques are further characterized by their size, shape, color, and surface change.
A clinical example is psoriasis (Fig. 5-2; see Chapter 18).
NODULE. A nodule is a solid, round or ellipsoidal,
palpable lesion that has a diameter larger than 0.5 cm.
However, size is not the major consideration in the
Figure 5-1 Papule. Multiple, well-defined papules of

varying sizes are seen. Flat tops and glistening surface are
characteristic of lichen planus.
definition of nodule. Depth of involvement and/or
substantive palpability, rather than diameter, differentiates a nodule from a large papule or plaque. Depending on the anatomic component(s) primarily involved,
nodules are of five main types: (1) epidermal, (2) epidermaldermal, (3) dermal, (4) dermalsubdermal, and
(5) subcutaneous. Some additional features of a nodule
that may help reveal a diagnosis include whether it is
warm, hard, soft, fluctuant, movable, fixed, or painful. Similarly, different surfaces of nodules, such as
smooth, keratotic, ulcerated, or fungating, also help
direct diagnostic considerations. A clinical example of
a nodule is nodular basal cell carcinoma (Fig. 5-3; see
Chapter 115).
Tumor, also sometimes included under the heading
of nodule, is a general term for any mass, benign or
malignant. A gumma is, specifically, the granulomatous
nodular lesion of tertiary syphilis.
CYST. A cyst is an encapsulated cavity or sac lined

with a true epithelium that contains fluid or semi-
TABLE 5-1
The Lesions of the Skin
30
Raised
Depressed
Flat
Surface Change
Fluid Filled
Vascular
Papule
Plaque
Nodule
Cyst
Wheal
Scar
Comedo
Horn
Calcinosis
Erosion
Ulcer
Atrophy
Poikiloderma
Sinus
Striae
Burrow
Sclerosis
Macule
Patch
Erythema
Erythroderma
Scale
Crust
Excoriation
Fissure
Lichenification
Keratoderma
Eschar
Vesicle
Bulla
Pustule
Furuncle
Abscess
Purpura
Telangiectasia
Infarct
Chapter 5
Figure 5-2 Plaque. Well-demarcated pink plaques with a

silvery scale representing psoriasis vulgaris.
::
WHEAL. A wheal is a swelling of the skin that is characteristically evanescent, disappearing within hours.
These lesions, also known as hives or urticaria, are the
result of edema produced by the escape of plasma
through vessel walls in the upper portion of the dermis. Wheals may be tiny papules or giant plaques, and
they may take the form of various shapes (round, oval,
serpiginous, or annular), often in the same patient.
Borders of a wheal, although sharp, are not stable and
in fact move from involved to adjacent uninvolved
areas over a period of hours. The flare, or ring of pink
erythema, of a wheal may be intense if superficial vessels are dilated. If the amount of edema is sufficient
to compress superficial vessels, wheals may in fact be
white in the center or around the periphery, producing
a zone of pallor. With associated inflammatory disruption of the vessels walls, wheals may have a deeper
red color, may be purpuric, and are more persistent.
Figure 5-3 Nodule. A nodular basal cell carcinoma

with well-defined, firm nodule with a glistening surface
through which telangiectasia can be seen.
Figure 5-4 Cyst. A bluish colored resilient cyst filled with a

mucous-like material on the cheek is cystic hidradenoma.
A clinical example is dermatographism (Fig. 5-5; see
Chapter 38).
Angioedema is a deeper, edematous reaction that
occurs in areas with very loose dermis and subcutaneous tissue such as the lip, eyelid, or scrotum. It may
occur on the hands and feet as well, and result in grotesque deformity.
SCAR. A scar arises from proliferation of fibrous tissue that replaces previously normal collagen after a
wound or ulceration breaches the reticular dermis.
Scars have a deeper pink to red color early on before
becoming hypo- or hyperpigmented. In most scars, the
epidermis is thinned and imparts a wrinkled appearance at the surface. Adnexal structures, such as hair
Figure 5-5 Wheal. A sharply demarcated wheal with a

surrounding erythematous flare occurring within seconds
of the skin being stroked.
solid material (cells and cell products such as keratin).

Its spherical or oval shape results from the tendency
of the contents to spread equally in all directions.
Depending on the nature of the contents, cysts may be
hard, doughy, or fluctuant. A clinical example is a cystic hidradenoma (Fig. 5-4; see Chapter 119).
31
CALCINOSIS. Deposits of calcium in the dermis or

subcutaneous tissue may be appreciated as hard, whitish nodules or plaques, with or without visible alteration of the skins surface. A clinical example is cutaneous calcinosis in dermatomyositis (see eFig. 5-6.2 in
online edition; see Chapter 156).
DEPRESSED LESIONS
Section 2
Figure 5-6 Comedo. Open and closed comedones on the

face of this patient with acne.
::
32
follicles, normally present in the dermis are absent.

Hypertrophic scars typically take the form of firm papules, plaques, or nodules. Keloid scars are also elevated.
Unlike hypertrophic scars (see eFig. 5-5.1 in online edition; see Chapter 66), keloids exceed, with web-like
extensions, the area of initial wounding. Atrophic scars
are thin depressed plaques.
COMEDO. A comedo is a hair follicle infundibulum that is dilated and plugged by keratin and lipids.
When the pilosebaceous unit is open to the surface of
the skin with a visible keratinaceous plug, the lesion
is referred to as an open comedo. The black color of the
comedo is due to the oxidized sebaceous content of the
infundibulum (blackhead). A closed infundibulum
in which the follicular opening is unapparent accumulates whitish keratin and is called a closed comedo. A
clinical example is comedonal acne (Fig. 5-6; see Chapter 80).
EROSION. An erosion is a moist, circumscribed,

depressed lesion that results from loss of a portion
or all of the viable epidermal or mucosal epithelium.
The defect extending to the most superficial part of
the dermis may result in pinpoint bleeding in a sievelike fashion. Erosions may result from trauma, detachment of epidermal layers with maceration, rupture of
vesicles or bullae, or epidermal necrosis, for example.
Unless they become secondarily infected, erosions do
not scar. A clinical example is toxic epidermal necrolysis (Fig. 5-7; see Chapter 40).
ULCERS. An ulcer is a defect in which the epidermis
and at least the upper (papillary) dermis have been
destroyed. Breach of the dermis and destruction of
adnexal structures impede reepithelialization, and
the defect heals with scarring. Borders of the ulcer
may be rolled, undermined, punched out, jagged, or
angular. The base may be clean, ragged, or necrotic.
Discharge may be purulent, granular, or malodorous.
Surrounding skin may be red, purple, pigmented,
reticulated, indurated, sclerotic, or infarcted. A clinical example is pyoderma gangrenosum (Fig. 5-8; see
Chapter 33).
HORN. A horn is a hyperkeratotic conical mass of

cornified cells arising over an abnormally differentiating epidermis. A clinical example is verruca vulgaris
(see eFig. 5-6.1 in online edition; see Chapter 196).
ATROPHY. Atrophy refers to a diminution in the size

of a cell, tissue, organ, or part of the body. An atrophic
epidermis is glossy, almost transparent, paper thin and
wrinkled, and may not retain normal skin lines. Atrophy of the papillary or reticular dermal connective tissue manifests as a depression of the skin. Atrophy of
the panniculus results in a more substantial depression
of the skin. eFig. 5-8.1 in online edition shows aged
skin of the arm in an elderly woman (see Chapter 109).
Figure 5-7 Erosion. Sloughing of the skin in this patient

with toxic epidermal necrolysis leaves behind a large
erosion.
Figure 5-8 Ulcer. A large ulcer with a ragged base and

heaped-up pink erythematous border on the leg representing progressing pyoderma gangrenosum.
POIKILODERMA. As
a morphologic term, poikiloderma refers to the combination of atrophy, telangiectasia, and varied pigmentary changes (hyper- and hypo-)
over an area of skin. This combination of features may
give rise to a dappled appearance to the skin. A clinical
example is chronic radiodermatitis (see eFig. 5-8.2 in
online edition).
SINUS. A sinus is a tract connecting deep suppurative cavities to each other or to the surface of the skin.
A clinical example is hidradenitis suppurativa (see
eFig. 5-8.3 in online edition; see Chapter 85).
FLAT AND MACULAR LESIONS

MACULE. A macule is flat, even with the surface
level of surrounding skin, and perceptible only as an
area of color different from the surrounding skin or
mucous membrane. Maculosquamous is a neologism
invented to describe macules with fine nonpalpable
scaling, which may become apparent only after light
scraping and scratching.
Perhaps the most important additional feature
of a lesion other than primary morphology is color.
Lesional color, which is often the first visual assessment made, is reliably reproducible with particular
types of pathologies, such as destruction of melanocytes, dilatation of dermal blood vessels, or inflammation of vessel walls with extravasation of red blood
cells. As such, color provides meaningful insight into
pathologic processes of the skin and facilitates clinical
diagnosis. Pigmentary changes represent an important
and common type of macular color change and may
be described as hyperpigmented (as in postinflammatory hyperpigmentation), hypopigmented (as in tinea
versicolor), or depigmented (as in vitiligo).
Table 5-2 describes characteristic colors that may be
noted with inspection of altered skin. A clinical example is lentigo (Fig. 5-9; see Chapter 122).
PATCH. A patch is similar to a macule; it is a flat area
of skin or mucous membranes with a different color
from its surrounding. However, a patch is larger than
ERYTHEMA. Erythema represents the blanchable

pink to red color of skin or mucous membrane that
is due to dilatation of arteries and veins in the papillary and reticular dermis. It exists in different colors,
and to dub a primary lesion as erythematous alone is
incomplete. Describing erythema with the color it
most closely resembles provides a meaningful clue to
diagnosis. For example, violaceous erythema brings to
mind a differential distinct from salmon pink-colored
erythema, even if both types of erythema involve papules. A clinical example is dusky erythema, as may be
seen in a fixed drug eruption (see eFig. 5-10.1 in online
edition; see Chapter 41).
ERYTHRODERMA. Erythroderma is a generalized
deep redness of the skin involving more than 90% of
the body surface within days to weeks. Type of scaling
Figure 5-10 Patch. Depigmented patches within areas of

normal skin tone representing vitiligo.
SCLEROSIS. Sclerosis refers to a circumscribed or diffuse hardening or induration of the skin that results
from dermal fibrosis. It is detected more easily by palpation, on which the skin may feel board-like, immobile, and difficult to pick up. A clinical example is morphea (see eFig. 5-8.6 in online edition; see Chapter 64).
0.5 cm, and it may have a fine, very thin scale. Clinical
examples include vitiligo, where the term patch may
be used to describe larger macules or a patchy configuration (Fig. 5-10; see Chapter 74), and also cutaneous T-cell lymphoma, where early lesions may be thin
slightly scaly patches.
::
BURROW. A burrow is a wavy, threadlike tunnel

through the outer portion of the epidermis excavated
by a parasite. A clinical example is scabetic burrow (see
Figure 5-9 Macule. Uniform-colored brown macule with

slightly irregular, sharply defined borders representing a
lentigo on the lip.
Chapter 5
STRIAE. Striae are linear depressions of the skin that

usually measure several centimeters in length and
result from changes to the reticular collagen that occur
with rapid stretching of the skin. A clinical example is
striae distensae (see eFig. 5-8.4 in online edition; see
Chapter 108).
33
TABLE 5-2
Implications of Color Changes in Altered Skin

Color
Section 2
Diagnostic Consideration
Apple jelly
Granulomatous inflammation
Tuberculosis, sarcoidosis, leishmaniasis
Black
Melanin, necrosis
Melanoma, purpura fulminans, calciphylaxis
Blue
Deep dermal pigment, reduced hemoglobin, tattoo,

medication
Blue nevus, amiodarone
Brown
Melanin, hemosiderin, chronic inflammation,

postinflammatory, dried serum
Nevus, melasma
Copper
Inflammation with plasma cells
Secondary syphilis
Green
Deep hemosiderin, pyocyanin pigment, tissue

eosinophilia
Pseudomonas infection, tattoo, Wells syndrome
Gray
Deep melanin or other pigment deposition
Chloroquine toxicity, Mongolian spot, erythema

dyschromicum perstans
Lilac
Inflammation, dilatation of deep dermal blood vessels
Borders of evolving morphea, dermatomyositis
Orange
Granulomatous inflammation with histiocytes having

abundant cytoplasm
Juvenile xanthogranuloma
Pearly
Epidermal proliferation without surface keratin
Basal cell carcinoma
Pink
Acute inflammation, dilatation of superficial dermal

blood vessels, hemorrhage
Eczema
Red
Hemorrhage, acute inflammation, dilatation of blood

vessels
Psoriasis, drug eruptions
Salmon pink
Inflammation with involvement of epidermis, dilatation

of blood vessels inflammation with edema
Pityriasis rubra pilaris, psoriasis, urticaria
Violet
Hemorrhage, deep hemosiderin, lichenoid inflammation
Lichen planus, Kaposi sarcoma
White
Reduced or absent melanin synthesis,

postinflammatory
Tinea versicolor, albinism, vitiligo
Yellow
Superficial Staphylococcus or Streptococcus infection

mixed with keratinized cells, carotenoids, hemosiderin,
bile pigment, accumulated lipid
Impetigo, xanthomas, sebaceous hyperplasia,

necrobiosis lipoidica diabeticorum, jaundice
::
Pathology
or desquamation, which follows establishment of the

generalized erythema, noted is suggestive of the primary process (Table 5-3). A clinical example is Szary
syndrome (see eFig. 5-10.2 in online edition; see Chapters 23 and 145).
SURFACE CHANGE
34
SCALE, DESQUAMATION (SCALING). A scale

is flat plate or flake arising from the outermost layer
of the stratum corneum. Groups of coherent cornified cells packed with filamentous proteins desquamate in scales imperceptibly from the skins surface under normal circumstances on a regular basis
as the epidermis is replaced completely every 27
days. When epidermal differentiation is disordered,
accumulation and casting of stratum corneum
become apparent as scale that ranges in size from
fine dust-like particles to extensive parchment-like
sheets. In some cases, scale is observed only after
scratching the lesion, a phenomenon known as latent
desquamation. Scaly lesions are often described as

hyperkeratotic, a term that is used both clinically
and histopathologically.
Not all scales are similar, and the expert dermatologist with a well-trained eye can obtain diagnostically
useful information from close examinations of the type
of scale present. Table 5-3 describes the types of scale
one may encounter. A clinical example is psoriasis vulgaris (Fig. 5-11; see Chapter 18).
HYPERKERATOSIS. Leider and Rosenblum define

hyperkeratosis as excessive cornification. Siemens
states that the stratum corneum may be thinned
or thickened. In the latter, thickening may consist
of normal keratin (hyperkeratosis) or of an abnormal keratin in which the cellular nuclei are retained
and are stainable (parakeratosis). Different types of
hyperkeratosis can be discerned histopathologically,
but in clinical parlance hyperkeratosis refers to an
excessive or thickened stratum corneum, often but
not always scaly.
TABLE 5-3
Types of Scale
Type of Scale
Crack-like/craquel
Desquamation giving the appearance of dried, cracked skin.
Eczema craquel
Exfoliative
Scales split of from the epidermis in finer scales or in sheets.
Drug reaction
Follicular
Scales appear as keratotic plugs, spines, or filaments.
Keratosis pilaris
Gritty
Densely adherent scale with a sandpaper texture.
Actinic keratosis
Ichthyosiform
Scales are regular polygonal plates arranged in parallel rows or

diamond patterns (fish-like, tesselated).
Ichthyosis vulgaris
Keratotic/hyperkeratotic
Scales appear as heaped-up column of scale.
Cutaneous horn
Lamellar
Scales are thin large plates or shields attached in the middle and
looser around the edges.
Lamellar ichthyosis
Pityriasiform
Scale is small and branny.
Pityriasis rosea
Psoriasiform (micaceous
and ostraceous)
Scale is silvery and brittle and forms thin platelets in several loose
sheets, like mica (micaceous scale). Large scales may accumulate in
heaps, giving the appearance of an oyster shell (ostraceous scale).
Psoriasis vulgaris
Seborrheic
Scales are thick, waxy or greasy, yellow-to-brown, flakes.
Wickham striae
Scale appears as a lacy white pattern overlying violaceous flat-topped

papules.
Lichen planus
::
Prototype Diagnosis
Chapter 5
Description
EXCORIATIONS. Excoriations (see eFig. 5-12.1 in

online edition) are surface excavations of epidermis
that result from scratching.
FISSURE. A fissure is a linear loss of continuity of
the skins surface or mucosa that results from excessive tension or decreased elasticity of the involved tissue. Fissures frequently occur on the palms and soles
where the thick stratum corneum is least expandable.
A clinical example is fissure on the palm associated
with contact dermatitis (see eFig. 5-12.2 in online edition; see Chapter 13).
LICHENIFICATION. Repeated rubbing of the skin
may induce a reactive thickening of the epidermis,
with changes in the collagen of the underlying superficial dermis. These changes produce a thickened skin
Figure 5-11 Scale. Brittle silvery scales forming thin platelets in several loose sheets, like mica, on this plaque of psoriasis.
Figure 5-12 Crust. Glistening, honey-colored, delicate

crusts under the nose representing impetigo.
CRUSTS (ENCRUSTED EXUDATES). Crusts are

hardened deposits that result when serum, blood, or
purulent exudate dries on the surface of the skin. The
color of crust is a yellow-brown when formed from
dried serous secretion; turbid yellowish-green when
formed from purulent secretion; and reddish-black
when formed from hemorrhagic secretion. Removal of
the crust may reveal an underlying erosion or ulcer. A
clinical example is impetigo (Fig. 5-12; see Chapter 176).
35
A clinical example of vesicle is the blistering aspect of

impetigo caused by toxin-producing staphylococci (Fig.
5-14A; see Chapter 177). A clinical example of bulla is a
bullous pemphigoid (Fig. 5-14B; see Chapter 56).
PUSTULE. A pustule is a circumscribed, raised cavity in the epidermis or infundibulum containing pus.
The purulent exudate, composed of leukocytes with
Section 2
::
Figure 5-13 Lichenification. An area of thickened skin

with accentuated skin markings induced by repeated
rubbing, representing lichenification noted in lichen
simplex chronicus.
A
with accentuated markings, which may resemble tree

bark. A clinical example is lichen simplex chronicus
(Fig. 5-13; see Chapter 15).
KERATODERMA. Keratoderma is an excessive

accumulation of scale (hyperkeratosis) that results in a
yellowish thickening of the skin, usually on the palms
or soles, that may be inherited (abnormal keratin formation) or acquired (mechanical stimulation). A clinical example is plantar keratoderma in psoriasis (see
ESCHAR. The presence of an eschar implies tissue
necrosis, infarction, deep burns, gangrene, or other ulcerating process. It is a circumscribed, adherent, hard, black
crust on the surface of the skin that is moist initially, protein rich, and avascular. A clinical example is thermal
burn (see eFig. 5-13.2 in online edition; see Chapter 95).
FLUID-FILLED LESIONS
36
VESICLE AND BULLA. A vesicle is a fluid-filled cavity or elevation smaller than or equal to 0.5 cm, whereas
a bulla (blister) measures larger than 0.5 cm. The fluid in
the cavity exerts equal pressure in all directions to give
rise to a spherical shape. Because of their size, bullae
are easily identifiable as tense or flaccid weepy blisters.
Clear, serous, hemorrhagic, or pus-filled contents may
be visualized when the cavity wall is thin and translucent enough. Vesicles and bullae arise from cleavage at
various levels of the epidermis (intraepidermal) or of
the dermalepidermal interface (subepidermal). The
amount of pressure required to collapse the lesion may
help predict whether the bulla is intraepidermal or subepidermal. However, reliable differentiation requires
histopathologic examination of the blister cavity edge.
Figure 5-14 Vesicle (A) and bulla (B). Fragile subcorneal

translucent vesicles representing impetigo caused by a
toxin-producing Staphylococcus (A) and large tense subepidermal bullae filled with serous or hemorrhagic fluid in
this patient with bullous pemphigoid (B).
Chapter 5
::
or without cellular debris, may contain bacteria or

may be sterile. Depending on its sterility, the exudate
may be white, yellow, or greenish-yellow in color. Pustules may vary in size and, in certain situations, may
coalesce to form lakes of pus. When associated with
hair follicles, pustules may appear conical and contain
a hair in the center. A clinical example is superficial
pyoderma (Fig. 5-15; see Chapter 176).
FURUNCLE. A furuncle (see eFig. 5-15.1 in online

edition; see Chapter 176) is a deep necrotizing folliculitis with suppuration. It presents as an inflamed follicle-centered nodule usually greater than 1 cm with a
central necrotic plug and an overlying pustule. Several
furuncles may coalesce to form a carbuncle.
ABSCESS. An abscess (see eFig. 5-15.2 in online edition; see Chapter 176) is a localized accumulation of
purulent material so deep in the dermis or subcutaneous tissue that the pus is usually not visible on the
surface of the skin. An abscess is a pink erythematous,
warm, tender, fluctuant nodule.
PURPURA/VASCULAR LESIONS
PURPURA. Extravasation of red blood from cutaneous vessels into skin or mucous membranes results in
reddish-purple lesions included under the term purpura. The application of pressure with two glass slides
or an unbreakable clear lens (diascopy) on a reddishpurple lesion is a simple and reliable method for differentiating redness due to vascular dilatation (erythema)
from redness due to extravasated erythrocytes or
erythrocyte products (purpura). If the redness is nonblanching under the pressure of the slide, the lesion is
purpuric. As extravasated red blood cells decompose
over time, the color of purpuric lesions change from
bluish-red to yellowish-brown or green.
Figure 5-16 Purpura. Nonblanching red erythematous

papules and plaques (palpable purpura) on the legs, representing leukocytoclastic vasculitis.
Petechiae are small, pinpoint purpuric macules. Ecchymoses are larger, bruise-like purpuric patches. These
lesions correspond to a noninflammatory extravasation
of blood. If a lesion is purpuric and palpable (palpable
purpura), the suggestion of an inflammatory insult to
the vessel wall as a cause of extravasation of blood and
inflammatory cells exists. A clinical example is leukocytoclastic vasculitis (Fig. 5-16; see Chapter 163).
TELANGIECTASIA. Telangiectasia (see eFig. 5-16.1

in online edition; see Chapter 174) are persistent dilatations of small capillaries in the superficial dermis that
are visible as fine, bright, nonpulsatile red lines or netlike patterns on the skin.
INFARCT. An infarct is an area of cutaneous necrosis
resulting from a bland or inflammatory occlusion of
blood vessels in the skin. A cutaneous infarct presents
as a tender, irregularly shaped dusky reddish-gray
macule or firm plaque that is sometimes depressed
slightly below the plane of the skin. A clinical example
is cholesterol emboli (Fig. 5-17; see Chapter 173).
Figure 5-15 Pustule. Two pustules representing superficial pyoderma.
SHAPE, ARRANGEMENT, AND

DISTRIBUTION OF LESIONS
Once the type or types of lesions have been identified, one needs to describe their shape, arrangement,
and pattern of distribution, all useful characteristics
in morphologic diagnosis. For example, a single scaly
plaque on a patients trunk may have a broad differential diagnosis, but the same plaques symmetrically
37
Section 2
::
Figure 5-17 Infarct. Dusky purple discoloration representing an area of infarction that eventuates in tissue necrosis. This patient had cholesterol emboli lodged in the
distal end arteries of the toes.
distributed on the elbows, knees, and umbilicus
would be highly suggestive of psoriasis. The following descriptions of shapes and arrangements of skin
lesions may be applied to single or multiple lesions.
For example, a single lesion may be linear or multiple
lesions may assume a linear pattern.
SHAPE OR CONFIGURATION
OF SKIN LESIONS

38
Annular (Fig. 5-18): Ring-shaped; implies that the

edge of the lesion differs from the center, either by
being raised, scaly, or differing in color (e.g., granuloma annulare, tinea corporis, erythema annulare
centrifugum).
Round/nummular/discoid (Fig. 5-19): Coin-shaped;
usually a round to oval lesion with uniform morphology from the edges to the center (e.g., nummular eczema, plaque-type psoriasis, discoid lupus).
Figure 5-18 Annular lesion. (Illustration by Glen Hintz,

MS. Dermatology Lexicon Project.)
Figure 5-19 Nummular lesion. (Illustration by Glen Hintz,


Polycyclic (see eFig. 5-19.1 in online edition): Formed

from coalescing circles, rings, or incomplete rings (e.g.,
urticaria, subacute cutaneous lupus erythematosus).
Arcuate (see eFig. 5-19.2 in online edition): Arc-shaped;
often a result of incomplete formation of an annular
lesion (e.g., urticaria, subacute cutaneous lupus
erythematosus).
Linear (see eFig. 5-19.3 in online edition): Resembling
a straight line; often implies an external contactant
or Koebner phenomenon has occurred in response
to scratching; may apply to a single lesion (e.g., a
scabies burrow, poison ivy dermatitis, or bleomycin
pigmentation) or to the arrangement of multiple
lesions (e.g., lichen nitidus or lichen planus).
Reticular (Fig. 5-20): Net-like or lacy in appearance,
with somewhat regularly spaced rings or partial
rings and sparing of intervening skin (e.g., livedo
reticularis, cutis marmorata).
Serpiginous (Fig. 5-21): Serpentine or snake-like
(e.g., cutaneous larva migrans, in which the larva
migrates this way and that through the skin in a
wandering pattern).
Figure 5-20 Reticular lesion. (Illustration by Glen Hintz,

erythematous base; also seen with certain arthropod

bites).
Scattered (see eFig. 5-23.1 in online edition): Irregularly
distributed.
DISTRIBUTIONS
OF MULTIPLE LESIONS
Grouped/herpetiform (Fig. 5-23): Lesions clustered

together (e.g., classic example is herpes simplex
virus 1 reactivation noted as grouped vesicles on an
Dermatomal/zosteriform: Unilateral and lying in the

distribution of a single spinal afferent nerve root; the
classic example is herpes zoster (see Chapter 194).
Blaschkoid (Fig. 5-24): Following lines of skin cell
migration during embryogenesis; generally longitudinally oriented on the limbs and circumferential on the trunk, but not perfectly linear (see also
Figure 5-22 Whorled: marbled appearance. (Illustration

by Glen Hintz, MS. Dermatology Lexicon Project.)
Figure 5-24 Lesions in the distribution described by

Blaschko for developmental lesions.
ARRANGEMENT
OF MULTIPLE LESIONS

Targetoid (see eFig. 5-21.1 in online edition): Targetlike, with at least three distinct zones (e.g., erythema
multiforme).
Whorled (Fig. 5-22): Like marble cake, with two
distinct colors interspersed in a wavy pattern;
usually seen in mosaic disorders in which cells of
differing genotypes are interspersed (e.g., incontinentia pigmenti, hypomelanosis of Ito, linear and
whorled nevoid hypermelanosis).
::
Figure 5-23 Grouped: clustered. (Illustration by Glen Hintz,

Chapter 5
Figure 5-21 Serpiginous lesion. (Illustration by Glen Hintz,

39
TABLE 5-4
Selection of Cutaneous Signsa

Cutaneous
Sign
Section 2
::
40
a
Description
Significance
Apple-jelly sign
A yellowish hue is produced from pressure on the lesion with

a glass slide.
Noted in granulomatous processes.
AsboeHansen
sign
Lateral extension of a blister with downward pressure.
Noted in blistering disorders in which the

pathology is above the basement membrane zone.
Auspitz sign
Pinpoint bleeding at the tops of ruptured capillaries with

forcible removal of outer scales from a psoriatic plaque.
Not entirely sensitive or specific for psoriasis.
Butterfly sign
Butterfly-shaped sparing from excoriations of the

nonreachable interscapular region.
Noted in disorders associated with pruritus

and implies that the physical findings are a
consequence of rubbing and scratching.
Buttonhole sign
A flesh-colored, soft papule feels as though it can be pushed

through a buttonhole into the skin.
Noted in a neurofibroma.
Carpet tack sign
Horny plugs at the undersurface of scale removed from a lesion.
Noted in lesions of chronic cutaneous lupus.
Crowe sign
Axillary freckling.
Noted in neurofibromatosis type I; may be seen

as part of lentiginosis profuse.
Darier sign
Urticarial wheal produced in a lesion after it is rubbed

with the rounded end of a pen. The wheal, which is strictly
confined to the borders of the lesion, may not appear for
several minutes.
Noted in urticaria pigmentosa and rarely with

cutaneous lymphoma or histiocytosis.
Dermatographism
Firmly stroking unaffected skin produces a wheal along the

shape of the stroke within seconds to minutes.
Symptomatic dermatographism represents a

physical urticaria.
Pseudo-Darier sign
Transient induration of a lesion or piloerection after rubbing.
Noted in congenital smooth muscle hamartoma.
Fitzpatrick (dimple)
sign
Dimpling of the skin with lateral compression of the lesion

with the thumb and index finger produces dimpling due to
tethering of the epidermis to the dermal lesion.
Characteristic of dermatofibroma.
Gottron sign
Raised or flat pink to violaceous erythema and/or papules of

metacarpal or interphalangeal joints, olecranon, patellae, or
malleoli.
Classically used in reference to dermatomyositis.
Hair collar
Ring of dark long scalp hair encircling a congenital lesion.
Associated with aplasia cutis, encephalocele,

meningocele, or heterotopic brain tissue.
Heliotrope sign
Violaceous erythema over eyelids.
Noted in dermatomyositis.
Hertoghe sign
Thinning or loss of the outer third of the eyebrow.
May be associated with atopic dermatitis,

hypothyroidism, systemic sclerosis.
Hutchinson nail
sign
Periungual extension of pigment to the proximal and lateral

nail folds.
Noted in subungual melanoma.
Hutchinson nose
sign
Vesicles on the tip of the nose in a patient with herpes zoster

of the face.
Due to the involvement of the nasociliary branch

of ophthalmic nerve (V1) and indicates a higher
likelihood of ocular disease.
LeserTrlat sign
Sudden eruption of inflammatory seborrheic keratoses-like

lesions.
Associated with systemic malignancy. Also

reported with benign neoplasms, eczema,
pregnancy, and leprosy.
Nikolsky sign
Lateral pressure on unblistered skin with resulting shearing of

the epidermis.
Noted in blistering disorders in which the

pathology is above the basement membrane
zone. Relevant entities include pemphigus
vulgaris and toxic epidermal necrolysis.
Oil drop sign
Area of yellowish discoloration resembling an oil drop involving

the nail bed distally (but not involving the free edge).
Indicates onycholysis noted in psoriatic nail

disease.
Russell sign
Abrasions, lacerations, callosities of metacarpal and proximal

interphalangeal joints.
Due to trauma from incisor teeth during selfinduced vomiting in bulimia.
Shawl sign
Erythema over upper back and shoulders.
Classically used in reference to dermatomyositis.
Trousseau sign
Recurrent migratory superficial thrombophlebitis of small and

large cutaneous veins.
Associated with internal malignancy (usually

pancreatic), Behet disease, rickettsial infections.
Ugly duckling sign
A pigmented lesion, among numerous atypical but clinically

benign nevi, that stands out from the rest and may be a
melanoma.
Helpful in screening numerous pigmented

lesions in a low-risk individual. Once the lesion
is distinguished from the others, it may be
evaluated further for abnormal clinical features.
Others are discussed in the chapters on diseases in which the signs occur.
TABLE 5-5
Ten Pointers and Pitfalls in Dermatologic Diagnosis

Approach each and every evaluation with patience and thoroughness.
Beware of snap, curbside, or doorway diagnoses.
Examine the entire mucocutaneous surface, as well as the hair and nails.
A new or changing mole should be carefully evaluated.
Do not remove tissue without sending a portion for histologic examination.
If the dermatopathologic findings are not consistent with the clinical impression, obtain another biopsy.
If forced to choose between incongruent clinical and pathologic impression, follow clinical lead (cautiously).
Generalized pruritus of more than 1 months duration mandates a complete systemic workup.
Seemingly nonspecific rashes may just be camouflaged specific disorders.
Drug-induced eruptions can mimic most skin conditions.
Be wary of the atypical diagnosis. Atypical this may be typical that to someone who has seen it before.
Consider all other reasonable possibilities before making a diagnosis of factitial disorder.
Table 5-4 describes some clinically relevant maneuvers

and morphologic signs that point to particular integumentary or systemic diseases.
As the late Thomas B. Fitzpatrick often said, dermatologists are physicians who can diagnose a rash! They may
also be internists, surgeons, biochemists, or immunologists; but without competency in dermatologic diagnosis they cannot qualify as dermatologists. However, this
skill is not specific to dermatologists. Any physician who
makes the effort to study the skin and learn the dermatologic lexicon can develop a functional appreciation of
the fundamentals of diagnosis. The advanced diagnostic
eye can only be acquired by endlessly repeated encounters in which the physician is forced not only to look at,
but also to observe, the rash while an experienced mentor
points the way. The most common error in dermatologic
diagnosis is to regard the lesions as nonspecific rashes
rather than as aggregates of specific individual lesions. As
in surveying a blood smear, a general impression is not
enough: The morphologic aspects of each individual cell
must be carefully scrutinized and judged to be normal or
abnormal. Too often, physicians adopt a speedy, superficial approach to the skin that they would not apply to any
other organ that they examine (Table 5-5).
Lewis Thomas has said that Medicine is no longer
the laying on of hands, it is more like the reading of
signals from machines. In dermatology, there can be
no replacement for the laying on of hands, and the
physician is repeatedly gratified by reading signals not
from machines, but from people.
Bilateral symmetric: Occurring with mirror-image

symmetry on both sides of the body (e.g., vitiligo,
plaque-type psoriasis).
Universal: Involving the entire cutaneous surface
(e.g., erythroderma, alopecia universalis).
::
Chapter 5
Section Shape or Configuration of Skin Lesions);

described by Alfred Blaschko and implies a mosaic
disorder (e.g., incontinentia pigmenti, inflammatory
linear verrucous epidermal nevus).
Lymphangitic: Lying along the distribution of a
lymph vessel; implies an infectious agent that is
spreading centrally from an acral site, usually a
red streak along a limb due to a staphylococcal or
streptococcal cellulitis.
Sun exposed: Occurring in areas usually not covered
by clothing, namely the face, dorsal hands, and a
triangular area corresponding to the opening of
a V-neck shirt on the upper chest (e.g., photodermatitis, subacute cutaneous lupus erythematosus,
polymorphous light eruption, squamous cell carcinoma).
Sun protected: Occurring in areas usually covered by
one or more layers of clothing; usually a dermatosis
that is improved by sun exposure (e.g., parapsoriasis, mycosis fungoides).
Acral: Occurring in distal locations, such as on the
hands, feet, wrists, and ankles (e.g., palmoplantar
pustulosis, chilblains).
Truncal: Occurring on the trunk or central body.
Extensor: Occurring over the dorsal extremities,
overlying the extensor muscles, knees, or elbows
(e.g., psoriasis).
Flexor: Overlying the flexor muscles of the extremities, the antecubital and popliteal fossae (e.g., atopic
dermatitis).
Intertriginous: Occurring in the skin folds, where
two skin surfaces are in contact, namely the axillae,
inguinal folds, inner thighs, inframammary skin,
and under an abdominal pannus; often related to
moisture and heat generated in these areas (e.g.,
candidiasis).
Localized: Confined to a single body location (e.g.,
cellulitis).
Generalized: Widespread. A generalized eruption
consisting of inflammatory (red) lesions is called an
exanthema (rash). A macular exanthema consists of
macules, a papular exanthema of papules, a vesicular exanthema of vesicles, etc. (e.g., viral exanthems,
drug eruption).
SUGGESTED READINGS
Bernhard JD et al: Maculopapularism. Am J Dermatopathol
8:173, 1986
Dermatology Lexicon Project. For Diagnostic Caretgories, http:/
www.aad.org/dermlex/, and Lesion Morphology and Diagrams, http://www.logicalimages.com/educationalTools/
learnDerm.htm (accessed Aug 29, 2011)
41
Federman, DG et al: Full-body skin examinations: the patients perspective. Arch Dermatol 140:530, 2004
Feinstein AR: Clinical Judgment. Baltimore, Williams &
Wilkins, 1967
Haxthausen H: How are dermatological diagnoses made?
Trans St Johns Hosp Dermatol Soc 30:3, 1951
Jackson R: Morphological Diagnosis of Skin Disease. Grimsby,
Ontario, Manticore, 1998
Jackson R: The importance of being visually literate. Arch Dermatol 111:632, 1975
Leider M, Rosenblum M: A Dictionary of Dermatological Words,
Terms, and Phrases. New York, McGraw-Hill, 1968
Siemens HW: General Diagnosis and Therapy of Skin Diseases.

Chicago, University of Chicago Press, 1958, Translated by
K Wiener
Thomas L: The Youngest Science: Notes of a Medicine-Watcher.
New York, Viking Press, 1983, p. 58
Winkelmann RK (chairman): The International League of
Dermatologic Societies Committee on Nomenclature.
Glossary of basic dermatologic lesions. Acta Derm Venereol
Suppl (Stockh) 130:1, 1987
Wolff K, Johnson RA: Fitzpatricks Color Atlas and Synopsis of
Clinical Dermatology, 5th edition. New York, McGraw-Hill,
2005 and 2009
Section 2
::
Chapter 6 :: Basic Pathologic Reactions of the Skin

:: M
artin C. Mihm Jr., Abdul-Ghani Kibbi,
George F. Murphy, & Klaus Wolff
BASIC PATHOLOGIC REACTIONS
AT A GLANCE
Different tissue compartments interconnect
anatomically and interact functionally. These
are the reactive units of skin.
The superficial reactive unit comprises
the epidermis, the junction zone, and the
papillary body with its vascular system.
The reticular dermis with the deeper dermal
vascular plexus is the second reactive unit.
The third reactive unit is the subcutaneous
tissue with its septal and lobular
compartments.
Hair follicles and glands are a fourth reactive
unit embedded into these three units.
Pathologic processes may involve these
reactive units alone or several of them in a
concerted fashion.
The heterogeneity and interaction of these
individual cutaneous compartments explain
why a few basic pathologic reactions lead
to a multiplicity of clinical and pathologic
reaction patterns.
epidermis, dermis, and subcutaneous tissue are heterogeneous in nature and an analysis of pathologic
processes involving the skin should therefore consider
both this heterogeneity and the interactions of the individual cutaneous compartments; only then will it be
understood why a few basic reactions lead to a multiplicity of reaction patterns within this tissue.
Pathophysiologically, the skin can be subdivided
into three reactive units that extend beyond anatomic
boundaries (Fig. 6-1); they overlap and can be divided
into different subunits that respond to pathologic stimuli according to their inherent reaction capacities in a
coordinated pattern.
The superficial reactive unit comprises the subunits
epidermis, the junction zone, the subjacent loose, delicate connective tissue of the papillary body and its
capillary network, and the superficial vascular plexus
(see Fig. 6-1, SRU). The reticular layer of the dermis
represents a second reactive unit and is composed of
coarse connective tissue and the deeper dermal vascular plexus (see Fig. 6-1, DRU). The third reactive unit,
the subcutaneous tissue, is also anatomically and functionally heterogeneous; septal and lobular compartments may be involved either alone or together (see
Fig. 6-1, S). Hair follicles and glands are a separate
(fourth) reactive unit embedded in these three basic
units.
SUPERFICIAL REACTIVE UNIT

EPIDERMIS
42
The skin is composed of different tissue compartments

that interconnect anatomically and interact functionally. It is difficult to envisage epidermal function without signals from the dermis or passenger leukocytes
traveling to and from the skin. On the other hand,
(See Fig. 6-1, E)

Keratinocytes, which have the capacity to synthesize keratin protein, represent the bulk of the epidermis. The epidermis, an ectodermal epithelium,
also harbors a number of other cell populations such
as melanocytes, Langerhans cells, Merkel cells, and
Reactive units of skin
SRU
E
J
PB
SVP
RD
DRU
DVP
Sep
L
DISTURBANCES OF EPIDERMAL CELL DIFFERENTIATION. A simple example of disturbed
epidermal differentiation is parakeratosis, in which
Basic Pathologic Reactions of the Skin
cellular migrants (see Chapter 7). The basal cells of the

epidermis undergo proliferation cycles that provide
for the renewal of the epidermis and, as they move
toward the surface of the skin, undergo a differentiation process that results in surface keratinization.
Thus, the epidermis is a dynamic tissue in which cells
are constantly in nonsynchronized replication and differentiation; this precisely coordinated physiological
balance between progressive keratinization as cells
approach the epidermal surface to eventually undergo
programed cell death and be sloughed, and their continuous replenishment by dividing basal cells is in
contrast to the relatively static minority populations of
Langerhans cells, melanocytes, and Merkel cells. However, at the same time, these dynamic keratinocytes
are interconnected through cohesive molecular interactions that guarantee the continuity, stability, and
integrity of the epithelium. Stability for this directional
cellular flow is provided by the basal membrane complex (see Chapter 53), which anchors the epidermis to
the dermis, and the stratum corneum, which encases
the epidermis on the outside. It is here that individual
cell differentiation ceases as the keratinizing cells are
firmly interconnected by an intercellular cement-like
substance forming a permeability barrier (see Chapter
47). These forces of cohesion are finally lost at the surface of the epidermis where the individual cornified
cells are sloughed (desquamated). Therefore, pathologic changes within the epidermis may relate to the
replicative kinetics of epidermal cells, their differentia-
the desquamation rate of corneocytes, and the generation time of epidermal cells determine the homeostasis
of the epidermis (see Chapter 46). Under physiologic
conditions, there is a balance among proliferation, differentiation, and desquamation. Enhanced cell proliferation accompanied by an enlargement of the germinative cell pool and increased mitotic rates lead to an
increase of the epidermal cell population and thus to
a thickening of the epidermis (acanthosis) (Fig. 6-2A).
A shift in the ratio of resting to proliferating cell as is
the case in psoriasis (see Chapter 18) will lead to both
an increase in the turnover of the entire epidermis and
to a considerable increase of the volume of germinative cells that have to be accommodated at the dermal
epidermal junction. This, in turn, results in a widening
and elongation of the rete ridges, which is accompanied by a compensatory elongation of the connective
tissue papillae, resulting in an expansion of the dermal
epidermal interface and, consequently, in an increased
surface area for dermalepidermal interactions (see
Fig. 6-2).
In contrast to acanthosis is epidermal atrophy.
Although there are many causes, one primary etiology is a decrease in epidermal proliferative capacity, as
may be seen with physiological aging or after the prolonged use of potent topical or systemic steroids. With
atrophy, the epidermal rete ridges are initially lost, followed by progressive thinning of the epidermal layer.
Depending on the underlying causes and how they
affect the keratinocyte differentiation program, there
may also be hyperkeratosis or parakeratosis (thickening of the stratum corneum or retention of nuclei into
the stratum corneum, respectively). It is likely that
many forms of acanthosis and atrophy have primary
effects of the homeostasis and function of keratinocyte
stem cells, critically important slow-cycling minority populations of epidermal cells that are normally
sequestered in the bulge areas of hair follicles and at
tips of epidermal rete ridges.
::
Figure 6-1 Reactive units of skin. The superficial reactive

unit (SRU) comprises the epidermis (E), the junction zone
(J), and the papillary body (PB) with the superficial microvascular plexus. The dermal reactive unit (DRU) consists
of the reticular dermis (RD) and the deep dermal microvascular plexus (DVP). The subcutaneous reactive unit (S)
consists of lobules (L) and septae (Sep). A fourth unit is the
appendages (A; hair and sebaceous glands are the only
appendages shown). HF = hair follicle.
DISTURBANCES OF EPIDERMAL CELL

KINETICS. The mitotic rate of germinative basal cells,
Chapter 6
HF
tion, alterations in cohesive forces, or a combination of

these factors (see Chapter 46). These primary factors
may also influence the stability and migratory characteristics of Langerhans cell, melanocytes, and migrant
lymphocytes, accounting for the complexity of certain
reaction patterns that arise from primary pathological
defects in the epidermal layer. For example, unless a
Langerhans cell expresses the chemokine receptor
CCR6, it cannot migrate from the dermis to the epidermis, and without expression of the CCR7 receptor,
migration to the lymph node is not possible. Because
cytokines that regulate the expression of such receptors
are synthesized and secreted by keratinocytes within
the immediate microenvironment of Langerhans cells,
impairment of keratinocyte homeostasis may have farreaching functional implications that are reflected in
the complexity of the resultant reaction patterns.
43
Section 2
::
44
Figure 6-2 A. Acanthosis. This sign of increased epidermal kinetics is illustrated in a photomicrograph of psoriasis.
B. Parakeratosis, the retention of nuclei in the horny layer, is evident.
faulty and accelerated cornification leads to a retention

of pyknotic nuclei of epidermal cells at the epidermal
surface that is normally formed by anucleate cell remnants that form a basket-weave architectural pattern
(see Fig. 6-2B). A parakeratotic stratum corneum is not
a continuous sheet of cornified cells but a loose structure with gaps between cells; these gaps lead to a loss
of the barrier function of the epidermis.
Parakeratosis can be the result of incomplete differentiation in postmitotic germinative cells due to factors that
influence the timing and complex integrity of the differentiation program whereby keratin pairs of relatively
low molecular weight are progressively assembled as
cells approach the epidermal surface. Alternatively,
parakeratosis can also be the result of reduced transit
time, which does not permit epidermal cells to complete
the entire differentiation process, as for example in psoriasis. However, parakeratosis of cellophane-stripped
epidermis becomes microscopically visible as early as
1 hour after trauma; here, parakeratosis does not represent disturbed differentiation; rather, it results from
direct cellular injury to a viable epidermis deprived of
its protective horny layer. Therefore, the morphologic
term parakeratosis may signify a programed disturbance
of differentiation and maturation, alterations in cell replication kinetics, or direct cellular injury.
Dyskeratosis represents altered, often premature or
abnormal, keratinization, of individual keratinocytes
but it also refers to the morphologic presentation of
apoptosis of keratinocytes. Dyskeratotic cells have an
eosinophilic cytoplasm and a pyknotic nucleus and are
packed with keratin filaments arranged in perinuclear
aggregates. Such a cell will tend to round up and lose
its attachments to the surrounding cells. Therefore,
dyskeratosis is often associated with acantholysis (see
Section Disturbances of Epidermal Cohesion) but
not vice versa (Fig. 6-3).
In some diseases, dyskeratosis is the expression of

a genetically programed disturbance of keratinization
as is the case in Darier disease (see Chapter 51). Dyskeratosis may occur in actinic keratosis and squamous
cell carcinoma. Dyskeratosis may also be caused by
direct physical and chemical injuries. In the sunburn
reaction, eosinophilic, apoptotic cellsso-called sunburn cellsare found within the epidermis within the
first 24 hours after irradiation with ultraviolet B (UVB)
(see Chapter 90), and similar cells may occur after
Figure 6-3 The association of dyskeratosis and acantholysis is seen in this high-power view of Darier disease, which
also demonstrates the intraepidermal cleft formation
resulting from these phenomena.
TABLE 6-1
Classification of Intraepidermal Blisters by
Anatomic Level with Clinical Examples
Granular layer
Friction blister
Pemphigus foliaceus
Subcorneal pustular dermatosis
Staphylococcal scalded-skin syndrome/bullous impetigo
Spinous layer
Eczematous dermatitis
Herpes virus infection
Familial benign pemphigus
high-dose systemic cytotoxic treatment. Individual cell

death within the epidermis is a regular phenomenon
in graft versus host reactions of the skin (see Chapter
28) and in erythema multiforme (see Chapter 39). It is
important to remember that although both premature
or abnormal keratinization and apoptosis may produce an end product referred to as dyskeratosis, the
early events and mechanisms responsible are different.
Whereas cells early in the process of abnormal keratinization often have increased eosinophilic keratin aggregates within their cytoplasm with viable-appearing
nuclei, apoptotic cells during early evolutionary stages
have shrunken, pyknotic, and sometimes fragmented
nuclei in the setting of normal-appearing cytoplasm.
::
Basal layer
Erythema multiforme
Lupus erythematosus
Lichen planus
Epidermolysis bullosa
equilibrium of forming and dissociating intercellular contacts. Specific intercellular attachment devices
(desmosomes) and the related intercellular molecular
interactions are responsible for intercellular cohesion.
However, epidermal cohesion must permit epidermal
cell motion. Desmosomes dissociate and reform at new
sites of intercellular contact as cells migrate through
the epidermis and keratinocytes mature toward the
epidermal surface. Intercellular cohesive forces are
strong enough to guarantee the continuity of the epidermis as an uninterrupted epithelium but, on the
other hand, are adaptable enough to permit locomotion, permeability of the intercellular space, and intercellular interactions.
The most common result of disturbed epidermal
cohesion is the intraepidermal vesicle, a small cavity
filled with fluid. A classification of intraepidermal blistering by anatomic level is shown in Table 6-1.
Three basic morphologic patterns of intraepidermal
vesicle formation are classically recognized. Spongiosis is an example of the secondary loss of cohesion
between epidermal cells due to the influx of tissue
fluid into the epidermis. Serous exudate may extend
from the dermis into the intercellular compartment of
the epidermis; as it expands, epidermal cells remain
in contact with each other only at the sites of desmosomes, acquiring a stellate appearance and giving the
epidermis a sponge-like morphology (spongiosis). As
the intercellular edema increases, individual cells rupture and lyse, and microcavities (spongiotic vesicles)
result (Fig. 6-4). Confluence of such microcavities
leads to larger blisters. Epidermal cells may also be
separated by leukocytes that disturb intraepidermal
coherence; thus, the migration of leukocytes into the
epidermis and spongiotic edema are often a combined
phenomenon, best illustrated by acute allergic contact
Chapter 6
Suprabasal
Pemphigus vulgaris
Darier disease
DISTURBANCES OF EPIDERMAL COHESION. Epidermal cohesion is the result of a dynamic
Figure 6-4 Spongiform vesicle resulting from edematous separation of keratinocytes (A). These are still partially attached
to each other by desmosomes and have thus acquired a stellate appearance as is evident at higher magnification (B).
45
Section 2
Figure 6-5 Acantholysis. Single as well as clusters of acantholytic cells are seen. The round shapes result from the
loss of intercellular connections. Cytologic smear preparation of pemphigus vulgaris.
::
46
dermatitis. The accumulation of polymorphonuclear

leukocytes within the epidermis, the resulting separation of epidermal cells, and their subsequent destruction by neutrophil-derived enzymes, eventually
lead to the formation of a spongiform pustule, one
of the histopathologic hallmarks of psoriasis (see
Chapter 18).
Acantholysis is a primary loss of cohesion of epidermal
cells. This is initially characterized by a widening and
separation of the interdesmosomal regions of the cell
membranes of keratinocytes, followed by splitting and
a disappearance of desmosomes (see Chapter 53). The
cells are intact but are no longer attached; they revert
to their smallest possible surface and round up (Figs.
6-3 and 6-5). Intercellular gaps and slits result, and the
influx of fluid from the dermis leads to a cavity, which
may form in a suprabasal (Fig. 6-6), midepidermal, or
even subcorneal location. Acantholytic cells can easily
be demonstrated in cytologic smears (see Fig. 6-5) and
in some conditions have diagnostic significance.
Acantholysis occurs in a number of different pathologic processes that do not have a common etiology
Figure 6-6 Pemphigus vulgaris. An intraepidermal suprabasal cleft is visible that has resulted from suprabasal acantholysis. It contains acantholytic and inflammatory cells.
and pathogenesis. Acantholysis may be a primary

event leading to intraepidermal cavitation (primary
acantholysis) or a secondary phenomenon in which
epidermal cells are shed from the walls of established
intraepidermal blisters (secondary acantholysis). Primary acantholysis is a pathogenetically relevant event
in diseases of the pemphigus group (see Chapter 54), in
which it results from the interaction of autoantibodies
and antigenic determinants on the keratinocyte membranes and related desmosomal adhesive proteins, and
in the staphylococcal scalded-skin syndrome, where it
is caused by a staphylococcal exotoxin (epidermolysin) (see Chapter 177). In familial benign pemphigus,
it results from the combination of a genetically determined defect of the keratinocyte cell membrane and
exogenous factors (see Chapter 51). A similar phenomenon, albeit more confined to the suprabasal epidermis, occurs in Darier disease, where it is combined
with dyskeratosis in the upper epidermal layers (see
Fig. 6-3) and a compensatory proliferation of basal
cells into the papillary body (see Chapter 51). When
acantholysis results from viral infection, it is usually
combined with other cellular phenomena such as
ballooning, giant cells, and cytolysis (Fig. 6-7; see
Chapters 193 and 194).
Indeed, a loss of epidermal cohesion can also result
from a primary dissolution of cells (i.e., cytolysis). In
the epidermolytic forms of epidermolysis bullosa,
genetically defective and thus structurally compromised basal cells rupture as a result of trauma so that
the cleft forms through the basal cell layer independently from preexisting anatomic boundaries (see
Chapter 62). Cytolytic phenomena in the stratum granulosum are characteristic for epidermolytic hyperkeratosis, bullous congenital ichthyosiform erythroderma,
ichthyosis hystrix, and some forms of hereditary palmoplantar keratoderma (see Chapters 49 and 50).
Figure 6-7 Herpes simplex infection. The epidermis

shows marked ballooning degeneration, cytolysis, and
intraepidermal vesiculation. Acantholytic and multinucleated epidermal giant cells are a clue to herpetic infection.
DERMALEPIDERMAL JUNCTION
TABLE 6-2
Classification of Blisters at the Dermal
Epidermal Junction by Anatomic Level with
Clinical Examples
(See Fig. 6-1, J)

Epidermis and dermis are structurally interlocked
by means of the epidermal rete ridges and the corresponding dermal papillae, and foot-like submicroscopic cytoplasmic microprocesses of basal cells that
extend into corresponding indentations of the dermis.
Dermalepidermal attachment is enforced by hemidesmosomes that anchor basal cells onto the basal lamina;
this, in turn, is attached to the dermis by means of
anchoring filaments and microfibrils (see Chapter 53).
These structural relationships correlate with complex
molecular interactions that serve to bind the epidermis,
basement membrane, and superficial dermis in a manner that promotes resistance to potentially life-threatening epidermal detachment. The basal lamina is not
a rigid or impermeable structure because leukocytes,
Langerhans cells, or other migratory cells pass through
it without causing a permanent breach in the junction.
After being destroyed by pathologic processes, the
basal lamina is reconstituted; this represents an important phenomenon in wound healing and other reparative processes. Functionally, the basal lamina is part of
a unit that, by light microscopy, appears as the periodic
acid-Schiffpositive basement membrane and, in
fact, represents the entire junction zone. This consists
of the lamina lucida, spanned by microfilaments, and
subjacent anchoring fibrils, small collagen fibers, and
extracellular matrix (see Chapter 53). The junction zone
is a functional complex that is primarily affected in a
number of pathologic processes.
Junctional (at the lamina lucida)

Junctional epidermolysis bullosa
Bullous pemphigoid
Dermolytic (below basal lamina)
Epidermolysis bullosa dystrophicans
Epidermolysis bullosa acquisita
Porphyria cutanea tarda
Dermatitis herpetiformis
::
or its components usually manifests as disturbance of

dermalepidermal cohesion and leads to blister formation. These blisters appear to be subepidermal by light
Chapter 6
microscopy (Fig. 6-8), but in reality may be localized

at different levels and result from pathogenetically
heterogeneous processes. A classification of blisters
at the junction by anatomic level is given in Table 6-2.
Subepidermal blister formation occurs in forms of
epidermolysis bullosa (see Chapter 62) or can be the
result of a complex inflammatory process that involves
the entire junction zone, as is the case in lupus erythematosus, erythema multiforme, or lichen planus; therefore, it may be a phenomenon occurring in a group of
etiologically and pathogenetically heterogeneous
conditions. In bullous pemphigoid (see Fig. 6-8), cleft
formation runs through the lamina lucida of the basal
membrane and is caused by autoantibodies directed
against specific antigens on the cytomembrane of basal
cells (junctional blistering) (see Fig. 6-8A; see Chapter
56). The presence of eosinophil granules that contain
major basic protein that is toxic to keratinocytes also
causes keratinocyte injury and may present as eosinophilic apongiosis (Fig. 6-8B). Junctional blistering also
occurs in the junctional forms of epidermolysis bullosa, but here it is due to the hereditary impairment or
absence of molecules important for dermalepidermal
cohesion (see Chapter 62; see Table 6-2).
DISTURBANCES OF DERMALEPIDERMAL
COHESION. The destruction of the junction zone
Figure 6-8 Bullous pemphigoid. Subepidermal (junctional) cleft formation and a perivascular and interstitial lymphoeosinophilic infiltrate are characteristic (A). Eosinophilic spongiosis can also occur (B).
47
Section 2
::
48
In subepidermal blistering, the target of the pathologic process is below the basal lamina (dermolytic
blistering) (see Table 6-2). Reduced anchoring filaments and increased collagenase production result in
dermolytic dermalepidermal separation in recessive
epidermolysis bullosa (see Chapter 62); circulating
autoantibodies directed against type VII collagen in
anchoring fibrils are the cause of dermolytic blistering in acquired epidermolysis bullosa (see Chapter 60).
Other immunologically mediated inflammatory mechanisms result in dermolytic blistering in dermatitis herpetiformis (see Chapter 61), and physical and chemical
changes in the junction zone and papillary body are the
cause for a dermolytic cleft formation after trauma in
porphyria cutanea tarda (see Chapter 132).
MOLECULAR AND CELLULAR

MECHANISMS FOR REACTION
PATTERNS AFFECTING THE
SUPERFICIAL REACTIVE UNIT
Although Virchow envisioned what is today known as
the superficial reactive unit as a simple layer of cells
involved in producing environmentally protective surface keratin, we now realize that this layer is a potent
producer of regulatory and stimulatory molecules
that, when perturbed, choreograph architectural and
cytologic changes that produce the reaction patterns
that we equate with specific clinical disorders. Upon
immunological stimulation via cytokines with attendant activation of signal transduction pathways, for
example, the keratinocyte often acquires an activated
phenotype whereby the nucleus enlarges, the nucleolus becomes more prominent, and the cell may actually appear atypical. Hyperproliferation frequently
accompanies keratinocyte activation, and biosynthetic
alterations also may develop, resulting in production
of additional factors, such as keratinocyte-derived
cytokines, that further fuel the activated phenotype.
In such instances, epidermal thickening and increased
mitotic activity is evidenced by conventional histology,
and Ki-67 staining will disclose evidence of suprabasal
cell cycling. It is likely that such activated and hyperproliferative states involve stimulation at the level of
the epidermal and follicular stem cell compartments,
as is also seen in wound healing responses. In such circumstances, normally quiescent stem cells that are normally sequestered at the tips of epidermal rete ridges
and in the bulge regions of hair follicles begin to proliferate and differentiate, further driving the acanthotic
epidermal thickening. Alterations in epidermal kinetics are frequently also evidenced by faulty differentiation. Premature differentiation may trigger defective
cell adhesion, and hence cells may seem abnormally
keratinized (dyskeratotic) as well as separated (acantholytic). Other factors that may perturb adhesion may
provide exquisite correlation between the molecular
composition of the superficial reactive unit and the
morphology of the reaction patterns themselves, as
is the case in various forms of pemphigus, where the
level of keratinocyte dyshesion and acantholytic blister formation follows precisely the concentration gra-
dients of the targeted adhesive proteins (desmogleins

1 and 3) that assist in binding keratinocytes at the level
of the desmosome.
The patterns of cellular inflammation that affect the
superficial reactive unit also are dictated at a molecular level. Circulating leukocytes, often T cells, bind the
endothelium of postcapillary venules of the superficial
vascular plexus upon cytokine-induced endothelial
activation (see also dermal reaction patterns in Section
Molecular and Cellular Mechanisms for Reaction Patterns Affecting the Dermis). This results in expression
of endothelialleukocyte adhesion molecules at the
endothelial surface that slows circulating leukocytes to
a roll, followed by more secure directed binding and
transvascular diapedesis. Cells so extravasated may
remain in the perivascular space or migrate upward
toward the nearby epidermal layer as a consequence
of chemokinetic and chemotactic gradients. Depending on their immunologic mission, the responding
leukocytes may either produce cytotoxic injury at the
dermalepidermal interface, or migrate through the
basement membrane into the epidermis in the company of transudate that contributes to the intercellular edema that forms the pattern of spongiosis. Thus,
depending on the nature of the provocative stimulus
as well as the complex downstream molecular events
that are set into motion, specific reaction patterns
result that, upon recognition, provide key diagnostic
information.
PATHOLOGIC REACTIONS OF THE

ENTIRE SUPERFICIAL REACTIVE UNIT
(See Fig. 6-1, SRU)
Most pathologic reactions of the superficial skin
involve the subunits of the superficial reactive unit
jointly and thus include the papillary body of the dermis with the superficial microvascular plexus. This is a
highly reactive tissue compartment consisting of capillaries, pre- and postcapillary vessels (see Chapter 162),
mast cells, fibroblasts, macrophages, dendritic cells,
and peripatetic lymphocytes all embedded in a loose
connective tissue and extracellular matrix (Fig. 6-9).
The prominence of involvement of one of the components over the others may lead to the development
of different clinical pictures. A few examples of such
interactions are detailed below.
ALLERGIC CONTACT DERMATITIS. (See Chapter 13.) In allergic contact dermatitis, there is an inflammatory reaction of the papillary body and superficial
microvascular plexus and spongiosis of the epidermis
(see Fig. 6-4) with signs of cellular injury and parakeratosis. Lymphocytes infiltrate the epidermis early in the
process and aggregate around Langerhans cells, and
this is followed by spongiotic vesiculation (Fig. 6-10).
Parakeratosis develops as a consequence of epidermal
injury and proliferative responses, and the inflammation in the papillary body and around the superficial
venular plexus stimulates mitotic processes within the
epidermis, which, in turn, result in acanthosis and epidermal hyperplasia in chronic lesions.
Compartment of the papillary body
Co
Mc
C
R
The reaction pattern that involves the superficial

vascular plexus of vessels is one of a superficial perivascular lymphocytic infiltrate, often with admixed
eosinophils and histiocytes. As noted above, many
of these lymphocytes also migrate into the epidermal
layer to produce a pattern referred to as exocytosis.
The superficial perivascular pattern of inflammation
is one of a number of inflammatory patterns that
::
Figure 6-9 The compartment of the papillary body consists of capillaries (C), fibroblasts (F), macrophages and
dendritic cells (M), peripatetic lymphocytes (L) and mast
cells (Mc), all embedded in a loose connective tissue of
extracellular matrix, thin collagen fibers (Co), elastic fibers
(E) that are mostly oriented perpendicularly to the skin
surface, and branched reticulin fibers (R).
PSORIASIS. (See Chapter 18.) The initial lesion of

psoriatic lesions appears to be the perivascular accumulation of lymphocytes and monocytoid elements
within the papillary body and superficial venules
and focal migration of leukocytes (often neutrophils,
although T cells are integral to pathogenesis as well)
into the epidermis. Acanthosis caused by increased
epidermal proliferation, elongation of rete ridges
sometimes accompanied by an undulant epidermal
surface (papillomatosis), and edema of the elongated
dermal papillae together with vasodilatation of the
capillary loops and a progressive perivascular inflammatory infiltrate develop almost simultaneously (see
Fig. 6-2); the disturbed differentiation of the epidermal
cells results in parakeratosis, and small aggregates of
neutrophils infiltrating the epithelium from tortuous
capillaries (squirting capillaries) result in spongiform
pustules and, in the parakeratotic stratum corneum,
to Munro microabscesses. The stimulus for increased
epidermal proliferation follows signals released from T
cells that are attracted to the epidermis by the expression of adhesion molecules at the keratinocyte surface
and are maintained by cytokines released by keratinocytes (see Chapter 18). Therefore, the composite picture characteristic of psoriasis results from a combined
pathology of the papillary body with participation of
superficial venules, the epidermis, and circulating cells.
Psoriasis is an instructive example of the limited
specificity of histopathologic reaction patterns within
the skin because psoriasiform histologic features occur
in a number of diseases unrelated to psoriasis.
Chapter 6
may be of assistance at low magnification in generating an initial differential diagnostic algorithm for
various types of dermatitis. Pathophysiologically, very
early forms of allergic contact dermatitis (e.g., within
24 hours) will exclusively involve perivascular lymphocytes, their influx preceded by mast cell degranulation that releases factors promoting adhesive
interactions with superficial dermal endothelium. The
epidermal changes follow soon thereafter.
INTERFACE DERMATITIS. Inflammation along

the dermalepidermal junction associated with vacuolation or destruction of the epidermal basal cell layer
characterizes interface dermatitis. This common type
of reaction may lead to papules or plaques in some
skin diseases and bullae in others.
ERYTHEMA MULTIFORME. (See Chapter 39.)
Two types of reactions occur. In both there is interface
dermatitis characterized by lymphocytes scattered
along a vacuolated dermalepidermal junction.
Figure 6-10 Contact dermatitis. Intraepidermal spongiotic vesicles and pronounced intercellular edema are
present in the epidermis. The dermis contains perivascular
aggregates of lymphocytes and histiocytes admixed with
occasional eosinophils.
LUPUS ERYTHEMATOSUS. (See Chapter 155.)

Inflammation, edema, and a lymphocytic infiltrate
in the papillary body and superficial venular plexus,
as well as in the deeper layers of the dermis, are hallmarks of lupus erythematosus. The main target is the
dermalepidermal junction, where scattered lymphocytes appear and immune complex deposition leads to
broadening of the PAS-positive basement membrane
zone, accompanied by hydropic degeneration and
49
Section 2
::
50
Figure 6-11 Lupus erythematosus. Hyperkeratosis, thinned

epidermis devoid of rete ridges, and vacuolization of the
basement membrane zone are present.
destruction of basal cells and progressive atrophy

(Fig. 6-11). Cytoid bodies in the form of anucleate keratin aggregates that may undergo amyloid transformation result from apoptosis of individual epidermal
cells that are infiltrated and coated by immunoglobulins. The changes in the junctional zone reflect on
epidermal differentiation resulting in thickening of
stratum corneum (orthokeratosis) and parakeratosis.
Lupus erythematosus readily illustrates the heterogeneity, as well as the lack of specificity, of cutaneous
reaction patterns: histologically, it is possible to distinguish between acute and chronic lesions but not
between cutaneous and systemic lupus erythematosus.
In certain chronic, persisting lesions, the changes in the
junctional zone initially associated with atrophy secondarily result in hyperplasia, hyperkeratosis, and an
increased interdigitation between epidermis and connective tissue, whereas in acute cases, the destruction of
the basal cell layer may lead to subepidermal blistering.
LICHEN PLANUS. (See Chapter 26.) This disease

also exhibits a primarily junctional reaction pattern
with accumulation of a dense lymphocytic infiltrate
in the subepidermal tissue and cytoid bodies at the
junction (Fig. 6-12). Lymphocytes encroach on the epidermis, destroying the basal cells, but they do not infiltrate the suprabasal layers and blister formation only
rarely ensues. These alterations are accompanied by
changes of epidermal differentiationthere is a widening of the stratum granulosum (hypergranulosis)
and hyperkeratosis. Identical changes can be seen in
the epidermal type of graft-versus-host disease (see
Chapter 28). Current thinking imputes a delayed
hypersensitivity reaction to a keratinocyte antigen,
the nature of which is unclear. The association of CD8+
lymphocytes in apposition to and even surrounding
apoptotic keratinocytes (so-called satellitosis) supports
Figure 6-12 Lichen planus. There is hyperkeratosis,

wedge-shaped hypergranulosis, basal cell vacuolization,
and a lymphocytic infiltrate at the dermalepidermal junction. This infiltrate hugs the basal cell layer and is associated with many cytoid bodies.
this view. The expression of Fas/FasL is also in favor of

a role for apoptosis in the pathogenesis of these lesions.
DERMATITIS HERPETIFORMIS. (See Chapter 61.)

This condition is usually included among the classic
bullous dermatoses; however, it illustrates that the
preponderance of one or several pathologic reaction
patterns may obscure the true pathogenesis of the condition. The deposition of immunoglobulin A and complement on fibrillar and nonfibrillar sites within the tips of
the dermal papillae, and the activation of the alternative
pathway of the complement cascade, lead to an influx
of leukocytes (primarily neutrophils), which form small
abscesses at the tips of the dermal papillae, as well as
inflammation and edema (Fig. 6-13). This explains why
Figure 6-13 Dermatitis herpetiformis. Two papillae show

microabscesses composed of neutrophils. Vacuolization
and early cleft formation are evident in both papillae.
the primary clinical lesion in dermatitis herpetiformis

is urticarial or papular in nature, because only in the
case of massive neutrophil infiltration will there be tissue destruction and cleft formation below the lamina
densa that results in clinically visible vesiculation.
RETICULAR DERMIS
Chapter 6
::
(See Fig. 6-1, DRU)

The dermis represents a strong fibroelastic tissue with
a network of collagen and elastic fibers embedded in an
extracellular matrix with a high water-binding capacity
(see Chapter 63). In contrast to the tightly interwoven
fibrous components of this reticular layer of the dermis (Fig. 6-14), the previously described fibrous texture of the papillary body and the perifollicular and
perivascular compartments is loose (see Fig. 6-9), and
the orientation of the collagen bundles here follows the
structures they surround.
The dermis contains a superficial and deep vascular
network. In the upper dermis, the superficial plexus
supplies individual vascular districts consisting of several dermal papillae. Superficial and deep networks
are connected so intimately that the entire dermal
vascular system represents a single three-dimensional
unit (see Chapter 162). On the other hand, there are
profound functional differences between superficial
and deep dermal vascular networks, which explain the
differences of homing patterns of inflammatory cells to
these sites.
As for the superficial microvascular system, two
reaction patterns occur: (1) acute inflammatory processes in which the epidermis and junctional zone
are often involved together with the vascular system,
and (2) more chronic processes that often remain confined to the perivascular compartment. In this con-
text, it should be noted that the cytologic composition

(acute vs. chronic inflammation) of an inflammatory
infiltrate within the skin does not always mirror the
temporal characteristics of an inflammatory process.
Thus, polymorphonuclear leukocytic infiltrates are not
always synonymous with an acute process; conversely,
chronic processes are not always represented by a lymphohistiocytic infiltrate.
Inflammation confined to the superficial connective
tissuevascular unit is characterized by endothelial
activation, vascular dilatation, increased permeability, edema, a reduction of intravascular blood flow, an
accumulation of red blood cells in the capillary loops,
and cellular infiltration of the perivascular tissue.
Depending on the degree of inflammation, the macroscopic corollary of the histologic changes represents
erythematous, urticarial, and infiltrative (papular)
lesions. The release of mediators from immunoglobulin E-laden mast cells in type I immune reactions,
such as immune forms of urticaria, is histologically
manifested primarily as vasodilatation, edema of the
papillary body, and a rather sparse infiltrate of leukocytes (neutrophils) and histiocytic elements around
the superficial venules (Fig. 6-15). These lesions usually resolve relatively rapidly without any residual
pathology. However, more massive reactions lead to a
dense perivascular infiltrate (Fig. 6-16A), and this may
represent a transition to those processes where edema
is less pronounced and where dense lymphocytic infiltrates surround the vessels in a sleeve-like fashion, as
is the case in cutaneous drug eruptions (see Figs. 6-16A
and 6-16B). More dramatic alterations occur when the
vascular system itself is the target of the inflammatory
process, resulting in a destruction of at least some of the
The reticular dermis
Co
Figure 6-14 The reticular dermis is tightly woven fibroelastic tissue with a network of thick, banded collagen
fibers (Co) and elastic (E) fibers embedded in an extracellular matrix. All are produced by fibroblasts (F). This tissue
is much denser, relatively acellular, and has fewer capillary
vessels than the papillary body (compare with Fig. 6-9).
Figure 6-15 Urticaria. Characteristic of this reaction is a

sparse, perivascular lymphocytic infiltrate with few eosinophils. Note the slight edema in the dermis and around
the postcapillary venules.
51
Section 2
::
Figure 6-16 Drug eruption. A. Throughout the dermis, perivascular sleeves of mononuclear cells, mainly
lymphocytes, are present about superficial and deep venules. There is slight edema in the papillary body
and minimal interface dermatitis in this reaction to nifedipine. B. More pronounced, even nodular, mononuclear cell infiltrates around vessels in a drug reaction to a blocker.
vessel components, as is the case in necrotizing vasculitis. These exudative changes result in clinical palpable purpura (Fig. 6-17; see Chapter 163).
Chronic inflammatory reactions of the superficial
microvascular plexus usually reveal lymphocytic infiltrates in close association with the vascular walls and
are clinically manifested as erythema. In purpura simplex (see Chapter 168), damage to the vessel wall is
52
much less evident than in necrotizing vasculitis, but the

integrity of the vessels is also impaired, as is evidenced
by hemorrhage into the tissue. Lymphocytes and, as
a secondary reaction, histiocytic elements partly laden
with phagocytosed material including iron, constitute
the inflammatory infiltrate.
The reaction patterns described for the vascular system of the papillary body and the superficial venular
Figure 6-17 Necrotizing vasculitis. An inflammatory infiltrate composed mostly of neutrophils and nuclear dust is
present both around and in the wall of a venule where fibrin is also deposited (A). More severe reaction with destruction
of vessels (B).
Although lymphocytic infiltrates occur in the majority of inflammatory dermatoses, there are a number
of pathologic processes in which such infiltrates are
the most prominent features and thus determine the
histologic picture. Lymphocytic infiltrates are formed
in inflammatory or proliferative conditions and in the
latter may represent a benign or malignant process.
They may differ in their cytologic appearance and
distribution, may be confined to the periadventitial
compartments of the vascular system (superficial and
deep perivascular dermatitis), or may occur diffusely
throughout the collagenous tissue (diffuse dermatitis).
They may be confined almost exclusively to the papillary dermis (interface dermatitis) and spare the subepidermal compartment or may exhibit pronounced
epidermotropism. They may be independent of vessels, sparse (interstitial dermatitis) or nodular (nodular
dermatitis). Because lymphocytes are a heterogeneous
population of cells, the analysis of such infiltrates
should take into account not only the cytomorphology
and distribution pattern but histochemical properties
and immunologic markers as well. The analysis of
round cell infiltrates by monoclonal antibodies (immunophenotyping) and determination of their clonality
are important aspects of dermatopathology (see Chapter 146).
Among the many possible reaction patterns characterized by lymphocytic infiltrates, several typical patterns can be distinguished.

Superficial perivascular infiltrates are often accompanied by secondary reactions of the epidermis.
Lymphoid cells surround the vascular channels in
a sleeve-like fashion but often extend diffusely to
the epidermis, which may reveal focal parakeratosis
Figure 6-18 Mucinosis in lupus erythematosus. The

prominent feature shown here is abundant mucin in the
superficial dermis and middermis.
LYMPHOCYTIC INFILTRATES
::
in these areas. Clinically, these changes are often

characterized as palpable figurate erythemas such
as erythema annulare centrifugum, but polymorphic light eruption, drug eruptions (see Fig. 6-16A),
or insect bites can produce a similar histopathologic
picture.
Lymphocytic cuffing of venules without involvement of the papillary body and the epidermis may
occur in figurate erythemas and in drug eruptions
(see Fig. 6-16B). The infiltrates of chronic lymphocytic leukemia show a similar distribution pattern
but are usually more pronounced.
Perivascular lymphocytic infiltrates with a mucinous infiltration of the nonperivascular connective
tissue may be found in lymphocytic infiltration of
JessnerKanof, reticular erythematous mucinosis
or in lupus erythematosus (Fig. 6-18) and dermatomyositis (see Chapters 155 and 156).
Nodular lymphocytic infiltrates, which extend
throughout the dermis exhibiting focal accumulations of histiocytic cells and thus acquiring the
appearance of lymphoid follicles, are typical of
lymphocytoma cutis (see Chapter 146). Phagocytosed polychrome bodies in histiocytic cells (tingible
body macrophages), mitoses in the center of the
lymphoid follicles, and an admixture of eosinophils
are characteristic features, as is the fact that the papillary body is usually spared so that a conspicuous
grenz zone is found between the infiltrate and the
epidermis.
Nonfollicular lymphocytic infiltrates sparing the
superficial reactive unit may also occur in benign
lymphoid hyperplasias, but in these cases, the differentiation from malignant lymphoma is very difficult. Polymorphic infiltrates showing histiocytes,
Chapter 6
plexus also occur in the deep dermis, but there are

morphologic and functional differences because here
larger vessels are involved. Lymphocytic infiltrates
surrounding the vessels in a sleeve-like fashion lead to
clinical signs only when they are substantial, and then
they represent the histopathologic substrate for papular or nodular lesions. This is the case with drug eruptions (see Chapter 41; see Fig. 6-16B) and it is also true
for deep-seated infiltrates in lupus erythematosus. In
the case of necrotizing vasculitis of the medium-sized
and larger vessels, there is usually a much more pronounced inflammatory infiltrate, clinically appearing
as papular and nodular lesions, and secondary changes
due to the interruption of the vascular flow are more
pronounced: necrosis, blistering, and ulceration result
as is the case in cutaneous panarteritis nodosa of the
macroscopic type (see Chapter 164). In contrast to the
macroscopic variant, microscopic polyarteritis nodosa
affects vessels of varying sizes including venules and
arterioles, involves lungs and kidneys, and is positive
for perinuclear neutrophil antibodies. Granulomatous
vasculitis also leads to nodular lesions, whereas the
hyalinizing vascular changes and vascular occlusion
in livedoid vasculitis result in ischemic necrosis (see
Chapter 163).
53
hyalin) and signs of vasculitis (see Chapter 163). The

neutrophil is also the predominant cell in the early
stages of the more common necrotizing vasculitis (see
Fig. 6-17). Neutrophils also represent the majority of
the often massive inflammatory infiltrate in acute
febrile neutrophilic dermatosis, which is accompanied
by pronounced subepidermal edema (see Chapter 32).
GRANULOMATOUS REACTIONS
Section 2
Figure 6-19 Angiolymphoid hyperplasia. Numerous vascular channels are surrounded by aggregates of inflammatory cells made up of lymphocytes and eosinophils. Note
the protrusion of endothelial cells into the lamina of these
vessels.
::
plasma cells, and occasional eosinophils are usually

benign, whereas most malignant non-Hodgkin lymphomas exhibit a more monomorphous cytologic
picture.
Nodular accumulations of lymphocytes with an
admixture of plasma cells and eosinophils accompanied by vascular hyperplasia are characteristic
of angiolymphoid hyperplasia (Fig. 6-19), in which
blood vessel walls are thickened and the endothelial
cells proliferate and become swollen, and enlarged.
Atypical lymphocytic infiltrates involving both the
superficial and deeper dermis, and cytologically
characterized by pronounced pleomorphism of the
cellular infiltrate, are characteristic of lymphomatoid papulosis, one of the spectrum of CD30+ lymphoproliferative disorders (see Chapter 145). This
condition exemplifies the problems that arise when
the histopathology of a lesion is used alone to determine whether a process is benign or malignant.
Without knowledge of the clinical features and the
course of disease, a definite diagnosis is extremely
difficult.
Skin is an ideal tissue for granuloma formation in

which histiocytes play a key role. Although these cells
are involved at one time or another in practically all
inflammatory processes, it is only the proliferation
and focal aggregation of histiocytic cells that may be
termed a granuloma. When such cells are closely clustered they resemble epithelial tissue, hence the designation epithelioid cells. Development of giant cells,
storage of phagocytosed material, and the admixture
of inflammatory cells, such as lymphocytes, plasma
cells, and eosinophils, may render the histologic picture of a granulomatous reaction more complex. To
these have to be added vascular changes and alterations in the fibrous structure of the connective tissue.
Granulomas almost always lead to destruction of preexisting tissue, particularly elastic fibers, and in such
instances result in atrophy, fibrosis, or scarring. Tissue
damage or destruction manifests either as necrobiosis
or fibrinoid or caseous necrosis, or it may result from
liquefaction and abscess formation or from replacement of preexisting tissue by fibrohistiocytic infiltrate
and fibrosis.
Sarcoidal granulomas (see Chapter 152) are typically
characterized by naked nodules consisting of epithelioid cells, occasional Langerhans giant cells, and only
a small number of lymphocytes (Fig. 6-20). Silica, zirconium, and beryllium granulomas and a number of
foreign-body granulomas may have such histopathologic features.
Granulomatous reactions of the skin comprise a
large spectrum of histopathologic features. Palisading granulomas surround necrobiotic areas of the
POLYMORPHONUCLEAR
LEUKOCYTIC INFILTRATES
54
Although neutrophils are the classic inflammatory cells

of acute bacterial infections, there are diseases in which
neutrophils dominate the histopathology, even in the
absence of a bacterial cause. In pyoderma gangrenosum, massive neutrophilic infiltration of the dermis
leads to sterile abscesses, breakdown of the tissue, and
ulceration (see Chapter 33). In dermatitis herpetiformis,
neutrophils accumulate in the tips of dermal papillae
and form papillary abscesses (see Fig. 6-13) that precede the dermolytic blister formation described in Section Disturbances of DermalEpidermal Cohesion
(see also Chapter 61). In erythema elevatum diutinum, neutrophils are the predominant cells centering around superficial and middermal vessels, which
exhibit fibrinoid homogenization of their walls (toxic
Figure 6-20 Sarcoidal granuloma. In the dermis, numerous naked tubercles consisting of epithelioid cells and
scant lymphocytes are seen. The overlying epidermis is
atrophic.
xanthomas occurring in the hyperlipoproteinemias

and xanthelasma (see Chapter 135).
FIBROUS DERMIS AND

EXTRACELLULAR MATRIX
::
connective tissue with histiocytes in radial alignment

(Fig. 6-21). Granuloma annulare, necrobiosis lipoidica,
rheumatoid nodules, and the juxtaarticular nodules
of syphilis belong to this group. These reactions may
have significance as signs of systemic disease. For
example, when there are prominent neutrophils in the
necrobiotic area of granuloma annulare or necrobiosis,
one may suspect an associated inflammatory bowel
disease. Endocrinopathies can also be associated with
these disorders, diabetes mellitus is a classic example
associated with necrobiosis lipoidica. Of course, rheumatoid nodules can be associated with rheumatoid
arthritis but can also occur as a result of trauma in
some cutaneous locations. Drugs may also cause these
reactions.
Infectious granulomas with a sarcoidal appearance
may occur in tuberculosis, syphilis, leishmaniasis, leprosy, or fungal infections. Necrosis can also develop
within the granuloma proper, as is the case for fibrinoid necrosis in sarcoidosis, caseation in tuberculosis,
or the necrosis developing in mycotic granulomas.
Many of the infectious granulomas are associated with
epidermal hyperplasia, often exhibiting intraepidermal abscesses in which the causative organism can be
found, often in a multinucleate giant cell. In the dermis
there is a mixture of cells, including histiocytes, epithelioid cells, eosinophils, neutrophils, and lymphocytes.
It is often difficult to classify granulomatous reactions within the skin by histopathology alone, for
even completely different etiologic conditions such as
immunopathies and some forms of vasculitis are associated with the development of granulomas.
A specific form of granulomatous reaction results
when the cellular infiltrate consists almost exclusively
of the key granuloma cell, the histiocyte. One property
of this cell is its capacity to store phagocytosed material. In xanthomatous reaction patterns, histiocytes
take up and store fat and are thus transformed into
foam cells. They are distributed either diffusely, as is
the case in diffuse normolipemic xanthomatosis, or as
an aggregate infiltrate mimicking a tumor, as in the
Chapter 6
Figure 6-21 Granuloma annulare. A well-circumscribed

palisading granuloma is seen in the dermis. Necrobiotic
collagen is surrounded by histiocytes, lymphocytes, and a
few scattered multinucleated giant cells.
(See Fig. 6-1, DRU)

Sclerosing processes of the skin involve mainly the
connective tissue of the dermis (see Figs. 6-1, DRU,
and 6-14) but usually reflect dynamic changes of structure and function that involve practically all compartments of this organ. The hallmark of scleroderma (see
Chapter 157) is the homogenization, thickening, and
dense packing of the collagen bundles, a narrowing of
the interfascicular clefts within the reticular dermis,
and the disappearance of the boundary between this
portion of the dermis and the papillary body. There
is also a diminution of the small papillary and subpapillary vessels, which appear narrowed, and, in the
early stages, a perivascular lymphocytic infiltrate and
edema. The impressive thickening of the dermis not
only results from an increase of its fibrous components,
but is also caused by the fibrosis of the superficial layers of the subcutaneous fat that follows lymphocytic
infiltration and a histiocytic reaction.
Sclerodermoid changes may be found in the toxic
oil syndrome and l-tryptophan disease, eosinophilic
fasciitis (see Chapter 36), and mixed connective tissue disease; they also occur in pachydermoperiostosis,
where an increase of fibroblasts and ground substance
accompany the sclerotic changes, and in porphyria
cutanea tarda, which shows typical hyalinization of
the papillary vessels. In lichen sclerosus, there is a
massive edema of the papillary body and a dense lymphocytic infiltrate that initially hugs the epidermis and
later separates the edematous papillary body from the
reticular dermis (see Chapter 65). As sclerosis sets in,
there is also a disappearance of elastic tissue from the
papillary body; the concomitant involvement of the
epidermis includes hydropic degeneration of basal
cells, atrophy, and, at the same time, hyperkeratosis.
Changes in the junctional zone in this condition may
occasionally lead to a separation of the epidermis from
the dermis and thus to blister formation.
Faulty synthesis or cross-linking of collagen results
in a number of well-defined diseases or syndromes but
leads to relatively few characteristic histopathologic
changes. In the different types of the EhlersDanlos
syndrome (see Chapter 137), the faulty collagen cannot
be recognized histopathologically, and only the relative
increase of elastic tissue may indicate that something
abnormal has occurred in the dermis. In generalized
elastolysis, a fragmentation of elastic fibers is the histopathologic substrate of the clinical appearance of cutis
laxa, and the fragmentation and curled and clumped
appearance of elastic fibers are similarly diagnostic in
pseudoxanthoma elasticum (see Chapter 137). On the
other hand, in actinic elastosis, the histologic correlate of dermatoheliosis, all components of the superficial connective tissue are involved (see Chapter 109).
Except for a narrow grenz zone below the epidermis,
the papillary body, and the superficial layers of the
55
Section 2
::
56
reticular dermis are filled with clumped and curled

fibers that progressively become homogenized and
basophilic. They are stained by dyes that have an affinity for elastic tissue and thus histochemically behave
similar to elastic fibers.
Such profound changes of dermal architecture
become clinically apparent: the taut and firm connective tissue in scleroderma reflects the sclerotic texture
and homogenization of the collagen bundles seen histologically; the loose folds of cutis laxa are a result of
the fragmentation of elastic fibers; the cobblestone-like
papules in pseudoxanthoma elasticum correspond
to the focal aggregation of the pathologically altered
elastic material; and the coarseness of skin lines and
surface profile in dermatoheliosis are the clinical manifestations of the focal aggregation of elastotic material.

DERMIS
The reaction patterns that affect the dermis take the
forms of cellular infiltrations as well as acellular patterns that primarily are based in the extracellular
matrix. However, these two general categories are
difficult to separate, as there is constant interplay
between the cellular and acellular components of the
dermis. As discussed above, the vascular plexuses in
the dermis are the primary conduits for influx of cellular elements, and leukocyteendothelial adhesion
molecule expression play a critical role in regulating
leukocyte entry and the reaction patterns that result.
The adhesive molecules themselves assist in regulating
the relative strength and kinetics of the influx of various cell types, and hence some stimuli may provoke
an adhesion cascade that favors entry of neutrophils or
eosinophils, whereas others may result in infiltration of
primarily mononuclear cells. Moreover, once inflammatory cells have extravasated into the dermal interstitium,
their migratory fate and secondary morphological
alterations are also in large part determined by molecular cues in their new microenvironment. Hence, an
encounter with insect bite venom may provoke interstitial accumulation of histiocytes and eosinophils,
and perhaps poorly formed granulomas, whereas
an immune response in the setting of Lyme disease
may provoke intensely perivascular localization of
lymphocytes conjuring up the appearance of a coatsleeve. Mediators released by cellular infiltrates may
have a profound effect on the extracellular matrix as
well, resulting in additional dermal reaction patterns.
For example, fibrogenic mediators such as TGFb,
may have a variety of effects on dermal homeostasis,
including fibroblast transformation in the direction of
myofibroblasts, with attendant collagen synthesis as
might be seen as a normal response to wounding, but
in this setting resulting in the diffuse dermal thickening that correlates with the reaction pattern typical of
morphea scleroderma.
SUBCUTANEOUS FAT
(See Fig. 6-1, S)
Inflammatory processes in the subcutaneous adipose tissue take a slightly different course than in
the connective tissue of the dermis because of the
specific anatomy of the subcutis (see Chapters 7
and 70). Inflammation of subcutaneous fat reflects
either an inflammatory process of the adipose tissue proper or the fat lobules (see Fig. 6-1, L) or a
process arising in the septa (see Fig. 6-1, Sep); it can
involve small venules and capillaries or arise from
the larger muscular vessels. The histopathologic
manifestations may vary accordingly. Small-vessel
pathology is usually manifested locally, involving
the neighboring fat lobules, whereas the destruction or occlusion of a larger vessel influences the
entire tissue segment. Destruction of fat, be it of
a traumatic or inflammatory nature, leads to the
release of fatty acids that by themselves are strong
inflammatory stimuli, attracting neutrophils and
scavenger histiocytes and macrophages; phagocytosis of destroyed fat usually results in lipogranuloma formation.
Septal processes that follow inflammatory changes
of the trabecular vessels are usually accompanied
by edema, infiltration of inflammatory cells, and a
histiocytic reaction. This is the classic appearance in
erythema nodosum (Fig. 6-22; see Chapter 70). Recurring septal inflammation may lead to a broadening
of the interlobular septa, fibrosis, the accumulation
of histiocytes and giant cells, and may result in vascular proliferation. By contrast, in nodular vasculitis
(Fig. 6-23), large-vessel vasculitis in the septal area is
accompanied by necrosis of the fat, followed by histiocytic reactions, epithelioid cell granulomas within the
fat lobules, and a fibrotic reaction sclerosing the entire
subcutaneous fat. On the other hand, lobular panniculitis results from the necrosis of fat lobules as the
primary event, as is the case in idiopathic nodular panniculitis (see Chapter 70), followed by an accumulation
of neutrophils and leukocytoclasia. The lipid material
Figure 6-22 Erythema nodosum. A chronic granulomatous inflammatory infiltrate with giant cells extends along
the thickened septum into the adjacent fat lobule.

SUBCUTIS
SUGGESTED READINGS
::
derived from necrotic adipocytes contains free and

esterified cholesterol, neutral fats, soaps, and free fatty
acids, which, in turn, exert an inflammatory stimulus.
Histiocytic cells migrate into the inflamed fat, and
phagocytosis leads to foam cell formation. Epithelioid
granulomas with giant cells may also result, and all
types of fibrosis may develop. Therefore, fat necrosis is
the primary, and inflammation the secondary, event in
this type of panniculitis.
The inherent capacity of the adipose tissue to
respond to pathologic stimuli also holds true for disease conditions that affect the subcutaneous tissue
only secondarily or result from exogenous factors.
Traumatic panniculitis leads to necrosis of fat lobules
and a reactive inflammatory and granulomatous tissue
response. After the injection of oils or silicone, large
cystic cavities may be formed, whereas after the injection of pentazocine, for instance, fibrosis and sclerosis
dominate the histopathologic picture. Oily substances
may remain within the adipose tissue for long periods without causing a significant tissue reaction; oil
cysts evolve that are surrounded by multiple layers of
residual connective tissue, so that the tissue acquires a
Swiss cheese appearance. Animal or vegetable oils
often lead to tuberculoid or lipophagic granulomas
with massive histiocytic reactions, foam cells, and secondary fibrosis.
Panniculitis also occurs as a result of infectious
agents (cocci, mycobacteria, and other bacterial and
fungal organisms) or a specific disease process. In sarcoidosis, fat is gradually replaced by epithelioid cell
nodules and, in lymphoma, by specific lymphomatous
infiltrates. In lupus panniculitis, a dense lymphocytic
infiltrate of the septal and lobular tissue determines
the histopathologic picture, as does involvement of
vessels manifesting as vasculitis. However, destruction of fat, liquefaction, and lipogranuloma may be so
pronounced that the vascular component can hardly
be recognized, and the histopathologic picture may
resemble idiopathic nodular panniculitis.
Chapter 6
Figure 6-23 Nodular vasculitis. The characteristic features

illustrated are severe vasculitis with necrosis of the large
vessel wall and occlusion of the lumen. Necrosis of the fat
lobules is present, as well as an acute and chronic inflammatory cell infiltrate.
We are in the infancy of understanding the molecular underpinnings of various reaction patterns in the
subcutis. This is in part because our understanding of
the normal physiology of subcutaneous fat has only
recently moved past the historical notion of energy storage. We now know that the subcutis is a potent source of
stem cells that have remarkable differentiation plasticity and thus implications for use in regenerative medicine. The fat lobule itself is much more that an energy
storage site; it also generates a variety of proinflammatory and thrombogenic cytokines that, as is the case
with epidermally derived cytokines, are likely to play
a key role in regulating the various reaction patterns to
which fat is heir. Moreover, given its location deep to the
dermalepidermal environmental interface, the subcutaneous fat has the spatial attributes to serve as a
barometer for systemic molecular cues that may herald generalized disease. Finally, perturbation in the fat
producing specific reaction patterns in association with
aberrant cytokine production may themselves contribute to systemic health and disease, as is currently
speculated with regard to proinflammatory mediators
produced in the subcutis that may contribute to the evolution of some forms of cardiovascular disease.
Ackerman AB et al: Histologic Diagnosis of Inflammatory Skin

Diseases: An Algorithmic Method Based on Pattern Analysis,
2nd edition. Baltimore, Williams & Wilkins, 1997
Bailey EA et al: Marginal zone lymphoma (low-grade B cell
lymphoma of mucosa-associated lymphoid tissue type) of
skin and subcutaneous tissue. Am J Surg Pathol 20:1011, 1996
Biederman T, Rocken M, Carballido JM: TH1 and TH2 lymphocyte development and regulation of TH cell-mediated
immune responses of the skin. J Invest Dermatol Symp Proc
9:5, 2004
Cerroni L et al: An Illustrated Guide to Skin Lymphoma. Oxford,
Blackwell Sciences, 1998
Crowson AN, Magro CM: The cutaneous pathology of lupus
erythematosus: A review. J Cutan Pathol 28:1, 2001
Crowson AN et al: Cutaneous vasculitis: A review. J Cutan
Pathol 30:161, 2003
Elder DE et al: Levers Histopathology of the Skin, 8th edition.
Philadelphia, Lippincott Williams and Wilkins, 2004
Magro CM et al: Granuloma annulare and necrobiosis lipoidica tissue reactions as a manifestation of systemic disease.
Hum Pathol 27:50, 1996
Magro CM et al: The Lymphoid Proliferations. New York, WileyLiss, 2006
McKee PH et al: Pathology of the Skin, 3rd edition. Philadelphia, Elsevier Mosby, 2005
Murphy GF, Mihm MC Jr.: Inflammatory Diseases of the Skin.
AFIP Fascicle, third series, AFIP September 2006
Schaerli P, Moser B: Chemokine: Control of primary and
memory T-cell traffic. Immunol Res 31:57, 2005
Udey MC: Skin dendritic cells in immunity and autoimmunity. J Investig Dermatol Symp Proc 9:1507, 2004
57
Overview of Biology, Development, and

Structure of Skin
Chapter 7 :: Development and Structure of Skin

:: David H. Chu
STRUCTURE AND FUNCTION OF
SKIN AT A GLANCE
Three major layersepidermis, dermis,
hypodermis:
Epidermis: major permeability barrier,
innate immune function, adhesion, and
ultraviolet protection.
Dermis: major structural element, three
types of componentscellular, fibrous
matrix, and diffuse and filamentous
matrix. Also site of vascular, lymphatic,
and nerve networks.
Hypodermis (subcutis): insulation,
mechanical integrity, containing the larger
source vessels and nerves.
SKIN: AN OVERVIEW
Skin is a complex organ that protects its host from its
environment, at the same time allowing interaction
with its environment. It is much more than a static,
impenetrable shield against external insults. Rather,
skin is a dynamic, complex, integrated arrangement
of cells, tissues, and matrix elements that mediates a
diverse array of functions: skin provides a physical
permeability barrier, protection from infectious agents,
thermoregulation, sensation, ultraviolet (UV) protection, wound repair and regeneration, and outward
physical appearance (Table 7-1). These various functions of skin are mediated by one or more of its major
regionsthe epidermis, dermis, and hypodermis
(Fig. 7-1; see also Fig. 6-1, Chapter 6). These divisions
are interdependent, functional units; each region of
skin relies upon, and is connected with, its surrounding tissue for regulation and modulation of normal
structure and function at molecular, cellular, and tissue
levels of organization (see Chapter 6).
Whereas the epidermis and its outer stratum corneum provide a large part of the physical barrier pro-
vided by skin, the structural integrity of skin as a whole

is provided primarily by the dermis and hypodermis.
Antimicrobial activities are provided by the innate
immune system and antigen-presenting dendritic cells
of the epidermis, circulating immune cells that migrate
from the dermis, and antigen-presenting cells of the
dermis (see Chapter 10). Protection from UV irradiation is provided in great measure by the most superficial cells of the epidermis. Inflammation begins with
the keratinocytes of the epidermis or immune cells
of the dermis, and sensory apparatus emanates from
nerves that initially traverse the hypodermis to the
dermis and epidermis, ending in specialized receptive
organs or free nerve endings. The largest blood vessels
of the skin are found in the hypodermis, which serve
to transport nutrients and immigrant cells (see Fig. 6-1,
Chapter 6). The cutaneous lymphatics course through
the dermis and hypodermis, serving to filter debris
and regulate tissue hydration. Epidermal appendages
provide special protective or sensory functions. Skin
also determines a persons physical appearance, influenced by pigmentation provided by melanocytes, with
body contours, appearance of age, and actinic damage
influenced by the epidermis, dermis, and hypodermis.
The skin begins to be organized during embryogenesis,
where intercellular and intracellular signals, as well as
reciprocal cross talk between different tissue layers, are
instrumental in regulating the eventual maturation of
the different components of skin.
What follows is an integrated description of the
major structural features of the skin and how these
structures allow the skin to achieve its major functions,
followed by a review of their embryologic origins.
Also highlighted are illustrative cutaneous diseases
that manifest when these functions are defective.
Understanding the genetic and molecular bases of skin
disease has confirmed, and in some cases revealed, the
many factors and regulatory elements that play critical
roles in skin function.
EPIDERMIS
One of the most fundamental and visible features of
skin is the stratified, cornified epidermis (Fig. 7-2).
The epidermis is a continually renewing structure
that gives rise to derivative structures called append-
TABLE 7-1
Functions of Skin
Permeability barrier
Epidermis
Atopic dermatitis
Ectodermal dysplasias
Ichthyoses
Keratodermas
Exfoliative dermatitis
Bullous diseases
Protection from pathogens
Epidermis
Dermis
Verruca vulgaris
Ecthyma
Cellulitis
Leishmaniasis
Human immunodeficiency virus
Tinea pedis/corporis
Thermoregulation
Epidermis
Dermis
Hypodermis
Ectodermal dysplasias
Raynaud
Hyperthermia
Sensation
Epidermis
Dermis
Hypodermis
Diabetic neuropathy
Leprosy
Pruritus
Postherpetic neuralgia
Ultraviolet protection
Epidermis
Xeroderma pigmentosum
Oculocutaneous albinism
Wound repair/regeneration
Epidermis
Dermis
Keloid
Venous stasis ulcer
Pyoderma gangrenosum
Physical appearance
Epidermis
Dermis
Hypodermis
Melasma
Vitiligo
Scleroderma
Lipodystrophy
Development and Structure of Skin
Some Associated Diseases
::
Tissue Layer
Chapter 7
Function
Schematic of epidermis
SC
GL
SL
BL
DEJ
Figure 7-1 The major regions of skin. Skin is composed of

three layers: (1) epidermis, (2) dermis, and (3) hypodermis.
The outermost epidermis is separated from the dermis by
a basement membrane zone, the dermalepidermal junction. Below the dermis lies the subcutaneous fat (hypodermis). Epidermal appendages, such as hair follicles and
eccrine and apocrine sweat glands, begin in the epidermis but course through the dermis and/or the epidermis.
Blood vessels, lymphatics, and nerves course through the
subcutaneous fat and emerge into the dermis.
Figure 7-2 Schematic of epidermis. The epidermis is a

stratified, cornified epithelium. The deepest layer consists
of basal cells (BL) that rest upon the basement membrane
of the dermalepidermal junction (DEJ). These cells differentiate into the cells of the spinous layer (SL), characterized by abundant desmosomal spines. Spinous cells eventually become granular layer cells (GL), producing many of
the components of the cornified envelope. Ultimately, the
terminally differentiated keratinocytes shed their nuclei
and become the stratum corneum (SC), a cross-linked
network of protein and glycolipids.
59
Section 3
::
Overview of Biology, Development, and Structure of Skin
ages (pilosebaceous units, nails, and sweat glands).

The epidermis ranges in thickness from 0.4 to 1.5 mm,
as compared with the 1.5- to 4.0-mm full-thickness
skin. The majority of cells in the epidermis are keratinocytes that are organized into four layers, named
for either their position or a structural property of
the cells. These cells progressively differentiate from
proliferative basal cells, attached to the epidermal
basement membrane, to the terminally differentiated,
keratinized stratum corneum, the outermost layer and
barrier of skin (see Chapter 46). Intercalated among the
keratinocytes at various levels are the immigrant resident cellsmelanocytes, Langerhans cells, and Merkel
cells. Other cells, such as lymphocytes, are transient
inhabitants of the epidermis and are extremely sparse
in normal skin. There are many regional differences in
the epidermis and its appendages. Some of these differences are apparent grossly, such as thickness (e.g.,
palmoplantar skin vs. truncal skin, Fig. 7-3); other differences are microscopic.
Pathologic changes in the epidermis can occur as
a result of a number of different stimuli: repetitive
mechanical trauma (as in lichen simplex chronicus),
inflammation (as in atopic dermatitis and lichen planus), infection (as in verruca vulgaris), immune system
activity and cytokine abnormalities (as in psoriasis,
Fig. 7-4), autoantibodies (as in pemphigus vulgaris
and bullous pemphigoid), or genetic defects that influence differentiation or structural proteins [as in epider-
60
Figure 7-3 Anatomic variation in epidermal thickness.

A. Acral skin. B. Eyelid skin. Note that the epidermis is considerably thicker in (A) than (B), including the compact
layers of the stratum corneum, as well as the deeper epidermal layers.
Figure 7-4 Epidermal hyperplasia. Hyperproliferation

of the epidermis can occur due to a number of causes,
as manifested in diseases such as psoriasis (pictured), as
well as lichen simplex chronicus, atopic dermatitis, lichen
planus, and verruca vulgaris.
molysis bullosa (EB) simplex, epidermolytic ichthyosis

and other ichthyoses, and Darier disease].
LAYERS OF THE EPIDERMIS

BASAL LAYER. The keratinocyte is an ectodermally
derived cell and is the primary cell type in the epidermis, accounting for at least 80% of the total cells. The
ultimate fate of these cells is to contribute the components for the epidermal barrier as the stratum corneum. Thus, much of the function of the epidermis can
be gleaned from the study of the structure and development of the keratinocyte.
Keratinocyte differentiation (keratinization) is a genetically programed, carefully regulated, complex series of
morphologic changes and metabolic events whose endpoint is a terminally differentiated, dead keratinocyte
(corneocyte) that contains keratin filaments, matrix protein, and a protein-reinforced plasma membrane with
surface-associated lipids (see Chapter 46).
Keratins are a family of intermediate filaments and
are the hallmark of all epithelial cells, including keratinocytes.1,2 They serve a predominantly structural
role in the cells. Fifty-four different functional keratin
genes have been identified in humans34 epithelial
keratins and 17 hair keratins.3 The coexpression of specific keratin pairs is dependent on cell type, tissue type,
developmental stage, differentiation stage, and disease
condition (Table 7-2). Furthermore, the critical role of
these molecules is underscored by the numerous manifestations of disease that arise because of mutations in
these genes (see Table 7-2). Thus, knowledge of keratin
expression, regulation, and structure provides insight
into epidermal differentiation and structure.
The basal layer (stratum germinativum) contains
mitotically active, columnar-shaped keratinocytes
that attach via keratin filaments (K5 and K14) to the
basement membrane zone at hemidesmosomes (see
Chapter 53), attach to other surrounding cells through
TABLE 7-2
Expression Patterns of Keratin Genes and Keratin-Associated Diseases

Disease Association
10
Suprabasal keratinocytes
Epidermolytic ichthyosis; diffuse

nonepidermolytic PPK (keratin 1)
Suprabasal keratinocytes (palmoplantar skin)
Epidermolytic PPK (epidermolytic

hyperkeratosis)
10
Upper spinous and granular layers
Superficial epidermolytic ichthyosis
12
Cornea
Meesmanns corneal dystrophy
13
Mucosal epithelium
White sponge nevus
14
Basal keratinocytes
Epidermolysis bullosa simplex
6a
16
Outer root sheath, hyperproliferative

keratinocytes, palmoplantar keratinocytes
Pachyonychia congenita; focal

nonepidermolytic PPK
6b
17
Nail bed, epidermal appendages
Pachyonychia congenita; steatocystoma

multiplex
18
Simple epithelium
Cryptogenic cirrhosis
PPK = palmoplantar keratoderma.
desmosomes, and that give rise to cells of the more

superficial, differentiated epidermal layers. Membranebound vacuoles that contain pigmented melanosomes
are transferred from melanocytes by phagocytosis.4
The pigment within melanosomes contributes to the
overall skin pigmentation perceived macroscopically.5
The basal layer is the primary location of mitotically
active cells of the epidermis. Cell kinetic studies suggest that the basal layer cells exhibit different proliferative potentials (stem cells, transit amplifying cells, and
postmitotic cells), and in vivo and in vitro studies suggest that there exist long-lived epidermal stem cells (see
Chapter 45).6,7 Because basal cells can be expanded in
tissue culture and used to reconstitute sufficient epidermis to cover the entire skin surface of burn patients,8,9
such a starting population is presumed to contain longlived stem cells with extensive proliferative potential,
located within the basal epidermal layer (at the base of
epidermal proliferating units) and the hair follicle bulge.1013
The second type of cell, the transit amplifying cells of
the basal layer, arises as a subset of daughter cells produced by the infrequent division of stem cells, either
by symmetric or asymmetric cell division.14 These
cells provide the bulk of the cell divisions needed for
stable self-renewal and are the most common cells in
the basal compartment. These cells subsequently give
rise to the third class of epidermal basal cells, the postmitotic cells that undergo terminal differentiation. In
humans, the normal transit time for a basal cell, from
the time it loses contact with the basal layer to the
time it enters the stratum corneum, is at least 14 days.
Transit through the stratum corneum and subsequent
desquamation require another 14 days. These periods
of time can be altered in hyperproliferative or growtharrested states.
SPINOUS LAYER. The shape, structure, and subcellular properties of spinous cells correlate with their
position within the midepidermis. They are named for

the spine-like appearance of the cell margins in histologic sections. Suprabasal spinous cells are polyhedral
in shape with a rounded nucleus. As these cells differentiate and move upward through the epidermis,
they become progressively flatter and develop organelles known as lamellar granules (see Section Granular
Layer). Spinous cells also contain large bundles of
keratin filaments, organized around the nucleus and
inserted into desmosomes peripherally.
Spinous cells retain the stable K5/K14 keratins that
are produced in the basal layer and only synthesize
new messenger RNA (mRNA) for these proteins in
hyperproliferative disorders. Instead, new synthesis
of the K1/K10 keratin pair occurs in this epidermal
layer. These keratins are characteristic of an epidermal pattern of differentiation and thus are referred
to as the differentiation-specific or keratinization-specific
keratins. However, in hyperproliferative conditions
such as psoriasis, actinic keratoses, and wound healing, synthesis of K1 and K10 mRNA and protein is
downregulated, and the synthesis and translation
of messages for K6 and K16 are favored. Correlated
with this change in keratin expression is a disruption
of normal differentiation in the subsequent granular
and cornified epidermal layers (see Sections Granular Layer and Stratum Corneum). mRNA for K6
and K16 are present throughout the epidermis normally, but the message is only translated on stimulation of proliferation.
The spines of spinous cells are abundant desmosomes, calcium-dependent cell surface modifications
that promote adhesion of epidermal cells and resistance to mechanical stress (see Chapters 46 and 53).15
Although desmosomes are related to adherens junctions, the latter associate with actin microfilaments
at cellcell interfaces, via a distinct set of cadherins
(e.g., E-cadherin) and intracellular catenin adapter
Tissue Expression
::
Acidic
Chapter 7
Basic
61
TABLE 7-3
Diseases Resulting from Disruption of Desmosomal Proteins
Section 3
::
62
Protein
Diseases
Desmoglein 1
Pemphigus foliaceus
Striate palmoplantar keratoderma
Staphylococcal scalded-skin syndrome
Bullous impetigo
Desmoglein 3
Pemphigus vulgaris
Desmoglein 4
Autosomal recessive hypotrichosis
Plakoglobin
Palmoplantar keratoderma with wooly hair and arrhythmogenic right ventricular cardiomyopathy
(Naxos disease)
Plakophilin 1
Ectodermal dysplasia/skin fragility syndrome (skin erosions, dystrophic nails, sparse hair, and
painful palmoplantar keratoderma)
Plakophilin 2
Arrhythmogenic right ventricular cardiomyopathy
Desmoplakin
Lethal acantholytic epidermolysis bullosa

Striate palmoplantar keratoderma, type I
Palmoplantar keratoderma with left ventricular cardiomyopathy and wooly hair
Autosomal dominant arrhythmogenic right ventricular cardiomyopathy
molecules. That the desmosomes are integral mediators of intercellular adhesion is clearly demonstrated
in diseases in which these structures are disrupted, by
genetic disorders, autoantibodies, or bacterial proteases (Table 7-3).16,17
The importance of calcium as a mediator of adhesion is well illustrated in the cases of two conditions
that exhibit characteristic epidermal dyscohesion: (1)
Darier disease (keratosis follicularis) and (2) Hailey
Hailey disease (benign chronic pemphigus) (see Chapter 51).18 Both of these diseases are caused by mutations
in genes that regulate calcium transport, SERCA2 in
Darier disease and ATP2C1 in HaileyHailey disease.
Lamellar granules are also formed in this layer of
epidermal cells (Fig. 7-5). These secretory organelles
deliver precursors of stratum corneum lipids into
the intercellular space (see Chapter 47). Genetic diseases demonstrate the importance of steroid and lipid
metabolism for sloughing of cornified cellsin recessive X-linked ichthyosis, for example, mutation of steroid sulfatase results in a retention hyperkeratosis (see
Chapter 49).19
GRANULAR LAYER. Named for the basophilic

keratohyalin granules that are prominent within cells
at this level of the epidermis, the granular layer is the
site of generation of a number of the structural components that will form the epidermal barrier, as well as
a number of proteins that process these components
(see Fig. 7-2).20,21 Keratohyalin granules (see Fig. 7-5)
are composed primarily of profilaggrin, keratin filaments, and loricrin. It is in this layer that the cornified cell envelope begins to form, with the conversion
of profilaggrin to filaggrin. After aggregation with
keratin to form macrofilaments, filaggrin is degraded
into molecules such as urocanic acid and pyrrolidone
carboxylic acid, which contribute to hydration of the
stratum corneum and help filter UV radiation. Loricrin
is a cysteine-rich protein that forms the major protein
component of the cornified envelope. Upon its release
from keratohyalin granules, loricrin binds to desmosomal structures and is subsequently cross-linked to
the plasma membrane by tissue transglutaminases
(TGMs, primarily TGMs 3 and 1) to form the cornified
cell envelope.
Figure 7-5 Junction of the stratum granulosum (SG) and stratum corneum (SC). Lamellar
granules (LG) are in the intercellular space and
cytoplasm of the granular cell. Keratohyalin
granules (KHG) are also evident. Inset: Lamellar
granule, 28,750. (From Holbrook K: Structure
and development of the skin. In: Pathophysiology
of Dermatologic Disease, 2nd edition, edited by
Soter NA, Baden HP. New York, McGraw-Hill,
1991, p. 7, with permission. Inset used with permission from EC Wolff-Schreiner, MD.)
Chapter 7
Mutations in the TGM1 gene have been shown to

be the basis of some cases of lamellar ichthyosis.22,23
Another form of ichthyosis, ichthyosis vulgaris, is
caused by mutations in the gene encoding filaggrin.24,25
Loricrin abnormalities result in a form of Vohwinkel
syndrome with ichthyosis and pseudoainhum, as
well as the disease progressive symmetric keratodermia.2628 These findings emphasize the importance of
proper formation of the cornified envelope in normal
epidermal keratinization.
The final stage of granular cell differentiation into a
corneocyte involves the cells own programed destruction, during which process almost all cellular contents
are destroyed, with the exception of the keratin filaments and filaggrin matrix.20
STRATUM CORNEUM (SEE CHAPTER 47).
Melanocytes are neural crest-derived, pigmentsynthesizing dendritic cells that reside primarily in the
basal layer (see Chapter 72).30 The function of melanocytes has been highlighted by disorders in melanocyte
number or function. The classic dermatologic disease,
vitiligo, is caused by the autoimmune depletion of
melanocytes.31 Causes of other disorders of pigmentation are found in various defects in melanogenesis,
including melanin synthesis, melanosome production,
and melanosome transport and transfer to keratinocytes (see Chapters 72 and 75). Regulation of melanocyte proliferation and homeostasis is under intensive
study as well as a means to understanding melanoma
(see Chapter 124).32 Keratinocytemelanocyte interactions are critical for melanocyte homeostasis and differentiation, influencing proliferation, dentricity, and
melanization.
Merkel cells are slow-adapting type I mechanoreceptors located in sites of high-tactile sensitivity (see
Chapter 120).33 They are present among basal keratinocytes in hairy skin and in the glabrous skin of the
digits, lips, regions of the oral cavity, and the outer
root sheath of the hair follicle. Keratin 20 is restricted

to Merkel cells in the skin and thus may be the most
reliable molecular marker. Ultrastructurally, Merkel
cells are easily identified by the membrane-bounded,
dense-core granules that collect opposite the Golgi and
proximal to an unmyelinated neurite (Fig. 7-6). These
granules contain neurotransmitter-like substances
and markers of neuroendocrine cells, including Metenkephalin, vasoactive intestinal peptide, neuron-specific enolase, and synaptophysin. Although increasingly more is being learned about the normal function
of Merkel cells, they are of particular clinical note
because Merkel cell-derived neoplasms are particularly aggressive and difficult to treat (see Chapter 120).
Langerhans cells are dendritic antigen-processing
and antigen-presenting cells in the epidermis (see
Chapter 10).34 Although they are not unique to the
epidermis, they form 2% to 8% of the total epidermal
cell population, mostly found in a suprabasal position.
The cytoplasm of the Langerhans cells contains characteristic small rod- or racket-shaped structures called
Langerhans cell granules or Birbeck granules (Fig. 7-7).
Langerhans cells principally function to sample and
present antigens to T cells of the epidermis. Because of
these functions, they are implicated in the pathologic
mechanisms underlying allergic contact dermatitis,
cutaneous leishmaniasis, and human immunodeficiency virus infection. Langerhans cells are reduced in
the epidermis of patients with certain conditions, such
as psoriasis, sarcoidosis, and contact dermatitis; they
are functionally impaired by UV radiation, especially
UVB.
Because of their effectiveness in antigen presentation and lymphocyte stimulation, dendritic cells and
Langerhans cells have become prospective vehicles
for tumor therapy and tumor vaccines. These cells
are loaded with tumor-specific antigens, which will
NONKERATINOCYTES
OF THE EPIDERMIS
Figure 7-6 Merkel cells from the finger of a 130-mm CR

(crown-rump) 21-week human fetus. Note nerve (N) in
direct contact with the lateral and basal surfaces of the cell
and dense core cytoplasmic granules (G). 13,925. Inset:
Merkel cell granules, 61,450.
::
Complete differentiation of granular cells results in

stacked layers of anucleate, flattened cornified cells
that form the stratum corneum. It is this layer that provides mechanical protection to the skin and a barrier
to water loss and permeation of soluble substances
from the environment.21,29 The stratum corneum barrier is formed by a two-compartment system of lipiddepleted, protein-enriched corneocytes surrounded
by a continuous extracellular lipid matrix. These two
compartments provide somewhat segregated but
complementary functions that together account for the
barrier activity of the epidermis. Regulation of permeability, desquamation, antimicrobial peptide activity, toxin exclusion, and selective chemical absorption
are all primarily functions of the extracellular lipid
matrix. On the other hand, mechanical reinforcement,
hydration, cytokine-mediated initiation of inflammation, and protection from UV damage are all provided
by the corneocytes.
63
DERMIS
Section 3
::
64
Figure 7-7 Langerhans cell. Note indented nucleus, lysosomes, as well as rod- and racket-shaped cytoplasmic
granules (Birbeck granules), and the absence of keratin
filaments. 13,200. Inset: Birbeck granules 88,000. (Used
with permission from N. Romani, MD.)
then stimulate the host immune response to mount
an antigen-specific, and therefore tumor-specific,
response.
The dermalepidermal junction (DEJ) is a basement
membrane zone that forms the interface between the
epidermis and dermis (see Chapter 53).35,36 The major
functions of the DEJ are to attach the epidermis and
dermis to each other and to provide resistance against
external shearing forces. It serves as a support for the
epidermis, determines the polarity of growth, directs
the organization of the cytoskeleton in basal cells, provides developmental signals, and serves as a semipermeable barrier.
The DEJ can be subdivided into three supramolecular networks: (1) the hemidesmosome-anchoring
filament complex, (2) the basement membrane itself,
and (3) the anchoring fibrils. The critical role of this
region in maintaining skin structural integrity is
revealed by the large number of mutations in DEJ
components that cause blistering diseases of varying severity, covered in detail in Chapter 62. These
bullous diseases are grouped according to the level
of the cleavage within the DEJthe most superficial,
EB simplex, involves basal keratinocyte cleavage.
Junctional EB occurs within the lamina lucida and
lamina densa regions. Dystrophic EB is the deepest level of blistering, within the sublamina densa/
anchoring filaments. Chapter 53 provides a detailed
discussion of the DEJ networks.
The dermis is an integrated system of fibrous, filamentous, diffuse, and cellular connective tissue elements that
accommodates nerve and vascular networks, epidermally derived appendages, and contains many resident
cell types, including fibroblasts, macrophages, mast cells,
and transient circulating cells of the immune system (see
Figs. 6-9 and 6-14). The dermis makes up the majority
of skin and provides its pliability, elasticity, and tensile
strength. It protects the body from mechanical injury,
binds water, aids in thermal regulation, and includes
receptors of sensory stimuli. The dermis interacts with
the epidermis in maintaining the properties of both
tissues, collaborates during development in the morphogenesis of the DEJ and epidermal appendages (see
Section Development of Skin Appendages), and interacts in repairing and remodeling skin after wounding.
The dermis is arranged into two major regions: (1)
the upper papillary dermis and (2) the deeper reticular
dermis. These two regions are readily identifiable on
histologic section, and they differ in their connective
tissue organization, cell density, and nerve and vascular patterns. The papillary dermis abuts the epidermis,
molds to its contours, and is usually no more than twice
its thickness (see Fig. 6-9). The reticular dermis forms
the bulk of the dermal tissue. It is composed primarily of large-diameter collagen fibrils, organized into
large, interwoven fiber bundles, with branching elastic
fibers surrounding the bundles (see Fig. 6-14). In normal individuals, the elastic fibers and collagen bundles
increase in size progressively toward the hypodermis.
The subpapillary plexus, a horizontal plane of vessels,
marks the boundary between the papillary and reticular dermis. The lowest boundary of the reticular dermis is defined by the transition of fibrous connective
tissue to adipose connective tissue of the hypodermis.
FIBROUS MATRIX OF THE DERMIS

The connective tissue matrix of the dermis is comprised primarily of collagenous and elastic fibrous
tissue.37,38 These are combined with other, nonfibrous
connective tissue molecules, including finely filamentous glycoproteins, proteoglycans (PGs), and glycosaminoglycans (GAGs) of the ground substance. 39
Collagen forms the bulk of the acellular portion of the
dermis, accounting for approximately 75% of the dry
weight of skin, and providing both tensile strength and
elasticity. (For details regarding the polypeptide structure and distribution of collagens, see Chapter 63.) The
periodically banded, interstitial collagens account for the
greatest proportion of collagen in adult dermis (type I,
80% to 90%; type III, 8% to 12%; and type V, <5%). Type
VI collagen is associated with fibril and in the interfibrillar spaces. Type IV collagen is confined to the basal lamina of the DEJ, vessels, and epidermal appendages. Type
VII collagen forms anchoring fibrils at the DEJ.
Elastic connective tissue (see Chapter 63) is a complex molecular mesh, extending from the lamina densa
of the DEJ throughout the dermis and into the connective tissue of the hypodermis.38 Elastic fibers return the
CELLULAR COMPONENTS
OF THE DERMIS
Fibroblasts, macrophages, and mast cells are the regular residents of the dermis, mostly found around
the papillary region and surrounding vessels of the
subpapillary plexus (see Fig. 6-20), as well as in the
The fibrous and cellular matrix elements are embedded within more amorphous matrix components,
which also are found in basement membranes.4446
PGs are large molecules consisting of a core protein
that determines which GAGs will be incorporated into
the molecule. The PG/GAG complex can bind water
up to 1,000 times its own volume and have roles in
regulation of water binding and compressibility of the
dermis, as well as increasing local concentrations of
growth factors through binding (e.g., basic fibroblast
growth factor). They also link cells with the fibrillar
and filamentous matrix, influencing proliferation, differentiation, tissue repair, and morphogenesis.
The major PGs in the adult dermis are chondroitin sulfates/dermatan sulfate, including biglycan,
decorin, and versican; heparan/heparan sulfate PGs,
including perlecan and syndecan; and chondroitin-6
sulfate PGs, which are components of the DEJ (see
Chapter 63). Glycoproteins interact with other matrix
components via integrin receptors. They facilitate cell
migration, adhesion, morphogenesis, and differentiation. Fibronectin is synthesized by both epithelial and
mesenchymal cells, and it covers collagen bundles and
the elastic network. Vitronectin is present on all elastic
fibers except for oxytalan. Tenascin is found around
the smooth muscle of blood vessels, arrector pili muscles, and appendages such as sweat glands.
::
FILAMENTOUS AND DIFFUSE MATRIX

COMPONENTS OF THE DERMIS (SEE
CHAPTER 63)
reticular dermis between collagen fiber bundles. The

fibroblast is a mesenchymally derived cell that migrates
through the tissue and is responsible for the synthesis
and degradation of fibrous and nonfibrous connective
tissue matrix proteins and a number of soluble factors.
Fibroblasts provide a structural extracellular matrix
framework as well as promote interaction between
epidermis and dermis by synthesis of soluble mediators. Studies of human fibroblasts indicate that even
within a single tissue, phenotypically distinct populations exist, some of which relate to regional anatomical differences.47,48 These cells are also instrumental in
wound healing and scarring, increasing their proliferative and synthetic activity during these processes.
The monocytes, macrophages, and dermal dendrocytes constitute the mononuclear phagocytic system of
cells in the skin. Macrophages are derived from precursors in the bone marrow, differentiate into circulating
monocytes, and then migrate into the dermis to differentiate. These cells are phagocytic; process and present antigen to immunocompetent lymphoid cells; are
microbicidal, tumoricidal, secretory, and hematopoietic (see Chapter 10); and are involved in coagulation,
atherogenesis, wound healing, and tissue remodeling.
Mast cells (see Chapter 149) are specialized secretory
cells that, in skin, are present in greatest density in the
papillary dermis, near the DEJ, in sheaths of epidermal
appendages, and around blood vessels and nerves of
the subpapillary plexus. The surface of dermal mast
cells is coated with fibronectin, which probably assists
in securing cells within the connective tissue matrix.
Mast cells are secretory cells that are responsible for
immediate-type hypersensitivity reaction in skin and
are involved in the production of subacute and chronic
inflammatory disease. They synthesize secretory
granules composed of histamine, heparin, tryptase,
chymase, carboxypeptidase, neutrophil chemotactic
factor, and eosinophilic chemotactic factor of anaphylaxis, which are mediators in these processes. Mast
cells can become hyperplastic and hyperproliferative
in mastocytosis (see Chapter 149).
The dermal dendrocyte is a dendritic, highly phagocytic fixed connective tissue cell in the dermis of normal
skin. Similar to many other bone marrow-derived cells,
dermal dendrocytes express factor XIIIa and CD45,
and they lack typical markers of fibroblasts. These cells
are particularly abundant in the papillary dermis and
upper reticular dermis, frequently in the proximity of
vessels of the subpapillary plexus. Dermal dendrocytes
function in the afferent limb of an immune response as
antigen presenting cells (see Chapter 10). They are also
likely the cells of origin of a number of benign fibrotic
proliferative conditions in the skin, such as dermatofibromas and fibroxanthomas (see Chapter 66).
Chapter 7
skin to its normal configuration after being stretched or

deformed. They are also present in the walls of cutaneous blood vessels and lymphatics and in the sheaths
of hair follicles. Mutations in elastin, the elastic fiber
matrix component, cause the disease cutis laxa. Elastic
fibers are normally located between bundles of collagen
fibers, although in certain pathologic conditions, such as
BuschkeOllendorff syndrome, both elastic and collagen
fibers become assembled within the same bundle. The
importance of the elastic fiber network is clearly seen in
the number of multisystem diseases that arise because
of mutations in components of this network. The defect
underlying pseudoxanthoma elasticum (PXE) is a
mutation in ABCC6, a member of the large adenosine
triphosphate-dependent transmembrane transporter
family. Thus, this disease that is characterized by loss
of skin elasticity and calcified elastic fibers is unlikely
a primary defect in elastic tissue, but rather a metabolic disorder with secondary involvement of elastic
fibers.4042 In addition to genetic mutations, solar radiation and aging also contribute to elastic fiber damage.43
CUTANEOUS VASCULATURE
BLOOD VESSELS (SEE CHAPTER 162)
The blood vessels of skin provide nutrition for the tissue and are involved in temperature and blood pressure
regulation, wound repair, and numerous immunologic
65
Section 3
::
events.49 The microcirculatory beds in skin progress

from arterioles to precapillary sphincters. Extending
from the sphincters are arterial and venous capillaries,
which become postcapillary venules, and finally, collecting venules. When compared with vasculature of
other organs, the vessels of skin are adapted to shearing forces, as they have thick walls supported by connective tissue and smooth muscle cells. Special cells,
known as veil cells, surround the cutaneous microcirculation, defining a domain for the vessels within the
dermis while remaining separate from the vessel walls.
The rich vascular network of the skin is located at
boundaries within the dermis and supplies the epidermal appendages (see Fig. 163-2). The vessels that supply the dermis branch from musculocutaneous arteries
that penetrate the subcutaneous fat and enter the deep
reticular dermis. At this point, they are organized into a
horizontal arteriolar plexus. From this plexus, ascending
arterioles extend toward the epidermis. These arterioles
contain two layers of smooth muscle cells, as well as
pericytes, a second type of contractile cell of the vessel
wall. At the junction between the papillary and reticular
dermis, terminal arterioles form the subpapillary plexus.
Capillary loops then extend from the terminal arterioles
of the plexus into the papillary dermis. At the apex of
each capillary loop is the thinnest portion, allowing for
transport of material out of the capillary. The descending limbs of capillary loops are venous capillaries that
drain into venous channels of the subpapillary plexus.
The postcapillary venules of the subpapillary plexus are
responsive to histamine and are therefore often the sites
of inflammatory cells during these responses.
Certain regions of skin, such as the palms and soles,
contain direct connections between arterial and venous
circulation as potential shunts around congested capillary beds. These sites consist of an ascending arteriole
(a glomus body), which is modified by three to six layers of smooth muscle cells and has associated sympathetic nerve fibers.
In the adult, the cutaneous vasculature normally
remains quiescent, in part due to inhibition of angiogenesis by factors such as thrombospondin. Pathogenic
stimuli sometimes result in secondary angiogenesis,
from tumors or during wounding. One of the key
mediators of such angiogenesis is vascular endothelial
growth factor (VEGF), often secreted by tumors or by
keratinocytes (see Chapter 162).50,51
Numerous disorders can manifest themselves within
the cutaneous vasculature. Leukocytoclastic vasculitis
(cutaneous necrotizing venulitis) occurs within the
venules in response to a number of potential pathogenic mechanisms (see Chapter 163). Stasis dermatitis,
urticaria, polyarteritis nodosa, thrombosis, and thrombophlebitis all affect vessels in the skin, of different
sizes, some by occlusion of vessels (vasculopathy) and
others by inflammation of the vessels (vasculitis).
LYMPHATICS
66
The lymph channels of the skin regulate pressure of

the interstitial fluid by resorption of fluid released
from vessels and in clearing the tissues of cells, pro-
teins, lipids, bacteria, and degraded substances.52,53 The

vessels begin in blind-ending initial lymphatics in the
papillary dermis. They drain into a horizontal plexus
of larger lymph vessels located deep to the subpapillary venous plexus. A vertical system of lymphatics
then carries fluid and debris through the reticular dermis to another deeper collecting plexus at the reticular
dermishypodermis border. Lymph flow within the
skin depends on movements of the tissue caused by
arterial pulsations and larger scale muscle contractions
and movement of the body, with backflow prevented
by bicuspid-like valves within the vessels.
Lymphatic vessels are often collapsed in skin and
therefore are only seen with difficulty on histologic section. They are composed of a large lumen and a thinner
wall than blood vessels. Molecular characterization
of these vessels has identified Prox1, VEGFR-3, and
LYVE-1 as specific markers of lymphatic character.53
Certain pathologic conditions involve or highlight
the function of lymphatic vessels, such as lymphedema,
lymphangioma circumscriptum, and stasis dermatitis. The importance of lymphatics in the progression
and spread of cancer is also becoming more clear, as
melanoma cells destroy endothelial cells of the initial
lymphatics to gain entry to the lymph circulation, and
recent studies have shown that tumors themselves
can promote lymphangiogenesis as part of their early
program on the way to metastasis.51,54 The discovery
of the molecular defects in hereditary lymphedemas
has implicated the VEGFR-3 and FoxC2 in lymphatic
development. One of the most heavily studied lymphangiogenic molecules is VEGF-C (Chapter 162).
CUTANEOUS NERVES AND

RECEPTORS (SEE CHAPTERS 102
AND 103)
The nerve networks of the skin contain somatic sensory and sympathetic autonomic fibers.55 The sensory
fibers alone (free nerve endings) or in conjunction with
specialized structures (corpuscular receptors) function as receptors of touch, pain, temperature, itch, and
mechanical stimuli. The density and types of receptors
are regionally variable, accounting for the variation
in acuity at different sites of the body. Receptors are
particularly dense in hairless areas such as the areola,
labia, and glans penis. Sympathetic motor fibers are
codistributed with the sensory nerves in the dermis
until they branch to innervate the sweat glands, vascular smooth muscle, the arrector pili muscle of hair
follicles, and sebaceous glands.
The nerves of skin branch from musculocutaneous
nerves that arise segmentally from spinal nerves. The
pattern of nerve fibers in skin is similar to the vascular
patternsnerve fibers form a deep plexus, then ascend
to a superficial, subpapillary plexus.
Free nerve endings include the penicillate and papillary nerve fibers and are the most widespread sensory
receptors in skin. In humans, they are ensheathed by
Schwann cells and a basal lamina. Free nerve endings
are particularly common in the papillary dermis.
Figure 7-9 Pacinian corpuscle. Note the characteristic perineural capsule, likened to the appearance of an
onion-skin. Pacinian corpuscles serve as rapidly adapting
mechanoreceptors that respond to vibrational stimuli.
HYPODERMIS (SUBCUTIS)
The tissue of the hypodermis insulates the body, serves
as a reserve energy supply, cushions and protects
the skin, and allows for its mobility over underlying
structures. It has a cosmetic effect in molding body
contours. The boundary between the deep reticular
dermis and the hypodermis is an abrupt transition
from a predominantly fibrous dermal connective tissue to a primarily adipose subcutaneous one (see Fig.
6-1, Chapter 6). Despite this clear distinction anatomically, the two regions are still structurally and functionally integrated through networks of nerves and vessels
and through the continuity of epidermal appendages.
Actively growing hair follicles span the dermis and
extend into the subcutaneous fat, and the apocrine
and eccrine sweat glands are normally confined to this
depth of the skin.
Adipocytes form the bulk of the cells in the hypodermis.56,57 They are organized into lobules defined
by septa of fibrous connective tissue. Nerves, vessels,
and lymphatics are located within the septa and supply the region. The synthesis and storage of fat continues throughout life by enhanced accumulation of lipid
within fat cells, proliferation of existing adipocytes,
or by recruitment of new cells from undifferentiated
mesenchyme. The hormone leptin, secreted by adipocytes, provides a long-term feedback signal regulating
fat mass. Leptin levels are higher in subcutaneous than
omental adipose, suggesting a role for leptin in control
of adipose distribution as well.
The importance of the subcutaneous tissue is apparent in patients with Werner syndrome (see Chapter 139),
The Pacinian corpuscle lies in the deep dermis and

subcutaneous tissue of skin that covers weight-bearing
surfaces of the body. It has a characteristic capsule
and lamellar wrappings (Fig. 7-9). Pacinian corpuscles serve as rapidly adapting mechanoreceptors that
respond to vibrational stimuli.
::
Figure 7-8 Meissners corpuscle. Note the capsule and

inner core located in the dermal papillae. These collections
of cells serve as mechanoreceptors.
Chapter 7
The penicillate fibers are the primary nerve fibers

found subepidermally in haired skin. These are rapidly adapting receptors that function in the perception
of touch, temperature, pain, and itch. Because of overlapping innervation, discrimination tends to be generalized in these regions. On the other hand, free nerve
endings present in nonhaired, ridged skin, such as the
palms and soles, project individually without overlapping distribution and so are thought to function in fine
discrimination.
Papillary nerve endings are found at the orifice of a
follicle and are thought to be particularly receptive to
cold sensation. Hair follicles also contain other receptors, slow-adapting receptors that respond to the bending or movement of hairs. Cholinergic sympathetic
fibers en route to the eccrine sweat gland and adrenergic and cholinergic fibers en route to the arrector pili
muscle are carried along with the sensory fibers in the
hair basket.
Free nerve endings are also associated with individual Merkel cells. In haired skin, touch domes are
associated with hair follicles. In palmoplantar skin,
these complexes are found at the site where the eccrine
sweat duct penetrates a glandular epidermal papilla.
Corpuscular receptors, both Meissners and Pacinian, contain a capsule and inner core and are composed of both neural and nonneural components. The
capsule is a continuation of the perineurium, and the
core includes the nerve fiber surrounded by lamellated
wrappings of Schwann cells. Meissners corpuscles are
elongated or ovoid mechanoreceptors located in the
dermal papillae of digital skin and oriented vertically
toward the epidermal surface (Fig. 7-8).
67
Section 3
::
68
in which subcutaneous fat is absent in lesion areas over

bone, or with scleroderma (see Chapter 157), where the
subcutaneous fat is replaced with dense fibrous connective tissue. Such regions in Werner patients ulcerate
and heal poorly. The skin of patients with scleroderma
is taut and painful. In the hereditary and acquired lipodystrophies, loss of subcutaneous fat disrupts glucose,
triglyceride, and cholesterol regulation, and causes
significant cosmetic alteration, increasing the interest
in possible hormonal therapy for these disorders (see
Chapter 71).58 The subcutaneous tissue is involved in
different inflammatory conditions (Chapter 70).
DEVELOPMENT OF SKIN
Significant advances in the understanding of the
molecular processes responsible for the development
of skin have been made over the last several years.
Such advances increase the understanding of clinicopathologic correlation among some inherited disorders of skin and allow for the early diagnosis of such
diseases. The developmental progression of various
components of the skin is well documented, and a time
line indicating the events that occur during embryonic and fetal development is provided (Table 7-4).59,60
Of note, the estimated gestational age (EGA) is used
throughout this chapter; this system refers to the age
of the fetus, with fertilization occurring on day 1. To
avoid confusion, it should be pointed out that obstetricians and most clinicians define day 1 as the first day
of the last menstrual period (menstrual age), in which
fertilization occurs on approximately day 14. Thus, the
two dating systems differ by approximately 2 weeks,
such that a woman who is 14 weeks pregnant (menstrual age) is carrying a 12-week-old fetus (EGA).
Conceptually, fetal skin development can be divided
into three distinct but temporally overlapping stages,
those of (1) specification, (2) morphogenesis, and (3)
differentiation. These stages roughly correspond to the
embryonic period (060 days), the early fetal period (25
months), and the late fetal period (59 months) of development, respectively. The earliest stage, specification,
refers to the process by which the ectoderm lateral to
the neural plate is committed to become epidermis, and
subsets of mesenchymal and neural crest cells are committed to form the dermis. It is at this time that patterning of the future layers and specialized structures of the
skin occurs, often via a combination of gradients of proteins and cellcell signals. The second stage, morphogenesis, is the process by which these committed tissues
begin to form their specialized structures, including epidermal stratification, epidermal appendage formation,
subdivision between the dermis and subcutis, and vascular formation. The last stage, differentiation, denotes
the process by which these newly specialized tissues further develop and assume their mature forms. Table 7-5
integrates specification, morphogenesis, and differentiation with skin morphology and genetic diseases.
For simplification and greater clarity, the stages of
development of the epidermisdermis and hypodermis, dermalepidermal junction, and epidermal
appendagesare presented sequentially.
EPIDERMIS
EMBRYONIC DEVELOPMENT. During the third
week after fertilization, the human embryo undergoes
gastrulation, a complex process of involution and cell
redistribution that results in the formation of the three
primary embryonic germ layers: (1) ectoderm, (2)
mesoderm, and (3) endoderm. Shortly after gastrulation, ectoderm further subdivides into neuroectoderm
and presumptive epidermis. The specification of the
presumptive epidermis is believed to be mediated by
the bone morphogenetic proteins (BMPs). Later during
this period, BMPs again appear to play a critical role,
along with Engrailed-1 (En1), in specifying the volar
versus interfollicular skin.6163 By 6 weeks EGA, the
ectoderm that covers the body consists of basal cells
and superficial periderm cells.
The basal cells of the embryonic epidermis differ
from those of later developmental stages. Embryonic
basal cells are more columnar than fetal basal cells, and
they have not yet formed hemidesmosomes. Although
certain integrins (e.g., a6b4) are expressed in these
cells, they are not yet localized to the basal pole of the
cells. Before the formation of hemidesmosomes and
desmosomes, intercellular attachment between individual basal cells appears to be mediated by adhesion
molecules such as E- and P-cadherin, which have been
detected on basal cells as early as 6 weeks EGA. Keratins K5 and K14, proteins restricted to definitive stratified epithelia, are expressed even at these early stages
of epidermal formation.
At this stage, periderm cells form a pavement epithelium. These cells are embryonic epidermal cells
that are larger and flatter than the underlying basal
cells. Apical surfaces contact the amniotic fluid and are
studded with microvilli. Connections between periderm cells are sealed with tight junctions rather than
desmosomes. By the end of the second trimester, these
cells are sloughed and eventually form part of the vernix caseosa. Like stratified epithelial cells, periderm
cells express K5 and K14, but they also express simple
epithelial keratins K8, K18, and K19.
Aplasia cutis (see Chapter 107) may reflect focal
defects in either epidermal specification or development caused by somatic mosaicism, or mutations that
occur postzygotically. However, the molecular defect
for this disorder is not known. The fact that few genetic
diseases have been described in which either epidermal specification or morphogenesis is defective likely
reflects the fact that such defects would be incompatible with survival.
EARLY FETAL DEVELOPMENT (MORPHOGENESIS). By the end of 8 weeks of gestation, hema-
topoiesis has switched from the extraembryonic yolk

sac to the bone marrow, the classical division between
embryonic and fetal development. By this time, the
epidermis begins its stratification and formation of an
intermediate layer between the two preexisting cell
layers. The cells in this new layer are similar to the cells
of the spinous layer in mature epidermis. Like spinous
cells, they express keratins K1/K10 and the desmosomal
TABLE 7-4
Timing of the Major Events in the Embryogenesis of Human Skina

First Trimester
1
X
X
X
X
X
X
X
X
X
Keratinization of epidermis and appendages

Dorsal ridge of presumptive nail
Nail plate
Palmar/plantar surface of digits
Hair cone
Hair tract
Hair shaft
Sebaceous duct
Eccrine sweat gland duct (intraepidermal)
Apocrine duct
::
Epidermal appendages
Pilosebaceous apparatus
Hair follicle development begins
Hair exposed on skin surface and
patterns established on the scalp
Sebaceous gland primordium
Sebaceous gland function
Apocrine gland primordium
Apocrine gland function
Eccrine sweat glands (trunk)
Duct and gland patent and functioning
Nails
Nail fold and establishment of matrix
primordium
Nail plate forms
Third Trimester
Chapter 7
Epidermis
Appearance of epidermal cell layers
Stratum basale
Periderm
Stratum intermedium
Stratum granulosum
Stratum corneum
Periderm disappearance
Epidermal cell junctions
Desmosomes without associated
keratin filaments
Desmosomes with associated keratin
filaments
Tight junctions
Hemidesmosomes
Antigens
Pemphigus and pemphigoid antigen
A, B, H blood group antigens
Immigrant cells
Present, but type uncertain
Melanocyte
With premelanosomes
With melanosomes that synthesize
melanin
Transfer of melanosomes to
keratinocytes
Langerhans cells
Merkel cells
Second Trimester
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(continued)
69
TABLE 7-4
Timing of the Major Events in the Embryogenesis of Human Skina (Continued)

First Trimester
1
Section 3
::
70
Dermis
Structural organization
Papillary and reticular regions
established
Dermal papillae established
Dermalsubcutaneous boundary
Panniculus adiposus established
Connective tissue matrix proteins
Collagen present by ultrastructural
observation
Collagen present by biochemical
analysis
Type I
Type III
?
?
X
X
Elastic microfibrils
Third Trimester
X
X
X
X
X
Elastic matrix
Elastic fibrous networks
a
Second Trimester
X
X
Data are representative of the trunk unless stated otherwise.
protein desmoglein-3. The cells are still highly proliferative and, during this period of development, they
evolve into a multilayer structure that will eventually
replace the degenerating periderm.
Expression of the p63 gene plays a critical role in
the proliferation and maintenance of the basal layer
cells. Epidermal stratification does not occur in mice
deficient for p63. In humans, although no null mutations have been isolated, partial loss of p63 function
mutations have been identified in ankyloblepharon,
ectodermal dysplasia, and cleft lip/palate syndrome
(HayWells syndrome) as well as ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome (see
Chapter 142).6466 The preexisting basal cell layer also
undergoes morphologic changes at this time, becoming more cuboidal and expressing new keratin genes,
K6, K8, K19, and K6/K16, that are usually expressed in
hyperproliferative tissues. The basal layer also begins
to elaborate proteins that will ultimately anchor them
to the developing basal lamina (see Section Dermal
Epidermal Junction), including hemidesmosomal
proteins BPAG1, BPAG2, and collagens V and VII (see
Chapters 53, 56, and 62).
Embryonic lines of ectodermal formation are
revealed in mosaic disorders that follow the lines of
Blaschko, including congenital, nevoid, and acquired
conditions.6769 Molecular demonstration of genetic
mosaicism has been reported for a number of X-linked
disorders, as well as epidermal nevi in epidermolytic
hyperkeratosis.70
LATE FETAL DEVELOPMENT (DIFFERENTIATION). Late fetal development reveals the further
specialization and differentiation of keratinocytes in

the epidermis. It is at this time that the granular and
stratum corneal layers are formed, and the rudimentary periderm is sloughed. Keratinization of the surface epidermis is a process of keratinocyte terminal
differentiation, which begins at 15 weeks EGA. The
granular layer becomes prominent, and important
structural proteins are elaborated in the basal layer
cells. The hemidesmosomal proteins plectin and a6b4
integrin are expressed and correctly localized at this
time. Mutations in these genes result in various bullous genodermatoses (reviewed in Chapter 62). The
more superficial cells undergo further terminal differentiation, and the keratin-aggregating protein filaggrin
is expressed at this time.
The formation of the cornified envelope is a late
feature of differentiating keratinocytes, and it relies
on a number of different modifications to create an
impermeable barrier. Enzymes such as transglutaminase, LEKTI (encoded by the gene SPINK-5), phytanoyl
coenzyme A reductase, fatty aldehyde dehydrogenase,
and steroid sulfatase are all important in the elaboration of the cornified envelope and mature lipid barrier,
and defects in these enzymes can lead to abnormal epidermal barrier formation (see Chapter 49).
SPECIALIZED CELLS WITHIN THE EPIDERMIS. The three major nonepidermal cell types(1)
melanocytes, (2) Langerhans cells, and (3) Merkel

cellscan be detected within the epidermis by the
end of the embryonic period. Melanocytes are derived
from the neural crest, a subset of neuroectoderm cells.
Pigment mosaicism (formerly called hypomelanosis of
TABLE 7-5
Proteins Involved in Cutaneous Development and Differentiation

Epidermis
Dermis/SQ
DEJ
Appendages
Not known
Lmx-1B
Wnt7a
NGFR
Morphogenesis
p63
Dlx-3 (Tricho-dento-osseous
syndrome)
PORCN (Focal dermal
hypoplasia/Goltz syndrome)
Lamin A/C, ZMPE STE24

(Progeria, restrictive
dermopathy)
PTEN (Proteus-like
syndrome)
AKT1 mosaic activating
mutation (Proteus
syndrome).
Laminin 1
Collagen IV
Heparin sulfate
Proteoglycans
Ectodysplasin A (EDA)
(X-linked hypohidrotic
ectodermal dysplasia)
Connexin 30 (Autosomal
hypohidrotic ectodermal
dysplasia, type 2)
EDA receptor (Autosomal
hypohidrotic ectodermal
dysplasia, type 3)
MSX1 (Witkop syndrome/
tooth and nail syndrome)
c-kit (Piebaldism)
PAX-3 (Waardenburg types
1,3)
p63 (Hay-Wells/AEC, EEC)
b-catenin (pilomatricomas)
Shh
Wnt
BMPs
FGF5
LEF1
Dlx-3
Capillary morphogenesis
protein-2 (juvenile hyaline
fibromatosis, infantile
systemic hyalinosis)
Collagen I, a1, or a2
(osteogenesis imperfecta)
Collagen V, a1, or a2
(EhlersDanlos syndrome)
Collagen VII (dystrophic
EB)
Fibrillin (Marfan
syndrome)
Elastin (cutis laxa)
ABCC6 (PXE)
Tie-2 (inherited venous
malformations)
Endoglin, activin
receptor-like kinase 1
(HHT/Osler-Weber-Rendu)
VEGF receptor-3
(hereditary lymphedema
type I)
MFH1 (hereditary
lymphedema type II)
Prox-1
LYVE-1
BPAG2
Collagen VII
a6 b4 integrin
Laminin 5
(junctional EB)
Hair
BMPs
Hoxc13
Foxn1
Plakoglobin (Naxos disease)
Plakophilin/desmosomal
band 6 (ectodermal
dysplasia, skin fragility
syndrome)
Hairless (papular atrichia)
Nail
K6a, K16 (pachyonychia
congenita)
K6b, K17 (pachyonychia
congenita, steatocystoma
multiplex)
Plakophilin
Sebaceous gland
Blimp-1
K6b, K17
Differentiation
Structural proteins
K5, K14 (EB simplex)
Plectin (EB with MD)
BPAG2 (GABEB)
a6 b4 integrin (EB with PA)
K1, K10 (EI)
K1, K9 (Vorner, Unna-Thost,
Greither)
Loricrin (NCIE, Vohwinkel,
progressive symmetric
erythrokeratodermia)
Filaggrin (ichthyosis vulgaris)
Post-translational modifiers
LEKTI (Netherton)
Transglutaminase 1 (lamellar
ichthyosis; NCIE)
Phytanoyl CoA hydroxylase
(Refsum)
Fatty aldehyde dehydrogenase
(Sjgren-Larsson)
Steroid sulfatase/arylsulfatase C
(X-linked ichthyosis)
Transporter/channel proteins
ABCA12 (harlequin fetus)
Connexin 26 (KID syndrome,
palmoplantar keratoderma with
deafness)
Connexin 30.3 or 31 (erythrokeratoderma variabilis, progressive symmetric erythrokeratodermia)
SERCA2 (keratosis follicularis)
ATP2C1 (HaileyHailey disease)
Signal transduction proteins
Patched (basal cell nevus
syndrome)
AEC = ankyloblepharon-ectodermal dysplasia-clefting; BMPs = bone morphogenetic proteins; BPAG = bullous pemphigoid antigen; EB = epidermolysis bullosa;
EEC = ectrodactyly-ectodermal dysplasia-clefting; EI = epidermolytic ichthyosis; GABEB = generalized atrophic benign epidermolysis bullosa form of non-Herlitz
junctional EB; HHT = hereditary hemorrhagic telangiectasia; K = keratin; KID = keratitis-ichthyosis-deafness; MD = multiple dystrophy; NCIE = nonbullous congenital
ichthyosiform erythroderma; NGFR = nerve growth factor receptor; PA = pyloric atresia; PXE = pseudoxanthoma elasticum.
Protein names are indicated in boldface. Associated diseases/genodermatoses are listed in parentheses. Multiple names for the same protein or syndrome are separated by /. Genes and associated diseases can be found in Online Mendelian Inheritance in Man (OMIM) at http://www.ncbi.nlm.nih.gov/omim.
Lmx-1B (Nailpatella
syndrome)
Engrailed-1
Wnt7a
::
BMPs
Engrailed-1
(Aplasia cutis)
Chapter 7
Specification
71
Section 3
::
72
Ito and linear and whorled hypermelanosis) (see Chapter 75) following the lines of Blaschko may reflect
the migratory paths of melanoblasts, or alternatively,
mosaic defects in pigment transfer from melanocytes
to keratinocytes. The founders of each melanoblast
clone originate at distinct points along the dorsal midline, traversing ventrally and distally to take up residence in the epidermis.
Melanocytes are first seen within the epidermis at
50 days EGA. Melanocytes express integrin receptors
in vivo and in vitro and may use these to migrate to
the epidermis during embryonic development. Migration, colonization, proliferation, and survival of melanocytes in developing skin depend on the cell surface
tyrosine kinase receptor, c-kit, and its ligand, stem cell
factor.71,72 Melanin becomes detectable between 3 and 4
months EGA, and by 5 months, melanosomes begin to
transfer pigment to keratinocytes. Many genetic disorders of pigmentation have been characterized and are
presented in detail in Chapters 73, 75, and 143. In the
adult, a pool of melanocyte precursor cells resides in
the upper permanent portion of the hair follicle, capable of producing mature melanocytes.71,73,74
Langerhans cells, another immigrant population,
are detectable by 40 days EGA. They begin to express
CD1 on their surface and to produce their characteristic Birbeck granules by the embryonicfetal transition.
By the third trimester, most of the adult numbers of
Langerhans cells will have been produced.75
Merkel cells, as described earlier in the chapter (see
Section Nonkeratinocytes of the Epidermis), reside
in the epidermis. They are first detectable in the volar
epidermis of the 11- to 12-week EGA human fetus.
The embryonic derivation of this population of cells is
controversial, as there is experimental evidence supporting both in situ differentiation of Merkel cells from
epidermal ectoderm as well as migration from the neural crest.33,76
DERMAL AND SUBCUTANEOUS

DEVELOPMENT
The origin of the dermis and subcutaneous tissue
is more diverse than that of the epidermis, which is
exclusively ectodermally derived. The embryonic tissue that forms the dermis depends on the specific body
site.77,78 Dermal mesenchyme of the face and anterior
scalp is derived from neural crest ectoderm. The limb
and ventral body wall mesenchyme is derived from
the lateral plate mesoderm. The dorsal body wall mesenchyme derives from the dermomyotomes of the
embryonic somite. LIM homeobox transcription factor
1b (Lmx1B) and Wnt7a are important in the specification of the dorsal limb.7981 En1 and BMPs, on the other
hand, specify the volar (ventral) limb mesenchyme
(see Table 7-5).66,80
The embryonic dermis, in contrast to the mature
dermis, is cellular and amorphous, with few organized
fibers. The mature dermis contains a complex mesh
of collagen and elastic fibers embedded in a matrix of
PGs, whereas the embryonic mesenchyme contains a
large variety of pluripotent cells in a hydrated gel that
is rich in hyaluronic acid. These mesenchymal cells are

thought to be the progenitors of cartilage-producing
cells, adipose tissue, dermal fibroblasts, and intramembranous bone. Dermal fibers exist as fine filaments but
not thick fibers. The protein components of the future
elastin and collagen fibers are synthesized during
this period but not assembled. At this point, there is
no obvious separation between cells that will become
musculoskeletal elements and those that will give rise
to the skin dermis.
Proteus syndrome, exhibits focal defects in multiple
tissues, probably and is the result of genetic mosaicism
affecting genes important in this process caused by
AKT1 associated activating mutations.81a Rarely is the
mutation found in peripheral blood cells demonstrating the importance of studying affected tissues. (see
Chapter 118). Mutations causing a global defect in this
process would likely be incompatible with life.
The superficial mesenchyme becomes distinct from
the underlying tissue by the embryonicfetal transition (about 60 days EGA). By 1215 weeks, the reticular dermis begins to take on its characteristic fibrillar
appearance in contrast to the papillary dermis, which
is more finely woven. Large collagen fibers continue to
accumulate in the reticular dermis, as well as elastin
fibers, beginning around midgestation and continuing
until birth. By the end of the second trimester, the dermis has changed from a nonscarring tissue to one that
is capable of forming scars. As the dermis matures,
it also becomes thicker and well organized, such that at
birth, it resembles the dermis of the adult, although it
is still more cellular.
Many well-known clinical syndromes and molecules
have been discovered that affect this final stage of dermal differentiation. These diseases include dystrophic
EB (see Chapter 62), Marfan syndrome, EhlersDanlos
syndrome, cutis laxa, PXE, hereditary hemorrhagic telangiectasia, and osteogenesis imperfecta (see Chapter
137).
SPECIALIZED COMPONENTS
OF THE DERMIS
BLOOD VESSELS AND NERVES. Cutaneous
nerves and vessels begin to form early during gestation, but they do not evolve into those of the adult until
a few months after birth. The process of vasculogenesis
requires the in situ differentiation of the endothelial
cells at the endodermmesoderm interface. Originally,
horizontal plexuses are formed within the subpapillary and deep reticular dermis, which are interconnected by groups of vertical vessels. This lattice of vessels is in place by 4550 days EGA.
At 9 weeks EGA, blood vessels are seen at the dermal
hypodermal junction. By 3 months, the distinct networks of horizontal and vertical vessels have formed.
By the fifth month, further changes in the vasculature
derive from budding and migration of endothelium
from preexisting vessels, the process of angiogenesis.
Depending on the body region, gestational age, and
presence of hair follicles and glands, this pattern can
vary with blood supply requirements.
Defects in vascular development have been

described (see Chapter 172). In the KlippelTrnaunay
syndrome, unilateral cutaneous vascular malformations develop, with associated venous varicosities,
edema, and hypertrophy of associated soft tissue and
bone. In SturgeWeber syndrome, many cutaneous
capillary malformations are seen in the lips, tongue,
nasal, and buccal mucosae. Some familial defects in
vascular formation result from mutations in the gene
encoding Tie-2 receptor tyrosine kinase. Capillary
malformations seen in hereditary hemorrhagic telangiectasia have been linked to mutations in transforming growth factor-b-binding proteinsendoglin, and
activin receptor-like kinase 1.
As mentioned in Section Specialized Components

of the Dermis, by 5060 days EGA, the hypodermis
is separated from the overlying dermis by a plane of
thin-walled vessels. Toward the end of the first trimester, the matrix of the hypodermis can be distinguished from the more fibrous matrix of the dermis.
By the second trimester, adipocyte precursors begin
to differentiate and accumulate lipids. By the third
trimester, fat lobules and fibrous septae are found to
separate the mature adipocytes. The molecular pathways that define this process are currently an area of
intense investigation. Although few regulators important in embryonic adipose specification and development have been identified, several factors critical for
preadipocyte differentiation have been demonstrated,
including leptin, a hormone important in fat regulation, and the peroxisome proliferator-activated receptor family of transcription factors.57
The dermalepidermal junction is an interface where
many inductive interactions occur that result in the
specification or differentiation of the characteristics of the dermis and epidermis. This zone includes
SUBCUTIS
DEVELOPMENT OF SKIN
APPENDAGES
::
NERVES. The development of cutaneous nerves parallels that of the vascular system in terms of patterning, maturation, and organization. Nerves of the skin
consist of somatic sensory and sympathetic autonomic
fibers, which are predominantly small and unmyelinated. As these nerves develop, they become myelinated, with associated decrease in the number of axons.
This process may continue as long as puberty.
Chapter 7
LYMPHATICS. Accumulating evidence suggests

that lymphatics originate from endothelial cells that
bud off from veins. The pattern of embryonic lymphatic vessel development parallels that of blood vessels. Recent studies have identified new genes that
appear to be specific for some of the earliest lymphatic
precursors. LYVE-1 and Prox-1 are genes considered to
be critical for earliest lymphatic specification, whereas
VEGF-R3 and SLC may be important in later lymphatic
differentiation.53
specialized basement membrane, basal cell extracellular matrix, the basal-most portion of the basal cells,
and the superficial-most fibrillar structures of the papillary dermis. Both the epidermis and dermis contribute to this region.
As early as 8 weeks EGA, a simple basement membrane separates the dermis from the epidermis and
contains many of the major protein elements common to all basement membranes, including laminin
1, collagen IV, heparin sulfate, and PGs. Components
specific to the cutaneous basement membrane zone,
such as proteins of the hemidesmosome and anchoring filaments, are first detected at the embryonicfetal
transition. By the end of the first trimester, or around
the time of late embryonic development, all basement
membrane proteins are in place. The a6 and b4 integrin
subunits are expressed earlier than most of the other
basement membrane components. However, they are
not localized to the basal surface until 9.5 weeks EGA,
coincident with the time that the hemidesmosomal
proteins are expressed and hemidesmosomes are
first observed. At the same time, anchoring filaments
(laminin-332) and anchoring fibrils (collagen VII)
begin to be assembled. The actual synthesis of collagen
VII can be detected slightly earlier, at 8 weeks EGA.
Many congenital blistering disorders have been
demonstrated to be a result of defects in proteins of the
DEJ (for details, see Chapters 53 and 62). The severity
of the disease, plane of tissue separation, and involvement of noncutaneous tissues depend on the proteins
involved and the specific mutations. These genes are
important candidates for prenatal testing.
Skin appendages, which include hair, nails, and sweat

and mammary glands, are composed of two distinct
components: (1) an epidermal portion, which produces
the differentiated product, and (2) the dermal component, which regulates differentiation of the appendage.
During embryonic development, dermalepidermal
interactions are critical for the induction and differentiation of these structures (Fig. 7-10). Disruption of these
signals often has profound influences on development
of skin appendages. Hair differentiation serves as a
paradigm for appendageal development, because it is
the appendage that has been studied most intensely.82,83
HAIR (SEE CHAPTER 86)

Dermal signals are initially responsible for instructing
the basal cells of the epidermis to begin to crowd at
regularly spaced intervals, starting between days 75
and 80 on the scalp. This initial grouping is known
as the follicular placode or anlage. From the scalp, follicular placode formation spreads ventrally and caudally, eventually covering the skin. The placodes then
signal back to the underlying dermis to form a dermal condensate, which occurs at 1214 weeks EGA.
This process is thought to be a balance of placode
73
Appendageal morphogenesis
Hair
Gland
Wnt
Epidermis
Shh
Placode
Nog
Germ/Peg
Section 3
::
74
Epi
Epi
Derm
Du
Bu
the surface of the fetal epidermis. They continue

to lengthen until 2428 weeks, at which time they
complete the first hair cycle (see Chapter 86). With
subsequent hair cycles, hairs increase in diameter
and coarseness. During adolescence, vellus hairs of
androgen-sensitive areas mature to terminal-type hair
follicles.
SEBACEOUS GLANDS
(SEE CHAPTER 79)
Sebaceous glands mature during the course of follicular differentiation. This process begins between 13 and
16 weeks EGA, at which point the presumptive sebaceous gland is first visible as the most superficial bulge
of the maturing hair follicle. The outer proliferative
cells of the gland give rise to the differentiated cells
that accumulate lipid and sebum. After they terminally differentiate, these cells disintegrate and release
their products into the upper portion of the hair canal.
Sebum production is accelerated in the second and
third trimesters, during which time maternal steroids
cause stimulation of the sebaceous glands. Hormonal
activity is once again thought to influence the production of increased sebum during adolescence, resulting
in the increased incidence in acne at this age.
Gld
Figure 7-10 Appendageal morphogenesis. Through a

series of reciprocal epithelial (epidermal)mesenchymal
(dermal) signals, including Wnt, sonic hedgehog (Shh),
and Noggin (Nog), appendages such as the hair follicle and eccrine gland begin as epidermal invaginations
(placodes), which signal the organization of specialized
dermis (dermal condensate). This dermal condensate
subsequently signals the differentiation of the epidermal
downgrowth into the germ, peg, and mature appendageal structure. Bu = bulge; Derm = dermis; Du = duct;
Epi = epidermis; Gld = gland.
promoters and placode inhibitors.83 Wnt family signaling molecules are proposed to promote placode formation, whereas BMP family molecules are postulated to
inhibit follicle formation. Subsequent reciprocal signaling between the epidermal and dermal components of
the appendage result in its ultimate development and
maturation.
In addition to the widened bulge at the base, two
other bulges form along the length of the developing
follicle, termed the bulbous hair peg. The uppermost
bulge is the presumptive sebaceous gland, whereas
the middle bulge serves as the site for insertion of
the arrector pili muscle. This middle bulge is also the
location of the multipotent hair stem cells, which are
capable of differentiating into any of the cells of the
hair follicle, and also have the potential to replenish
the entire epidermis, as has been seen in cases of extensive surface wounds or burns.
By 1921 weeks EGA, the hair canal is completely
formed and the hairs on the scalp are visible above
NAIL DEVELOPMENT
(SEE CHAPTER 89)
Presumptive nail structures begin to appear on the
dorsal digit tip at 810 weeks EGA, slightly earlier
than the initiation of hair follicle development. The
first sign is the delineation of the flat surface of the
future nail bed. A portion of ectoderm buds inward
at the proximal boundary of the early nail field, and
gives rise to the proximal nail fold. The presumptive nail matrix cells, which differentiate to become
the nail plate, are present on the ventral side of the
proximal invagination. At 11 weeks, the dorsal nail
bed surface begins to keratinize. By the fourth month
of gestation, the nail plate grows out from the proximal nail fold, completely covering the nail bed by the
fifth month. Mutations in p63 affect nail development
in syndromes such as ankyloblepharon, ectodermal
dysplasia, and cleft lip/palate syndrome, as well as
ectrodactyly, ectodermal dysplasia, and cleft lip/
palate syndrome. Functional p63 is required for the
formation and maintenance of the apical ectodermal
ridge, an embryonic signaling center essential for
limb outgrowth and hand plate formation. Wnt7a
is thought to be important for dorsal limb patterning, and thus nail formation. In contrast to follicular
development, Shh is not required for nail plate formation. Also similar to follicular differentiation, LMX1b
and MSX1 are important for nail specification; LMX1b
and MSX1 are mutated in nailpatella syndrome and
Witkop syndrome, respectively.8486 Hoxc13 appears
to be an important homeodomain-containing gene
for both follicular and nail appendages, at least in
murine models.87
ECCRINE AND APOCRINE SWEAT GLAND

DEVELOPMENT (SEE CHAPTER 83)

Genetics in Relation to the Skin
In the 30 years since the first human gene, placental lactogen, was cloned in 1977, huge investments
in time, money, and effort have gone into disclosing
the innermost workings of the human genome. The
Human Genome Project, which began in 1990, has led
to sequence information on more than 3 billion base
pairs (bp) of DNA, with identification of most of the
estimated 25,000 genes in the entire human genome.1
Although a few relatively small gaps remain, the
near completion of the entire sequence of the human
genome is having a huge impact on both the clinical
practice of genetics and the strategies used to identify
disease-associated genes. Laborious positional cloning approaches and traditional functional studies are
gradually being transformed by the emergence of new
genomic and proteomic databases.2 Some of the exciting challenges that clinicians and geneticists now face
are determining the function of these genes, defining
disease associations and, relevant to patients, correlating genotype with phenotype. Nevertheless, many
discoveries are already influencing how clinical genetics is practiced throughout the world, particularly for
patients and families with rare, monogenic inherited
disorders. The key benefits of dissection of the genome
::
7. Blanpain C, Fuchs E: Epidermal stem cells of the skin.

Annu Rev Cell Dev Biol. 22:339-373, 2006
17. Lai-Cheong JE et al: Genetic diseases of junctions. J Invest Dermatol 127(12):2713-2725, 2007
21. Segre JA: Epidermal barrier formation and recovery in
skin disorders. J Clin Invest 116(5):1150-1158, 2006
35. Ko MS, Marinkovich MP: Role of dermal-epidermal
basement membrane zone in skin, cancer, and developmental disorders. Dermatol Clin 28(1):1-16, 2010
48. Rinn JL et al: Anatomic demarcation by positional variation in fibroblast gene expression programs. PLoS Genet
2(7):e119, 2006
54. Tammela T, Alitalo K: Lymphangiogenesis: Molecular
mechanisms and future promise. Cell 140(4):460-476, 2010
60. Loomis CA: Development and morphogenesis of the
skin. Adv Dermatol 17:183-210, 2001
66. Koster MI: p63 in skin development and ectodermal
dysplasias. J Invest Dermatol 130(10):2352-2358, 2010
72. Robinson KC, Fisher DE: Specification and loss of melanocyte stem cells. Semin Cell Dev Biol 20(1):111-116, 2009
75. Liu K, Nussenzweig MC: Origin and development of
dendritic cells. Immunol Rev 234(1):45-54, 2010
81a. Lindhurst MJ et al: A mosaic activating mutation in
AKT1 associated with the Proteus syndrome. N Eng J
Med 365:611-619, 2011
Chapter 8 :: Genetics in Relation to the Skin

:: John A. McGrath & W. H. Irwin McLean
THE HUMAN GENOME
IN DERMATOLOGY
Chapter 8
Eccrine glands begin to develop on the volar surfaces

of the hands and feet, beginning as mesenchymal
pads between 55 and 65 days EGA. By 1214 weeks
EGA, parallel ectodermal ridges are induced, which
overlay these pads. The eccrine glands arise from the
ectodermal ridge. By 16 weeks EGA, the secretory
portion of the gland becomes detectable. The dermal
duct begins around week 16, but the epidermal portion of the duct and opening are not complete until
2 weeks EGA.
Interfollicular eccrine and apocrine glands, in contrast, do not begin to bud until the fifth month of
gestation. Apocrine sweat glands usually bud from
the upper portion of the hair follicle. By 7 months
EGA, the cells of the apocrine glands become distinguishable.
Although not much is known with regard to the
molecular signals responsible for the differentiation
of these structures, the EDA, EDAR, En1, and Wnt10b
genes have been implicated. Hypohidrotic ectodermal
dysplasia results from mutations in EDA or the EDAR
(see Chapter 142).
KEY REFERENCES
thus far have been the documentation of new information about disease causation, improving the accuracy
of diagnosis and genetic counseling, and making DNAbased prenatal testing feasible.3 Indeed, the genetic
basis of more than 2,000 inherited single gene disorders
has now been determined, of which about 25% have
a skin phenotype. Therefore, these discoveries have
direct relevance to dermatologists and their patients.
Recently, studies in rare inherited skin disorders have
also led to new insight into the pathophysiology of
more common complex trait skin disorders.4 This new
information is expected to have significant implications
for the development of new therapies and management
strategies for patients. Therefore, for the dermatologist
understanding the basic language and principles of
clinical and molecular genetics has become a vital part
of day-to-day practice. The aim of this chapter is to provide an overview of key terminology in genetics that is
clinically relevant to the dermatologist.
THE HUMAN GENOME

Normal human beings have a large complex genome
packaged in the form of 46 chromosomes. These consist
of 22 pairs of autosomes, numbered in descending order
of size from the largest (chromosome 1) to the smallest
(chromosome 22), in addition to two sex chromosomes, X
75
Section 3
::
and Y. Females possess two copies of the X chromosome,

whereas males carry one X and one Y chromosome.
The haploid genome consists of about 3.3 billion bp of
DNA. Of this, only about 1.5% corresponds to proteinencoding exons of genes. Apart from genes and regulatory sequences, perhaps as much as 97% of the genome
is of unknown function, often referred to as junk DNA.
However, caution should be exercised in labeling the noncoding genome as junk, because other unknown functions may reside in these regions. Much of the noncoding
DNA is in the form of repetitive sequences, pseudogenes
(dead copies of genes lost in recent evolution), and
transposable elements of uncertain relevance. Although
initial estimates for the number of human genes was in
the order of 100,000, current predictions, based on the
essentially complete genome sequence, are in the range
of 20,000 to 25,000.1 Surprisingly, therefore, the human
genome is comparable in size and complexity to primitive organisms such as the fruit fly. However, it is thought
that the generation of multiple protein isoforms from a
single gene via alternate splicing of exons, each with a
discrete function, is what contributes to increased complexity in higher organisms, including humans. In addition to protein-encoding genes, there are also many genes
encoding untranslated RNA molecules, including transfer RNA, ribosomal RNA, and, as recently described,
microRNA genes. MicroRNA is thought to be involved in
the control of a large number of other genes through the
RNA inhibition pathway. Very recently, it has emerged
that tracts of the genome are transcribed at low levels in
the form of exotic new RNA species, including natural
antisense RNA and long interspersed noncoding RNA.
These transcripts are emerging as key regulatory molecules. Thus, a much greater proportion of the genome is
actively transcribed than was previously recognized and
this trend is likely to continue in the current postgenome era of human genetics.
The draft sequence of the human genome was completed in 2003. Subsequently, small gaps have been
filled, and the sequence has now been extensively annotated in terms of genes, repetitive elements, regulatory
sequences, polymorphisms, and many other features
recognizable by in silico data mining methods informed,
wherever possible, by functional analysis. This annotation process will continue for some time as more features
are uncovered. The human genome data, and that for an
increasing number of other species, is freely available on
Web sites (Table 8-1). Some regions of the genome, particularly near the centromeres, consist of long stretches
of highly repetitive sequences that are difficult or impossible to clone and/or sequence. These heterochromatic
regions of the genome are unlikely to be sequenced and
are thought to be structural in nature, mediating the
chromosomal architecture required for cell division,
rather than contributing to heritable characteristics.
GENETIC AND GENOMIC

DATABASES
76
Given the size and complexity of the human genome

and other genomes now available, analysis of these
TABLE 8-1
Websites for Accessing Human Genome Data

Website
URL
University of California,
Santa Cruz
http://genome.ucsc.edu/
National Center for

Biotechnology
Information
http://www.ncbi.nlm.nih.gov
ENSEMBL
http://www.ensembl.org/
Online Mendelian
Inheritance in Man
http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi?db=omim
enormous datasets in any kind of meaningful way

is heavily reliant on computers. Even storage and
retrieval of the sequence data associated with mammalian genome require considerable computer power and
memory, and even the assembly of the raw sequence of
any mammalian genome would have been unfeasible
without computers. Many Web browsers for accessing
genome data are available and the most useful of these
are listed in Table 8-1. Each of these interfaces, which
are the ones which the authors find most useful and
user-friendly, contains a wide variety of tools for analysis and searching of sequences according to keyword,
gene name, protein name, and homology to DNA or
protein sequence data.
The main source of historical, clinical, molecular, and
biochemical data relating to human genetic diseases
is the Online Mendelian Inheritance in Man (OMIM)
(see Table 8-1). All recognized genetic diseases and
nonpathogenic heritable traits, including common diseases with a genetic component, as well as all known
genes and proteins, are listed and reviewed by OMIM
number with links to PubMed.
CHROMOSOME AND GENE

STRUCTURE
Human chromosomes share common structural features (Fig. 8-1). All consist of two chromosomal arms,
designated as p and q. If the arms are of unequal
length, the short arm is always designated as the p
arm. Chromosomal maps to seek abnormalities are
based on the stained, banded appearance of condensed
chromosomes during metaphase of mitosis. During
interphase, the uncondensed chromosomes are not discernible by normal microscopy techniques. Genes can
now be located with absolute precision in terms of the
range of bp that they span within the DNA sequence
for a given chromosome. The bands are numbered
from the centromere outwards using a system that has
evolved as increasingly discriminating chromosome
stains, as well as higher resolution light microscopes,
became available. A typical cytogenetic chromosome
band is 17q21.2, within which the type I keratin genes
reside (see Fig. 8-1).
3
The human genome
17q
17p
17pter
Centromere
17p13.3
17p13.2
17p13.1
17p12
17p11
17cen
17q11.2
17q12
17q21.1
17q21.2
17q21.31
17q21.32
17q21.33
17q22
17q23.1
17q23.2
17q23.3
17q24.1
17q24.2
17q24.3
17q24.1
17q25.2
17q25.3
17qter
Telomere
Telomere
Type I keratin gene cluster (~900,000 bp)

Keratin-associated protein
Type I keratin
genes
genes
genes
Chapter 8
KRT14
Type I keratin
::
Cap site (start and direction of transcription)

ATG (translation initiation codon)
TGA (stop codon)
Promoter region
Exon 1
Exon 8
Figure 8-1 Illustration of the complexity of the human genome. At the top, the short (p) and long (q) arms of human
chromosome 17 are depicted with their cytogenetic chromosome bands. One of these band regions, 17q21.2, is then
highlighted to show that it is made up of approximately 900,000 base pairs (bp) and contains several genes, including 27
functional type I keratin genes. Part of this region is then further amplified to show one keratin gene, KRT14, encoding
keratin 14, which is composed of eight exons.
The ends of the chromosomal arms are known as

telomeres, and these consist of multiple tandem repeats
of short DNA sequences. In germ cells and certain
other cellular contexts, additional repeats are added to
telomeres by a proteinRNA enzyme complex known
as telomerase. During each round of cell division in
somatic cells, one of the telomere repeats is trimmed
off as a consequence of the DNA replication mechanism. By measuring the length of telomeres, the age
of somatic cells, in terms of the number of times they
have divided during the lifetime of the organism, can
be determined. Once the telomere length falls below a
certain threshold, the cell undergoes senescence. Thus,
telomeres contribute to an important biological clock
function that removes somatic cells that have gone
through too many rounds of replication and are at a
high risk of accumulating mutations that could lead to
tumorigenesis or other functional aberration.5
The chromosome arms are separated by the centromere, which is a large stretch of highly repetitious
DNA sequence. The centromere has important functions in terms of the movement and interactions of
chromosomes. The centromeres of sister chromatids
are where the double chromosomes align and attach
during the prophase and anaphase stages of mitosis

(and meiosis). The centromeres of sister chromatids
are also the site of kinetochore formation. The latter is
a multiprotein complex to which microtubules attach,
allowing mitotic spindle formation, which ultimately
results in pulling apart of the chromatids during anaphase of the cell division cycle.
The majority of chromosomal DNA contains genes
interspersed with noncoding stretches of DNA of varying sizes. The density of genes varies widely across the
chromosomes so that there are gene-dense regions or,
alternately, large areas almost devoid of functional
genes. An example of a comparatively gene-rich region
of particular relevance to inherited skin diseases is
the type I keratin gene cluster on chromosome band
17q21.2 (see Fig. 8-1). This diagram also gives an idea
of the sizes in bp of DNA of a typical chromosome and
a typical gene located within it. This gene cluster spans
about 900,000 bp of DNA and contains 27 functional
type I keratin genes, several genes encoding keratinassociated proteins, and a number of pseudogenes (not
shown). Because chromosome 17 is one of the smaller
chromosomes, Fig. 8-1 starts to give some idea of the
overall complexity and organization of the genome.
KRT14 gene encoding keratin K14 protein (~7,000 bp)
77
Section 3
::
78
Protein-encoding genes normally consist of several exons, which collectively code for the amino acid
sequence of the protein (or open reading frame). These
are separated by noncoding introns. In human genes,
few exons are much greater than 1,000 bp in size, and
introns vary from less than 100 bp to more than 1 million bp. A typical exon might be 100 to 300 bp in size.
The KRT14 gene encoding keratin 14 (K14) protein is
one of the genes in which mutations lead to epidermolysis bullosa (EB) simplex (see Chapter 62) and is
illustrated in Fig. 8-1. KRT14 is contained within about
7,000 bp of DNA and consists of eight modestly sized
exons interspersed by seven small introns. Although
all genes are present in all human cells that contain
a nucleus, not every gene is expressed in all cells of
tissues. For example, the KRT14 gene is only active in
basal keratinocytes of the epidermis and other stratified epithelial tissues and is essentially silent in all other
tissues. When a protein-encoding gene is expressed,
the RNA polymerase II enzyme transcribes the coding strand of the gene, starting from the cap site and
continuing to the end of the final exon, where various
signals lead to termination of transcription. The initial
RNA transcript, known as heteronuclear RNA, contains
intronic as well as exonic sequences. This primary
transcript undergoes splicing to remove the introns,
resulting in the messenger RNA (mRNA) molecule.6 In
addition, the bases at the 5 end (start) of the mRNA
are chemically modified (capping) and a large number
of adenosine bases are added at the 3 end, known as
the poly-A tail. These posttranscriptional modifications
stabilize the mRNA and facilitate its transport within
the cell. The mature mRNA undergoes a test round
of translation which, if successful, leads to the transport of the mRNA to the cytoplasm, where it undergoes multiple rounds of translation by the ribosomes,
leading to accumulation of the encoded protein. If
the mRNA contains a nonsense mutation, otherwise
known as a premature termination codon mutation, the
test round of translation fails, and the cell degrades
this mRNA via the nonsense-mediated mRNA pathway.7 This is a mechanism that the cell has evolved to
remove aberrant transcripts, and it may also contribute
to gene regulation, particularly when very low levels
of a particular protein are required within a given cell.
Splicing out of introns is a complex process. The
genes of prokaryotes, such as bacteria, do not contain introns, and so mRNA splicing is a process that
is specific to higher organisms. In some more primitive eukaryotes, RNA molecules contain catalytic
sequences known as ribozymes, which mediate the
self-splicing out of introns without any requirement
for additional factors. In mammals, splicing involves a
large number of protein and RNA factors encoded by
several genes. This allows another level of control over
gene expression and also facilitates alternative splicing
of exons, so that a single gene can encode several functionally distinct variants of a protein. These isoforms
are often differentially expressed in different tissues.
In terms of the gene sequences important for splicing,
a few bp at the beginning and at the end of an intron,
known as the 5 splice site (or splice donor site) and the
3 splice site (or splice acceptor site) are crucial. A few
other bp within the intron, such as the branch point

site located 18100 bp away from the 3 end, are also
critical. Mutations affecting any of the invariant residues of these splice sites lead to aberrant splicing and
either complete loss of protein expression or generation of a highly abnormal protein.
The mRNA also contains two untranslated regions
(UTR): (1) the 5UTR upstream of the initiating ATG
codon and (2) the 3UTR downstream of the terminator
(or stop codon, which can be TGA, TAA, or TAG). The
5 UTR can and often does possess introns, whereas
the 3UTR of more than 99% of mammalian genes
does not contain introns. The nonsense-mediated
mRNA decay pathway identifies mutant transcripts
by means of assessing where the termination codon
occurs in relation to introns. The natural stop codon is
always followed immediately by the 3UTR, which, in
turn, does not normally possess any introns. If a stop
codon occurs in an mRNA upstream of a site where an
intron has been excised, this message is targeted for
nonsense-mediated decay. The only genes that contain
introns within their 3UTR sequences are expressed at
extremely low levels. This is one of the ways in which
the cell can determine how much protein is made from
a particular gene.
Gene complexity is widely variable and not necessarily related to the size of the protein encoded. Some
genes consist of only a single small exon, such as those
encoding the connexin family of gap junction proteins.
Such single exon genes are rapid and inexpensive to
analyze routinely. In contrast, the type VII collagen
gene, COL7A1, in which mutations lead to the dystrophic forms of EB (see Chapter 62), has 118 exons,
meaning that 118 different parts of the gene need to
be isolated and analyzed for molecular diagnosis of
each dystrophic EB patient. The filaggrin gene (FLG)
on chromosome 1, recently shown to be the causative
gene for ichthyosis vulgaris (see Chapter 49) and a susceptibility gene for atopic dermatitis (see Chapter 14),
has only three exons. However, the third exon of FLG
is made up of repeats of a 1,000-bp sequence and varies
in size from 12,000 to 14,000 bp among different individuals in the population. This unusual gene structure
makes routine sequencing of genes such as COL7A1 or
FLG difficult, time consuming, and expensive.
GENE EXPRESSION
Each specific gene is generally only actively transcribed in a subset of cells or tissues within the body.
Gene expression is largely determined by the promoter
elements of the gene. In general, the most important
region of the promoter is the stretch of sequence
immediately upstream of the cap site. This proximal
promoter region contains consensus binding sites for a
variety of transcription factors, some of which are general in nature and required for all gene expression, others are specific to particular tissue or cell lineage, and
some are absolutely specific for a given cell type and/
or stage of development or differentiation. The size of
the promoter can vary widely according to gene family or between the individual genes themselves. For
and are therefore very difficult to find, this class of

mutation may, in fact, be more common than is immediately obvious. In general, relatively few disease-causing mutations have been shown to involve promoters,
but this class of defect is probably greatly underrepresented because the sequences that are important for
promoter activity are poorly characterized. Prediction of transcription factor binding sites by computer
analysis is an area for further study. Although these
undoubtedly exist, there are relatively few examples
so far of pathogenic defects in microRNA or other noncoding regulatory RNA species.
FINDING DISEASE GENES
::
In establishing the molecular basis of an inherited skin

disease, there are two key steps. First, the gene linked
to a particular disorder must be identified, and second, pathogenic mutations within that gene should be
determined. Diseases can be matched to genes either
by genetic linkage analysis or by a candidate gene
approach.10 Genetic linkage involves studying pedigrees of affected and unaffected individuals and isolating which bits of the genome are specifically associated
with the disease phenotype. The goal is to identify a
region of the genome that all the affected individuals and none of the unaffected individuals have in
common; this region is likely to harbor the gene for
the disorder, as well as perhaps other nonpathogenic
neighboring genes that have been inherited by linkage disequilibrium. Traditionally, genome-wide linkage strategies make use of variably sized microsatellite
markers scattered throughout the genome, although
for recessive diseases involving consanguineous pedigrees, a more rapid approach may be to carry out
homozygosity mapping using single nucleotide polymorphism (SNP) chip arrays. By contrast, the candidate gene approach involves first looking for a clue to
the likely gene by finding a specific disease abnormality, perhaps in the expression (or lack thereof) of a particular protein or RNA, or from an ultrastructural or
biochemical difference between the diseased and control tissues. Nevertheless, the genetic linkage and candidate gene approaches are not mutually exclusive and
are often used in combination. For example, to identify the gene responsible for the autosomal recessive
disorder, lipoid proteinosis (see Chapter 137), genetic
linkage using microsatellites was first used to establish
a region of linkage on 1q21 that contained 68 genes.11
The putative gene for this disorder, ECM1 encoding
extracellular matrix protein 1, was then identified by
a candidate gene approach that searched for reduced
gene expression (lack of fibroblast complementary
DNA) in all these genes. A reduction in ECM1 gene
expression in lipoid proteinosis compared with control provided the clue to the candidate gene because
there were no differences in any of the other patterns
of gene expression. Ultrastructural and immunohistochemical analyses can also provide clues to underlying
gene pathology. For example, loss of hemidesmosomal
inner plaques noted on transmission electron microscopy and a complete absence of skin immunostaining
Chapter 8
example, the keratin genes are tightly spaced within

two gene clusters on chromosomes 12q and 17q, but
these are exquisitely tissue specific in two different
ways. First, these genes are only expressed in epithelial cells, and therefore their promoters must possess
regulatory sequences that determine epithelial expression. Therefore, these regulatory elements are specific
for cells of ectodermal origin. Second, these genes are
expressed in very specific subsets of epithelial cells,
and so there must be a second level of control that
specifies which epithelial cell layers express specific
keratin genes. This is best illustrated in the hair follicle,
where there are many different epithelial cell layers,
each with a specific pattern of keratin gene expression
(see Chapter 86).8
Transcription factors are proteins that either bind to
DNA directly or indirectly by associating with other
DNA-binding proteins. Binding of these factors to the
promoter region of a gene leads to activation of the
transcription machinery and transcription of the gene
by RNA polymerase II. The transcription factor proteins are encoded by genes that are in turn controlled
by promoters that are regulated by other transcription
factors encoded by other genes. Thus, there are several
tiers of control over gene expression in a given cell
type, and the intricacies of this can be difficult to fully
unravel experimentally. Nevertheless, by isolation of
promoter sequences from genes of interest and placing these in front of reporter genes that can be assayed
biochemically, such as firefly luciferase that can be
assayed by light emission, the activity of promoters can
be reproduced in cultured cells that normally express
the gene. Combining such a reporter gene system with
site-directed mutagenesis to make deletions or alter
small numbers of bp within the promoter can help
define the extent of the promoter and the important
sequences within it that are required for gene expression. A variety of biochemical techniques, such as DNA
footprinting, ribonuclease protection, electrophoretic
mobility shift assays, or chromatin immunoprecipitation, can be used to determine which transcription factors bind to a particular promoter and help delineate
the specific promoter sequences bound. Expression
of reporter genes under the control of a cloned promoter in transgenic mice also helps shed light on the
important sequences that are required to recapitulate
the endogenous expression of the gene under study.
Keratin promoters are unusual in that, generally, a
small fragment of only 2,000 to 3,000 bp upstream of
the gene can confer most of the tissue specificity. For
this reason, keratin promoters are widely used to drive
exogenous transgene expression in the various specific cellular compartments of the epidermis and its
appendages for experiments to determine gene, cell, or
tissue function.9
Some promoter or enhancer sequences act over very
long distances. In some cases, sequences located millions of bp distant, with several other genes in the
intervening region, somehow influence expression
of a target gene. In some genetic diseases, mutations
affecting such long-range promoter elements are now
emerging. These types of mutations appear to be rare,
but since they occur so far away from the target gene
79
Section 3
::
80
for the 230-kDA bullous pemphigoid antigen (BP230)

at the dermalepidermal junction, led to the discovery
of loss-of-function mutations in the dystonin (DST)
gene, which codes for BP230, in a new form of autosomal recessive epidermolysis bullosa simplex.12
Having identified a putative gene for an inherited disorder, the next stage is to find the pathogenic
mutation(s). This can be done by sequencing the entire
gene, a feat which is becoming easier as technologic
advances make automated nucleotide sequencing
faster, cheaper, and more accessible. However, the
large size of some genes may make comprehensive
sequencing impractical, and therefore initial screening
approaches to identify the region of a gene that contains the mutation may be a necessary first step. There
are many mutation detection techniques available to
scan for sequence changes in cellular RNA or genomic
DNA, and these include denaturing gradient gel electrophoresis, chemical cleavage of mismatch, single
stranded conformation polymorphism, heteroduplex
analysis, conformation sensitive gel electrophoresis,
denaturing high-performance liquid chromatography
and the protein truncation test.13
The most critical factor that determines the success
of any gene screening protocol is the sensitivity of the
detection technique. In addition, when choosing a
mutation screening strategy using genomic DNA, the
size of the gene and its number of exons must be taken
into account. The sensitivities of these methods vary
greatly, depending on the size of template screened.
For example, single-stranded conformation polymorphism has a sensitivity of >95% for fragments of 155
bp, but this is reduced to only 3% for 600 bp. Once
optimized, denaturing gradient gel electrophoresis has
a sensitivity of about 99% for fragments of up to 500
bp, and conformation sensitive gel electrophoresis is
expected to have a sensitivity of 80% to 90% for fragments of up to 600 bp. Chemical cleavage of mismatch,
on the other hand, has a sensitivity of 95% to 100% for
fragments >1.5 kilobases (kb) in size and is ideal for
screening compact genes where more than one exon
can be amplified together using genomic DNA as the
template. All these techniques detect sequence changes
such as truncating and missense mutations as well as
polymorphisms; however, the protein truncation test
screens only for truncating mutations and is predicted
to have a sensitivity of >95% and can be used for RNA
or DNA fragments in excess of 3 kb.
Whichever approach is taken, having identified a
difference in the patients DNA compared with the
control sample, the next stage is to determine how this
segregates within a particular family and also whether
it is pathogenic or not. Very recently, great advances
have been made in DNA sequencing technology, with
the emergence of next generation sequencing (NGS)
technology. Currently, it is quite feasible to carry out
whole exome sequencing in an individual using NGS,
i.e., sequencing of all the protein-encoding exons in the
genome, in a matter of days and for only a few thousand
dollars. It is expected that whole genome sequencing,
at a cost of $1,000 or less will be a commonplace in 23
years. This incredible new technology is set to revolutionize human genetics once more, and in particular,
will facilitate identification of mutated genes in small kindreds that are not tractable by genetic linkage methods.
These advances will also impact on diagnosisin the
near future it may be faster and cheaper to sequence
a patients whole genome rather than to do targeted
sequencing of specific genes or regions.
GENE MUTATIONS AND

POLYMORPHISMS
Within the human genome, the genetic code of two
healthy individuals may show a number of sequence
dissimilarities that have no relevance to disease or phenotypic traits. Such changes within the normal population are referred to as polymorphisms (Fig. 8-2). Indeed,
even within the coding region of the genome, clinically
irrelevant substitutions of one bp, known as SNPs,
are common and occur approximately once every 250
bp.14 Oftentimes, these SNPs do not change the amino
acid composition; for example, a C-to-T transition in
the third position of a proline codon (CCC to CCT)
still encodes for proline, and is referred to as a silent
mutation. However, some SNPs do change the nature
of the amino acid; for example, a C-to-G transversion at the second position of the same proline codon
(CCC to CGC) changes the residue to arginine. It then
becomes necessary to determine whether a missense
change such as this represents a nonpathogenic polymorphism or a pathogenic mutation. Factors favoring
the latter include the sequence segregating only with
the disease phenotype in a particular family, the amino
acid change occurring within an evolutionarily conserved residue, the substitution affecting the function
of the encoded protein (size, charge, conformation,
etc.), and the nucleotide switch not being detectable in
at least 100 ethnically matched control chromosomes.
Nonpathogenic polymorphisms do not always involve
single nucleotide substitutions; occasionally, deletions
and insertions may also be nonpathogenic.
A mutation can be defined as a change in the chemical
composition of a gene. A missense mutation changes one
amino acid to another. Mutations may also be insertions
or deletions of bases, the consequences of which will
depend on whether this disrupts the normal reading
frame of a gene or not, as well as nonsense mutations,
which lead to premature termination of translation
(see Fig. 8-2). For example, a single nucleotide deletion within an exon causes a shift in the reading frame,
which usually leads to a downstream stop codon, thus
giving a truncated protein, or often an unstable mRNA
that is readily degraded by the cell. However, a deletion of three nucleotides (or multiples thereof) will not
significantly perturb the overall reading frame, and the
consequences will depend on the nature of what has
been deleted. Nonsense mutations typically, but not
exclusively, occur at CpG dinucleotides, where methylation of a cytosine nucleotide often occurs. Inherent
chemical instability of this modified cytosine leads to
a high rate of mutation to thymine. Where this alters
the codon (e.g., from CGA to TGA), it will change an
arginine residue to a stop codon. Nonsense mutations
Examples of nucleotide sequence changes
A
A G G A C A G A G G C A G C
T G A G G C
T G A G G C
Figure 8-2 Examples of nucleotide sequence changes

resulting in a polymorphism and a nonsense mutation.
A. Two adjacent codons are highlighted. The AGG codon
encodes arginine and the CAG codon encodes glutamine.
B. The sequence shows two homozygous nucleotide substitutions. The AGG codon now reads AGT (i.e., coding for
serine rather than arginine). This is a common sequence
variant in the normal population and is referred to as a
nonpathogenic missense polymorphism. In contrast, the
glutamine codon CAG now reads TAG, which is a stop
codon. This is an example of a homozygous nonsense mutation. C. This sequence is from one of the parents of the
subject sequenced in B and shows heterozygosity for both
the missense polymorphism AGG > AGT and the nonsense
mutation CAG > TAG, indicating that this individual is a
carrier of both sequence changes.
usually lead to a reduced or absent expression of the

mutant allele at the mRNA and protein levels. In the
heterozygous state, this may have no clinical effect [e.g.,
parents of individuals with Herlitz junctional EB are typically carriers of nonsense mutations in one of the laminin
332 (laminin 5) genes but have no skin fragility themselves; see Chapter 62], but a heterozygous nonsense
mutation in the desmoplakin gene, for example, can
result in the autosomal dominant skin disorder, striate
palmoplantar keratoderma (see Chapter 50). This phenomenon is referred to as haploinsufficiency (i.e., half the
normal amount of protein is insufficient for function).
A G G A C A G A G N N A G C
::
Chapter 8
A G G A C A G A G T T A G C T G A G G C
Apart from changes in the coding region that result in

frameshift, missense, or nonsense mutations, approximately 15% of all mutations involve alterations in the
gene sequence close to the boundaries between the
introns and exons, referred to as splice site mutations.
This type of mutation may abolish the usual acceptor and donor splice sites that normally splice out the
introns during gene transcription. The consequences
of splice site mutations are complex; sometimes they
lead to skipping of the adjacent exon, and other times
they result in the generation of new mRNA transcripts
through utilization of cryptic splice sites within the
neighboring exon or intron.
Mutations within one gene do not always lead to a
single inherited disorder. For example, mutations in
the ERCC2 gene may lead to xeroderma pigmentosum
(type D), trichothiodystrophy, or cerebrofacioskeletal
syndrome, depending on the position and type of
mutation. Other transacting factors may further modulate phenotypic expression. This situation is known as
allelic heterogeneity. Conversely, some inherited diseases
can be caused by mutations in more than one gene (e.g.,
non-Herlitz junctional EB; see Chapter 62) and can
result from mutations in either the COL17A1, LAMA3,
LAMB3, or LAMC2 genes. This is known as genetic
heterogeneity. In addition, the same mutation in one
particular gene may lead to a range of clinical severity in different individuals. This variability in phenotype produced by a given genotype is referred to as the
expressivity. If an individual with such a genotype has
no phenotypic manifestations, the disorder is said to be
nonpenetrant. Variability in expression reflects the complex interplay between the mutation, modifying genes,
epigenetic factors, and the environment and demonstrates that interpreting what a specific gene mutation
does to an individual involves more than just detecting
one bit of mutated DNA in a single gene.
MENDELIAN DISORDERS
There are approximately 5,000 human single-gene disorders and, although the molecular basis of less than
one-half of these has been established, understanding
the pattern of inheritance is essential for counseling
prospective parents about the risk of having affected
children. The four main patterns of inheritance are
(1) autosomal dominant, (2) autosomal recessive,
(3) X-linked dominant, and (4) X-linked recessive.
For individuals with an autosomal dominant disorder, one parent is affected, unless there has been a
de novo mutation in a parental gamete. Males and
females are affected in approximately equal numbers,
and the disorder can be transmitted from generation to
generation; on average, half the offspring will have the
condition (Fig. 8-3). It is important to counsel affected
individuals that the risk of transmitting the disorder
is 50% for each of their children, and that this is not
influenced by the number of previously affected or
unaffected offspring. Any offspring that are affected
will have a 50% risk of transmitting the mutated gene
to the next generation, whereas for any unaffected
offspring, the risk of the next generation being affected
81
Section 3
::
82
is negligible, providing that the partner does not have

the autosomal dominant condition. Some dominant
alleles can behave in a partially dominant fashion. The
term semidominant is applied when the phenotype in
heterozygous individuals is less than that observed for
homozygous subjects. For example, ichthyosis vulgaris
is a semidominant disorder in which the presence of
one or two mutant profilaggrin gene (FLG) alleles can
strongly influence the clinical severity of the ichthyosis.
In autosomal recessive disorders, both parents are
carriers of one normal and one mutated allele for the
same gene and, typically, they are phenotypically
unaffected (Fig. 8-4). If both of the mutated alleles are
transmitted to the offspring, this will give rise to an

autosomal recessive disorder, the risk of which is 25%.
If one mutated and one wild-type allele is inherited
by the offspring, the child will be an unaffected carrier, similar to the parents. If both wild-type alleles are
transmitted, the child will be genotypically and phenotypically normal with respect to an affected individual.
If the mutations from both parents are the same, the
individual is referred to as a homozygote, but if different
parental mutations within a gene have been inherited,
the individual is termed a compound heterozygote. For
someone who has an autosomal recessive condition,
be it a homozygote or compound heterozygote, all
offspring will be carriers of one of the mutated alleles
but will be unaffected because of inheritance of a wildtype allele from the other, clinically and genetically
unaffected, parent. This assumes that the unaffected
parent is not a carrier. Although this is usually the case
in nonconsanguineous relationships, it may not hold
true in first-cousin marriages or other circumstances
where there is a familial interrelationship. For example, if the partner of an individual with an autosomal
recessive disorder is also a carrier of the same mutation, albeit clinically unaffected, then there is a 50%
chance of the offspring inheriting two mutant alleles
and therefore also inheriting the same autosomal recessive disorder. This pattern of inheritance is referred to
as pseudodominant.
In X-linked dominant inheritance, both males and
females are affected, and the pedigree pattern may
resemble that of autosomal dominant inheritance
(Fig. 8-5). However, there is one important difference. An affected male transmits the disorder to all
his daughters and to none of his sons. X-linked dominant inheritance has been postulated as a mechanism
in incontinentia pigmenti (see Chapter 75), ConradiHnermann syndrome, and focal dermal hypoplasia (Goltz syndrome), conditions that are almost
always limited to females. In most X-linked dominant
Autosomal recessive pattern of inheritance
X-linked dominant pattern of inheritance
Figure 8-4 Pedigree illustration of an autosomal recessive pattern of inheritance. Key observations include: the
disorder affects both males and females; there are mutations on both inherited copies of the gene; the parents
of an affected individual are both heterozygous carriers
and are usually clinically unaffected; autosomal recessive
disorders are more common in consanguineous families.
Filled circle indicates affected female; half-filled circles/
squares represent clinically unaffected heterozygous carriers of the mutation; unfilled circles/squares represent
unaffected individuals.
Figure 8-5 Pedigree illustration of an X-linked dominant

pattern of inheritance. Key observations include: affected
individuals are either hemizygous males or heterozygous
females; affected males will transmit the disorder to their
daughters but not to their sons (no male-to-male transmission); affected females will transmit the disorder to
half their daughters and half their sons; some disorders
of this type are lethal in hemizygous males and only heterozygous females survive. Filled circles indicate affected
females; filled squares indicate affected males; unfilled
circles/squares represent unaffected individuals.
Autosomal dominant pattern of inheritance
Figure 8-3 Pedigree illustration of an autosomal dominant pattern of inheritance. Key observations include:
the disorder affects both males and females; on average,
50% of the offspring of an affected individual will be affected; affected individuals have one normal copy and
one mutated copy of the gene; affected individuals usually
have one affected parent, unless the disorder has arisen
de novo. Importantly, examples of male-to-male transmission, seen here, distinguish this from X-linked dominant
and are therefore the best hallmark of autosomal dominant inheritance. Filled circles indicate affected females;
filled squares indicate affected males; unfilled circles/
squares represent unaffected individuals.
X-linked recessive pattern of inheritance
Aberrations in chromosomes are common. They occur

in about 6% of all conceptions, although most of
these lead to miscarriage, and the frequency of chro-
CHROMOSOMAL DISORDERS
::
disorders with cutaneous manifestations, affected

males may be aborted spontaneously or die before
implantation (leading to the appearance of female-tofemale transmission). Most viable male patients with
incontinentia pigmenti have a postzygotic mutation
in NEMO and no affected mother; occasionally, males
with an X-linked dominant disorder have Klinefelter
syndrome with an XXY genotype.
X-linked recessive conditions occur almost exclusively in males, but the gene is transmitted by carrier
females, who have the mutated gene only on one X chromosome (heterozygous state). The sons of an affected
male will all be normal (because their single X chromosome comes from their clinically unaffected mother)
(Fig. 8-6). However, the daughters of an affected male
will all be carriers (because all had to have received the
single X chromosome from their father that carries the
mutant copy of the gene). Some females show clinical abnormalities as evidence of the carrier state (such
as in hypohidrotic ectodermal dysplasia; see Chapter
142); the variable extent of phenotypic expression can
be explained by lyonization, the normally random process that inactivates either the wild-type or mutated X
chromosome in each cell during the first weeks of gestation and all progeny cells.15 Other carriers may not
show manifestations because the affected region on
the X chromosome escapes lyonization (as in recessive
X-linked ichthyosis) or the selective survival disadvantage of cells in which the mutated X chromosome is activated (as in the lymphocytes and platelets of carriers of
WiskottAldrich syndrome; see Section Mosaicism).
Chapter 8
Figure 8-6 Pedigree illustration of an X-linked recessive

pattern of inheritance. Key observations include: usually
affects only males but females can show some features
because of lyonization (X-chromosome inactivation);
transmitted through female carriers, with no male-to-male
transmission; for affected males, all daughters will be heterozygous carriers; female carrier will transmit the disorder to half her sons, and half her daughters will be heterozygous carriers. Dots within circles indicate heterozygous
carrier females who may or may not display some phenotypic abnormalities; filled squares indicate affected males;
unfilled circles/squares represent unaffected individuals.
mosomal abnormalities in live births is about 0.6%.

Approximately two-thirds of these involve abnormalities in either the number of sex chromosomes or the
number of autosomes; the remainder is chromosomal
rearrangements. The number and arrangement of the
chromosomes is referred to as the karyotype. The most
common numerical abnormality is trisomy, the presence of an extra chromosome. This occurs because
of nondisjunction, when pairs of homologous chromosomes fail to separate during meiosis, leading to
gametes with an additional chromosome. Loss of a
complete chromosome, monosomy, can affect the X
chromosome but is rarely seen in autosomes because
of nonviability. A number of chromosomal disorders
are also associated with skin abnormalities, as detailed
in Table 8-2.
Structural aberrations (fragility breaks) in chromosomes may be random, although some chromosomal
regions appear more vulnerable. Loss of part of a chromosome is referred to as a deletion. If the deletion leads
to loss of neighboring genes this may result in a contiguous gene disorder, such as a deletion on the X chromosome giving rise to X-linked ichthyosis (see Chapter
49) and Kallman syndrome. If two chromosomes break,
the detached fragments may be exchanged, known as
reciprocal translocation. If this process involves no loss
of DNA it is referred to as a balanced translocation. Other
structural aberrations include duplication of sections
of chromosomes, two breaks within one chromosome leading to inversion, and fusion of the ends of
two broken chromosomal arms, leading to joining of
the ends and formation of a ring chromosome. Chromosomal anomalies may be detected using standard
metaphase cytogenetics but newer approaches, such
as SNP arrays and comparative genomic hybridization
arrays, can also be used for karyotyping. Array-based
cytogenetic tools do not rely on cell division and are
very sensitive in detecting unbalanced lesions as well
as copy number-neutral loss of heterozygosity. These
new methods have become commonplace in diagnostic genetics laboratories. A further possible chromosomal abnormality is the inheritance of both copies
of a chromosome pair from just one parent (paternal
or maternal), known as uniparental disomy.16 Uniparental heterodisomy refers to the presence of a pair of
chromosome homologs, whereas uniparental isodisomy
describes two identical copies of a single homolog,
and meroisodisomy is a mixture of the two. Uniparental
disomy with homozygosity of recessive alleles is being
increasingly recognized as the molecular basis for
several autosomal recessive disorders, and there have
been more than 35 reported cases of recessive diseases,
including junctional and dystrophic EB (see Chapter
62), resulting from this type of chromosomal abnormality. For certain chromosomes, uniparental disomy
can also result in distinct phenotypes depending on the
parental origin of the chromosomes, a phenomenon
known as genomic imprinting.17,18 This parent-of-origin,
specific gene expression is determined by epigenetic
modification of a specific gene or, more often, a group
of genes, such that gene transcription is altered, and
only one inherited copy of the relevant imprinted
gene(s) is expressed in the embryo. This means that,
83
TABLE 8-2
Chromosomal Disorders with a Skin Phenotype

Chromosomal
Abnormality
Section 3
General Features
Skin Manifestations
Trisomy 21
Down
syndrome
Small head with flat face

Nose short and squat
Ears small and misshapen
Slanting palpebral fissures
Thickened eyelids
Eyelashes short and sparse
Shortened limbs, lax joints
Fingers short, sometimes webbed
Hypoplastic iris, lighter outer zone
(Brushfields spots)
110 year: dry skin, xerosis, lichenification

10+ year: increased frequency of atopic dermatitis, alopecia areata,
single crease in palm and fifth finger
Other associations: skin infections, angular cheilitis, geographic
tongue, blepharitis, red cheeks, folliculitis, seborrheic dermatitis,
boils, onychomycosis, fine hypopigmented hair, vitiligo, delayed
dentition and hypoplastic teeth, acrocyanosis, livedo reticularis,
cutis marmorata, calcinosis cutis, palmoplantar keratoderma,
pityriasis rubra pilaris, syringomas, elastosis perforans serpiginosa,
anetoderma, hyperkeratotic form of psoriasis, collagenoma, eruptive
dermatofibromas, urticaria pigmentosa, leukemia cutis, keratosis
follicularis spinulosa decalvans
Trisomy 18
Edwards
syndrome
Severe mental deficiency

Abnormal skull shape
Small chin, prominent occiput
Low-set, malformed ears
Rocker bottom feet
Short sternum
Malformations of internal organs
Only 10% survive beyond first year
Cutis laxa (neck), hypertrichosis of forehead and back, superficial

hemangiomas, abnormal dermatoglyphics, single palmar crease,
hyperpigmentation, ankyloblepharon filiforme adnatum
Trisomy 13
Patau
syndrome
Mental retardation
Sloping forehead due to forebrain
maldevelopment (holoprosencephaly)
Microphthalmia or anophthalmia
Cleft palate/cleft lip
Low-set ears
Rocker bottom feet
Malformations of internal organs
Survival beyond 6 months is rare
Vascular anomalies (especially on forehead)

Hyperconvex nails
Localized scalp defects
Cutis laxa (neck)
Abnormal palm print (distal palmar axial triradius)
Chromosome 4, short
arm deletion
Microcephaly
Mental retardation
Hypospadias
Cleft lip/palate
Low-set ears, preauricular pits
Scalp defects
Chromosome 5, short
arm deletion
Mental retardation
Microcephaly
Cat-like cry
Low-set ears, preauricular skin tag
Premature graying of hair
Chromosome 18,
long arm deletion
Hypoplasia of midface
Sunken eyes
Prominent ear antihelix
Multiple skeletal and ocular abnormalities
Eczema in 25% of cases
::
Synonym
84
45 XO
Turner
syndrome
Early embryonic loss; prenatal ultrasound

findings of cystic hygroma, chylothorax,
ascites and hydrops
Short stature, amenorrhea
Broad chest, widely spaced nipples
Wide carrying angle of arms
Low misshapen ears, high arched palate
Short fourth/fifth fingers and toes
Skeletal abnormalities, coarctation of aorta
Redundant neck skin and peripheral edema

Webbed neck, low posterior hairline
Cutis laxa (neck, buttocks)
Hypoplastic, soft upturned nails
Increased incidence of keloids
Increased number of melanocytic nevi and halo nevi
Failure to develop full secondary sexual characteristics
Lymphatic hypoplasia/lymphedema
47 XXY
Klinefelter
syndrome
No manifestations before puberty

Small testes, poorly developed secondary
sexual characteristics
Infertility
Tall, obese, osteoporosis
May develop gynecomastia

Sparse body and facial hair
Increased risk of leg ulcers
Increased incidence of systemic lupus erythematosus
48 XXYY
Similar to Klinefelter syndrome
Multiple cutaneous angiomas

Acrocyanosis, peripheral vascular disease
47 XYY
Phenotypic males (tall)

Mental retardation
Aggressive behavior
Severe acne
49 XXXXY
Low birth weight

Slow mental and physical development
Large, low-set, malformed ears
Small genitalia
Hypotrichosis (variable)
Fragile X syndrome
Mental retardation
Mild dysmorphism
Hyperextensible joints, flat feet
during development, the parental genomes function

unequally in the offspring. The most common examples of genomic imprinting are PraderWilli (OMIM
#176270) and Angelman (OMIM #105830) syndromes,
which can result from maternal or paternal uniparental
disomy for chromosome 15, respectively. Three phenotype abnormalities commonly associated with uniparental disomy for chromosomes with imprinting are
(1) intrauterine growth retardation, (2) developmental
delay, and (3) reduced stature.19
MITOCHONDRIAL DISORDERS
For Mendelian disorders, identifying genes that harbor pathogenic mutations has become relatively
straightforward, with hundreds of disease-associated
genes being discovered through a combination of linkage, positional cloning, and candidate gene analyses.
::
COMPLEX TRAIT GENETICS
Chapter 8
In addition to the 3.3 billion bp nuclear genome, each

cell contains hundreds or thousands of copies of a further 16.5-kb mitochondrial genome, which is inherited
solely from an individuals mother. This closed, circular genome contains 37 genes, 13 of which encode
proteins of the respiratory chain complexes, whereas
the other 24 genes generate 22 transfer RNAs and two
ribosomal RNAs used in mitochondrial protein synthesis.20 Mutations in mitochondrial DNA were first
reported in 1988, and more than 250 pathogenic point
mutations and genomic rearrangements have been
shown to underlie a number of myopathic disorders
and neurodegenerative diseases, some of which show
skin manifestations, including lipomas, abnormal
pigmentation or erythema, and hypo- or hypertrichosis.21 Mitochondrial DNA mutations are very common
in somatic mammalian cells, more than two orders
of magnitude higher than the mutation frequency in
nuclear DNA.22 Mitochondrial DNA has the capacity to form a mixture of both wild-type and mutant
DNA within a cell, leading to cellular dysfunction only
when the ratio of mutated to wild-type DNA reaches a
certain threshold. The phenomenon of having mixed
mitochondrial DNA species within a cell is known
as heteroplasmy. Mitochondrial mutations can induce,
or be induced by, reactive oxygen species, and may
be found in, or contribute to, both chronologic aging
and photoaging.23 Somatic mutations in mitochondrial DNA have also been reported in several premalignant and malignant tumors, including malignant
melanoma, although it is not yet known whether these
mutations are causally linked to cancer development
or simply a secondary bystander effect as a consequence of nuclear DNA instability. Indeed, currently
there is little understanding of the interplay between
the nuclear and mitochondrial genomes in both health
and disease. Nevertheless, it is evident that the genes
encoded by the mitochondrial genome have multiple
biologic functions linked to energy production, cell
proliferation, and apoptosis.24
By contrast, for complex traits, such as psoriasis and

atopic dermatitis, these traditional approaches have
been largely unsuccessful in mapping genes influencing the disease risk or phenotype because of low
statistical power and other factors.25,26 Complex traits
do not display simple Mendelian patterns of inheritance, although genes do have an influence, and close
relatives of affected individuals may have an increased
risk. To dissect out genes that contribute and influence
susceptibility to complex traits, several stages may be
necessary, including establishing a genetic basis for
the disease in one or more populations; measuring the
distribution of gene effects; studying statistical power
using models; and carrying out marker-based mapping studies using linkage or association. It is possible
to establish quantitative genetic models to estimate
the heritability of a complex trait, as well as to predict
the distribution of gene effects and to test whether one
or more quantitative trait loci exist. These models can
predict the power of different mapping approaches,
but often only provide approximate predictions. Moreover, low power often limits other strategies such as
transmission analyses, association studies, and familybased association tests. Another potential pitfall of
association studies is that they can generate spurious
associations due to population admixture. To counter this, alternative strategies for association mapping include the use of recent founder populations or
unique isolated populations that are genetically homogeneous, and the use of unlinked markers (so-called
genomic controls) to assign different regions of the
genome of an admixed individual to particular source
populations. In addition, and relevant to several studies on psoriasis, linkage disequilibrium observed in a
sample of unrelated affected and normal individuals
can also be used to fine-map a disease susceptibility
locus in a candidate region.
In recent years, advances in the identification of many
millions of SNPs across the entire genome, as well as
major advances in gene chip technology that allows
up to 2 million SNPs to be typed in a given individual
for a few hundred dollars, coupled with high powered
computation, have led to the current era of genomewide association studies (GWAS).27 This has become
the predominant technology for tacking complex
traits, with GWAS having already been performed for
psoriasis, atopic eczema, vitiligo, and alopecia areata.
GWAS for other dermatological complex traits are
underway. A typical GWAS design involves collecting
DNA from a well-phenotyped case series of the condition of choice, preferably from an ethnically homogenous population. Normally, 2,000 or more cases are
required versus 3,000 ethnically matched random population controls. Correct clinical ascertainment of the
cases is paramount and so GWAS represents a great
opportunity for close cooperation between physicians
and scientists. These 5,000 or more individuals are genotyped for 500,000 to 2 million SNPs, generating billions of data points. For each SNP across the genome, a
statistical test is performed and a P value derived. If an
SNP is closely linked to a disease susceptibility gene,
then a particular genotype will be greatly enriched in
the case series compared to the general unselected
85
Section 3
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population. The P values are plotted along each chromosome (Manhattan plot) and where disease susceptibility loci exist, there are clusters of strong association.
Typically, P values of 1010 or lower are indicative of a
true locus, although this generally has to be replicated
in a number of other case-control sets for confirmation.
Although SNP-based GWAS is currently the weapon of
choice in complex trait genetics, it has limitations. If a
causative lesion in a susceptibility locus is very heterogeneous, i.e., if there are multiple mutations or other
changes that cause the susceptibility, then the locus is
poorly identified by GWAS. Furthermore, across the
entire field of complex trait genetics, relatively few
causative genes have emerged (the role of the filaggrin
gene in atopic dermatitis, below, being a notable exception). In the majority of cases, there is currently little
clue about what defect the associated SNPs are linked
to that actually causes the disease susceptibility.
However, recently, a conventional genetics approach
has revealed fascinating new insight into the pathophysiology of one particular complex trait, namely
atopic dermatitis (eczema). This finding emanated
from the discovery that the disorder ichthyosis vulgaris was due to loss-of-function mutations in the
gene encoding the skin barrier protein filaggrin (see
Chapters 14 and 49).28 To dermatologists, the clinical
association between this condition and atopic dermatitis is well known, and the same loss-of-function mutations in filaggrin have subsequently been shown to be
a major susceptibility risk factor for atopic dermatitis,
as well as asthma associated with atopic dermatitis,
but not asthma alone.4 This suggests that asthma in
individuals with atopic dermatitis may be secondary
to allergic sensitization, which develops because of
the defective epidermal barrier that allows allergens
to penetrate the skin to make contact with antigenpresenting cells. Indeed, transmissiondisequilibrium
tests have demonstrated an association between filaggrin gene mutations and extrinsic atopic dermatitis
associated with high total serum immunoglobulin E
levels and concomitant allergic sensitizations.29 These
recent data on the genetics of atopic dermatitis demonstrate how the study of a simple genetic disorder
can also provide novel insight into a complex trait.
Therefore, Mendelian disorders may be useful in the
molecular dissection of more complex traits.30
MOSAICISM
86
The presence of a mixed population of cells bearing

different genetic or chromosomal characteristics leading to phenotypic diversity is referred to as mosaicism.
There are several different types of mosaicism, including single gene, chromosomal, functional, and revertant mosaicism.31 Multiple expression patterns are
recognized.32
Mosaicism for a single gene, referred to as somatic
mosaicism, indicates a mutational event occurring after
fertilization. The earlier this occurs, the more likely it
is that there will be clinical expression of a disease phenotype as well as involvement of gonadal tissue (gonosomal mosaicism); for example, when individuals with
segmental neurofibromatosis subsequently have offspring with full-blown neurofibromatosis (see Chapter
141). However, in general, if the mutation occurs after
generation of cells committed to gonad formation,
then the mosaicism will not involve the germ line,
and the reproductive risk of transmission is negligible.
Gonosomal mosaicism refers to involvement of both
gonads and somatic tissue, but mosaicism can occur
exclusively in gonadal tissue, referred to as gonadal
mosaicism. Clinically, this may explain recurrences
among siblings of autosomal dominant disorders such
as tuberous sclerosis or neurofibromatosis, when none
of the parents has any clinical manifestations and gene
screening using genomic DNA from peripheral blood
samples yields no mutation. Segmental mosaicism for
autosomal dominant disorders is thought to occur in
one of two ways: either there is a postzygotic mutation with the skin outside the segment and genomic
DNA being normal (type 1), or there is a heterozygous genomic mutation in all cells that is then exacerbated by loss of heterozygosity within a segment or
along the lines of Blaschko (type 2). This pattern has
been described in several autosomal dominant disorders, including Darier disease, HaileyHailey disease
(see Chapter 51), superficial actinic porokeratosis (see
Chapter 52), and tuberous sclerosis (see Chapter 140).
The lines of Blaschko were delineated over 100 years
ago; the pattern is attributed to the lines of migration
and proliferation of epidermal cells during embryogenesis (i.e., the bands of abnormal skin represent
clones of cells carrying a mutation in a gene expressed
in the skin).33 Apart from somatic mutations [either in
dominant disorders, such as epidermolytic ichthyosis (formerly called bullous congenital ichthyosiform
erythroderma) leading to linear epidermolytic ichthyosis (epidermal nevus of the epidermolytic hyperkeratosis type) (see Chapter 49), or in conditions involving
mutations in lethal dominant genes such as in McCune
Albright syndrome], mosaicism following Blaschkos
lines is also seen in chromosomal mosaicism and functional mosaicism (random X-chromosome inactivation
through lyonization). Monoallelic expression on autosomes (with random inactivation of either the maternal or paternal allele) is also feasible, and probably
underdocumented.34 Chromosomal mosaicism results
from nondisjunction events that occur after fertilization. Clinically, this is found in the linear mosaic pigmentary disorders (hypomelanosis of Ito (see Chapter
75) and linear and whorled hyperpigmentation). It is
important to point out that hypomelanosis of Ito is not
a specific diagnosis but may occur as a consequence
of several different chromosomal abnormalities that
perturb various genes relevant to skin pigmentation,
which has led to the term pigmentary mosaicism to
describe this group of disorders.
Functional mosaicism relates to genes on the X chromosome, because during embryonic development in
females, one of the X chromosomes, either the maternal or the paternal, is inactivated. For X-linked dominant disorders, such as focal dermal hypoplasia (Goltz
syndrome) or incontinentia pigmenti (see Chapter 75),
females survive because of the presence of some cells
in which the X chromosome without the mutation is
EPIGENETICS
Disease phenotypes reflect the result of the interaction

between a particular genotype and the environment,
but it is evident that some variation, for example, in
monozygotic twins, is attributable to neither. Additional influences at the biochemical, cellular, tissue,
and organism levels occur, and these are referred to
as epigenetic phenomena.38 Single genes are not solely
responsible for each separate function of a cell. Genes
may collaborate in circuits, be mobile, exist in plasmids
and cytoplasmic organelles, and can be imported by
nonsexual means from other organisms or as synthetic
products. Even prion proteins can simulate some gene
properties. Epigenetic effects reflect chemical modifications to DNA that do not alter DNA sequence but do
alter the probability of gene transcription. Mammalian
DNA methylation machinery is made up of two components: (1) DNA methyltransferases, which establish
and maintain genome-wide DNA methylation patterns,
and (2) the methyl-CpG-binding proteins, which are
involved in scanning and interpreting the methylation
patterns. Analysis of any changes in these processes
is known as epigenomics.39 Examples of modifications
include direct covalent modification of DNA by methylation of cytosines and alterations in proteins that bind
to DNA. Such changes may affect DNA accessibility to
local transcriptional complexes as well as influencing
chromatin structure at regional and genome-wide levels, thus providing a link between genome structure
and regulation of transcription. Indeed, epigenome
analysis is now being carried out in parallel with gene
expression to identify genome-wide methylation patterns and profiles of all human genes. For example,
there is considerable interindividual variation in
cytosine methylation of CpG dinucleotides within
the major histocompatibility complex (MHC) region
genes, although whether this has any bearing on the
expression of skin disorders such as psoriasis remains
to be seen. New sensitive and quantitative methylation-specific polymerase chain reaction-based assays
can identify epigenetic anomalies in cancers such as
melanoma.40 DNA hypermethylation contributes to
gene silencing by preventing the binding of activating
transcription factors and by attracting repressor complexes that induce the formation of inactive chromatin
structures. With regard to melanoma, such changes
may impact on several biologic processes, including cell cycle control, apoptosis, cell signaling, tumor
cell invasion, metastasis, angiogenesis, and immune
recognition. A further but as yet unresolved issue is
whether there is heritability of epigenetic characteristics. Likewise, it is unclear whether environmentally
induced changes in epigenetic status, and hence gene
transcription and phenotype, can be transmitted through
more than one generation. Such a phenomenon might
account for the cancer susceptibility of grandchildren
::
Figure 8-7 Revertant mosaicism in an individual with

non-Herlitz junctional epidermolysis bullosa. The subject
has loss-of-function mutations on both alleles of the type
XVII collagen gene, COL17A1, but spontaneous genetic correction of the mutation in some areas has led to patches of
normal-appearing skin (areas within black marker outline)
that do not blister. (From Jonkman MF et al: Revertant
mosaicism in epidermolysis bullosa caused by mitotic
gene conversion. Cell 88:543, 1997, with permission.)
ation. This phenomenon is known as epigenetic mosaicism; such events may be implicated in tumorigenesis
but have not been associated with any genetic skin
disorder.
Chapter 8
active and able to function. For males, these X-linked

dominant disorders are typically lethal, unless associated with an abnormal karyotype (e.g., Klinefelter
syndrome; 47, XXY) or if the mutation occurs during
embryonic development. For X-linked recessive conditions, such as X-linked recessive hypohidrotic ectodermal dysplasia (see Chapter 142), the clinical features
are evident in hemizygous males (who have only one
X chromosome), but females may show subtle abnormalities due to mosaicism caused by X-inactivation,
such as decreased sweating or reduced hair in areas
of the skin in which the normal X is selectively inactivated. There are 1,317 known genes on the X chromosome, and most undergo random inactivation but
a small percentage (approximately 27 genes on Xp,
including the steroid sulfatase gene, and 26 genes on
Xq) escape inactivation.
Revertant mosaicism, also known as natural gene
therapy, refers to genetic correction of an abnormality
by various different phenomena including back mutations, intragenic crossovers, mitotic gene conversion,
and second site mutations.35,36 Indeed, multiple different correcting events can occur in the same patient.
Such changes have been described in a few genes
expressed in the skin, including the keratin 14, laminin
332, collagen XVII, collagen VII, and kindlin-1 (fermitin family homolog 1) genes in different forms of EB
(Fig. 8-7; see Chapter 62). The clinical relevance of the
conversion process depends on several factors, including the number of cells involved, how much reversal
actually occurs, and at what stage in life the reversion takes place. Attempts have been made to culture
reverted keratinocytes and graft them to unreverted
sites,37 a pioneering approach that may have therapeutic potential for some patients.
Apart from mutations in nuclear DNA, mosaicism
can also be influenced by environmental factors, such
as viral DNA sequences (retrotransposons) that can be
incorporated into nuclear DNA, replicate, and activate
or silence genes through methylation or demethyl-
87
Section 3
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88
of individuals who have been exposed to diethylstilbestrol, but this has not been proved. However, germ
line epimutations have been identified in other human
diseases, such as colorectal cancers characterized by
microsatellite instability and hypermethylation of the
MLH1 DNA mismatch repair gene, although the risk
of transgenerational epigenetic inheritance of cancer
from such a mutation is not well established and probably small. Over the course of an individuals lifespan,
epigenetic mutations (affecting DNA methylation and
histone modifications) may occur more frequently than
DNA mutations, and it is expected that, over the next
decade, the role of epigenetic phenomena in influencing phenotypic variation will gradually become better
understood.41
HISTOCOMPATABILITY ANTIGEN
DISEASE ASSOCIATION
Human leukocyte antigen (HLA) molecules are glycoproteins that are expressed on almost all nucleated
cells. The HLA region is located on the short arm of
chromosome 6, at 6p21, referred to as the MHC. There
are three classic loci at HLA class I: (1) HLA-A, (2)
HLA-B, and (3) HLA-Cw, and five loci at class II: (1)
HLA-DR, (2) HLA-DQ, (3) HLA-DP, (4) HLA-DM, and
(5) HLA-DO. The HLA molecules are highly polymorphic, there being many alleles at each individual locus.
Thus, allelic variation contributes to defining a unique
fingerprint for each persons cells, which allows an
individuals immune system to define what is foreign
and what is self. The clinical significance of the HLA
system is highlighted in human tissue transplantation,
especially in kidney and bone marrow transplantation, where efforts are made to match at the HLA-A,
-B, and -DR loci. MHC class I molecules, complexed to
certain peptides, act as substrates for CD8+ T-cell activation, whereas MHC class II molecules on the surface
of antigen-presenting cells display a range of peptides
for recognition by the T-cell receptors of CD4+ T helper
cells (see Chapter 10). Therefore, MHC molecules are
central to effective adaptive immune responses. Conversely, however, genetic and epidemiologic data have
implicated these molecules in the pathogenesis of various autoimmune and chronic inflammatory diseases.
Several skin diseases, such as psoriasis (see Chapter
18), psoriatic arthropathy (central and peripheral),
dermatitis herpetiformis, pemphigus, reactive arthritis syndrome (see Chapter 20), and Behet disease (see
Chapter 166), all show an association with inheritance
of certain HLA haplotypes (i.e., there is a higher incidence of these conditions in individuals and families
with particular HLA alleles). However, the molecular
mechanisms by which polymorphisms in HLA molecules confer susceptibility to certain disorders are still
unclear. This situation is further complicated by the
fact that, for most diseases, it is unknown which autoantigens (presented by the disease-associated MHC
molecules) are primarily involved. For many diseases,
the MHC class association is the main genetic association. Nevertheless, for most of the MHC-associated
diseases, it has been difficult to unequivocally determine the primary disease-risk gene(s), owing to the
extended linkage disequilibrium in the MHC region.
However, recent genetic and functional studies support the long-held assumption that common MHC
class I and II alleles themselves are responsible for
many disease associations, such as the HLA cw6 allele
in psoriasis. Of practical clinical importance is the
strong genetic association between certain HLA alleles
and the risk of adverse drug reactions. For example, in
Han Chinese and some other Asian populations, HLAB*1502 confers a greatly increased risk of carbamazepine-induced StevensJohnson syndrome and toxic
epidermal necrolysis. Therefore, screening for HLAB*1502 before starting carbamazepine in patients from
high-risk populations is recommended or required by
regulatory agencies.42
GENETIC COUNSELING
The National Society of Genetic Counselors (http://
www.nsgc.org) has defined genetic counseling as the
process of helping people understand and adapt to the
medical, psychological and familial implications of
genetic contributions to disease. Genetic counseling
should include: (1) interpretation of family and medical histories to assess the chance of disease occurrence
or recurrence; (2) education about inheritance, testing,
management, prevention, resources, and research; and
(3) counseling to promote informed choice and adaptation to the risk or condition.43
Once the diagnosis of an inherited skin disease is
established and the mode of inheritance is known,
every dermatologist should be able to advise patients
correctly and appropriately, although additional support from specialists in medical genetics is often
necessary. Genetic counseling must be based on an
understanding of genetic principles and on a familiarity with the usual behavior of hereditary and congenital abnormalities. It is also important to be familiar
with the range of clinical severity of a particular disease, the social consequences of the disorder, the availability of therapy (if any), and the options for mutation
detection and prenatal testing in subsequent pregnancies at risk for recurrence (one useful site is http://
www.genetests.com).
A key component of genetic counseling is to help
parents, patients, and families know about the risks of
recurrence or transmission for a particular condition.
This information is not only practical but often relieves
guilt and can allay rather than increase anxiety. For
example, it may not be clear to the person that he or
she cannot transmit the given disorder. The unaffected
brother of a patient with an X-linked recessive disorder
such as Fabry disease (see Chapter 136), X-linked ichthyosis (see Chapter 49), WiskottAldrich syndrome
(see Chapter 143), or Menkes syndrome (see Chapter
88) need not worry about his children being affected
or even carrying the abnormal allele, but he may not
know this.
Prognosis and counseling for conditions such as
psoriasis in which the genetic basis is complex or still
PRENATAL DIAGNOSIS
::
In recent years, there has been considerable progress

in developing prenatal testing for severe inherited skin
disorders (Fig. 8-8). Initially, ultrastructural examination of fetal skin biopsies was established in a limited number of conditions. In the late 1970s, the first
diagnostic examination of fetal skin was reported for
epidermolytic hyperkeratosis and Herlitz junctional
EB (see Chapter 62).46,47 These initial biopsies were
performed with the aid of a fetoscope to visualize the
fetus. However, with improvements in sonographic

imaging, biopsies of fetal skin are now taken under
ultrasound guidance. The fetal skin biopsy samples
obtained during the early 1980s could be examined
only by light microscopy and transmission electron
microscopy. However, the introduction of a number
of monoclonal and polyclonal antibodies to various
basement membrane components during the mid-1980s
led to the development of immunohistochemical tests
to help complement ultrastructural analysis in establishing an accurate diagnosis, especially in cases of EB.48
Fetal skin biopsies are taken during the midtrimester.
For disorders such as EB, testing at 16 weeks gestation
is appropriate. However, for some forms of ichthyosis,
the disease-defining structural pathology may not be
evident at this time, and fetal skin sampling may need
to be deferred until 20 to 22 weeks of development.
Nevertheless, since the early 1990s, as the molecular basis of an increasing number of genodermatoses
has been elucidated, fetal skin biopsies have gradually
been superseded by DNA-based diagnostic screening
using fetal DNA from amniotic fluid cells or samples
of chorionic villi; the latter are usually taken at 10 to
12 weeks gestation (i.e., at the end of the first trimester).49,50 In addition, advances with in vitro fertilization
and embryo micromanipulation have led to the feasibility of even earlier DNA-based assessment through
preimplantation genetic diagnosis, an approach first
Chapter 8
unclear is more difficult (see Chapter 18). Persons can

be advised, for example, that if both parents have psoriasis, the probability is 60% to 75% that a child will
have psoriasis; if one parent and a child of that union
have psoriasis, then the chance is 30% that another
child will have psoriasis; and if two normal parents
have produced a child with psoriasis, the probability is
15% to 20% for another child with psoriasis.44 Ongoing
discoveries in other diseases, such as melanoma genetics, can also impact on genetic counseling. The identification of family-specific mutations in the CDKN2A
and CDK4 genes, as well as risk alleles in the MC1R
and OCA2 genes and other genetic variants, allow for
more accurate and informative patient and family consultations.45
Figure 8-8 Options for prenatal testing of inherited skin diseases. A. Fetal skin biopsy, here shown at 18 weeks gestation. B. Chorionic villi sampled at 11 weeks gestation. C. Preimplantation genetic diagnosis. A single cell is being
extracted from a 12-cell embryo using a suction pipette.
89
Section 3
::
90
successfully applied in 1990, for risk of recurrence of

cystic fibrosis.51 Successful preimplantation testing
has also been reported for severe inherited skin disorders.52 This is likely to become a more popular, though
still technically challenging, option for some couples,
in view of recent advances in amplifying the whole
genome in single cells and the application of multiple
linkage markers in an approach termed preimplantation
genetic haplotyping.53 This approach has been developed and applied successfully for Herlitz junctional
epidermolysis bullosa.54 For some disorders, alternative less invasive methods of testing are now also
being developed, including analysis of fetal DNA or
RNA from within the maternal circulation and the use
of three-dimensional ultrasonography.
In the current absence of effective treatment for
many hereditary skin diseases, prenatal diagnosis can
provide much appreciated information to couples at
risk of having affected children, although detailed and
supportive genetic counseling is also a vital element of
all prenatal testing procedures.
GENE THERAPY
The field of gene therapy can be subdivided in different ways.55 First, there are approaches aimed at treatment of recessive genetic diseases where homozygous
or compound heterozygous loss-of-function mutations
lead to complete absence or complete functional ablation of a vital protein. These types of diseases are amenable to gene replacement therapy, and it is this form of
gene therapy that has tended to predominate because
it is generally technically more feasible than treatment
of dominant genetic conditions.56 In dermatology, these
include diseases such as lamellar ichthyosis (see Chapter 49), where in most cases, there is hereditary absence
of transglutaminase-1 activity in the outer epidermis,
or the severe HallopeauSiemens form of recessive
dystrophic EB, where there is complete absence of type
VII collagen expression due to recessive mutations.57
The second form of gene therapy, in broad terms, is
aimed at treatment of dominant-negative genetic disorders and is known as gene inhibition therapy. Here, there
is a completely different type of problem to be tackled
because these patients already carry one normal copy
of the gene and one mutated copy. The disease results
because an abnormal protein product produced by
the mutant allele, dominant-negative mutant protein,
binds to and inhibits the function of the normal protein produced by the wild-type allele. In many cases,
it can be shown from the study of rare recessive variants of dominant diseases that one allele is sufficient
for normal skin function, and so if a means could be
found of specifically inhibiting the expression of the
mutant allele, this should be therapeutically beneficial.
However, finding a gene therapy agent that is capable
of discriminating the wild-type and mutant alleles,
which can differ by as little as one bp of DNA, is challenging and, until recently has resulted in little success.
A typical dominant-negative genetic skin disease is EB
simplex (see Chapter 62), caused by mutations in either
of the genes encoding keratins 5 or 14. The vast major-
ity of cases are caused by dominant-negative missense

mutations, changing only a single amino acid, carried
in a heterozygous manner on one allele.58
Gene therapy approaches can also be broadly subdivided according to whether they involve in vivo or ex
vivo strategies.55 Using an in vivo approach, the gene
therapy agent would be applied directly to the patients
skin or another tissue. A disadvantage of the skin as a target organ for gene therapy is that it is a barrier tissue that
is fundamentally designed to prevent entry of foreign
nucleic acid in the form of viruses or other pathogenic
agents. This is an impediment to in vivo gene therapy
development but is not insurmountable due to developments in liposome technology and other methods
for cutaneous macromolecule delivery.59 In an ex vivo
approach, a skin biopsy would be taken, keratinocytes
or fibroblasts would be grown and expanded in culture,
treated with the gene therapy agent, and then grafted
onto or injected back into the patient. The skin is a good
organ system for both these approaches because it is very
accessible for in vivo applications. In addition, the skin
can be readily biopsied, and cell culture and regrafting
of keratinocytes can be adapted for ex vivo gene therapy.
Gene replacement therapy systems have been
developed for lamellar ichthyosis (see Chapter 49)
and the recessive forms of EB (see Chapter 62), among
other diseases. These mostly consist of expressing
the normal complementary DNA encoding the gene
of interest from some form of gene therapy vector
adapted from viruses that can integrate their genomes
stably into the human genome. Therefore, such viral
vectors can lead to long-term stable expression of the
replacement gene.60 Early studies tended to use retroviral vectors or adeno-associated viral vectors, but
these have a number of limitations. For example, retroviruses only transduce dividing cells and therefore
fail to target stem cells; consequently, gene expression is quickly lost due to turnover of the epidermis
through keratinocyte differentiation. Furthermore,
there have been some safety issues in small-scale
human trials for both retroviral and adeno-associated
viral vectors. Lentiviral vectors, derived from short
integrating sequences found in a number of immunodeficiency viruses, have the advantage of being
able to stably transduce dividing and nondividing
cells, with close to 100% efficiency and at low copy
number. These may be the current vectors of choice,
but they also have potential problems because their
preferred integration sites in the human genome are
currently ill defined and may lead to concerns about
safety. However, with a wide variety of vectors under
development and testing, it should become clear in
future years which vectors are effective and safe for
human use. Ultimately, like all novel therapeutics,
animal testing can only act as a guide because the
human genome is quite different and may react differently to foreign DNA integration, so that phase I,
II, and III human trials or adaptations thereof will
ultimately have to be performed to determine efficacy and safety. Currently, small-scale clinical trials
are ongoing for junctional EB and are planned for a
number of other genodermatoses, mainly concentrating on the more severe recessive conditions.
and was shown to have an excellent toxicity profile in

rodents, as per a small molecule drug. This facilitated
FDA approval for a double blind split body Phase 1b
clinical trial in a single volunteer with PC. The trial was
successful, with a number of objective measures showing statistically significant clinical improvement. This
study, funded by the patient advocacy organization PC
Project (www.pachyonychia.org), was the first in human
siRNA trial using a mutation-specific gene silencing
approach and only the fifth siRNA trial in humans. This
personalized medicine strategy gives hope for patients
with incurably dominant genodermatoses and future
trials in EB simplex are currently in the planning stages.
KEY REFERENCES
Racial Considerations: Skin of Color
1. Hsu F et al: The UCSC known genes. Bioinformatics

22:1036, 2006
2. Tsongalis GJ, Silverman LM: Molecular diagnostics: A historical perspective. Clin Chim Acta 369:188, 2006
15. Happle R: X-chromosome inactivation: Role in skin disease expression. Acta Paediatr Suppl 95:16, 2006
39. Callinan PA, Feinberg AP: The emerging science of epigenomics. Hum Mol Genet 15:R95, 2006
56. Ferrari S et al: Gene therapy in combination with tissue
engineering to treat epidermolysis bullosa. Expert Opin
Biol Ther 6:367, 2006
::
Chapter 9
Treatment of dominant-negative disorders has

recently started to receive a great deal of attention with
the discovery of the RNA inhibition pathway in humans
and the finding that small synthetic double-stranded
RNA molecules of 19 to 21 bp, known as short inhibitory RNA (siRNA), can efficiently inhibit expression
of human genes in a sequence-specific, user-defined
manner.58,61 There is currently a great deal of attention
being focused on development of siRNA inhibitors to
selectively silence mutant alleles in dominant-negative
genetic diseases, such as the keratin disordersEB simplex and pachyonychia congenita (PC). Currently, the
big challenge in this rapidly evolving new field is finding
an effective, noninvasive method to get siRNA through
the stratum corneum and into keratinocytes or other target cells. A number of groups are working on means of
delivering siRNA to skin and other organ systems, and
there is currently much optimism about these developing into clinically applicable agents in the near future.
In particular, a great deal of rapid progress has been
made in PC in recent years. Following development of
reporter gene methodology to rapidly screen many different siRNA species, two siRNAs were identified that
could specifically and potently silence mutant keratin
K6a mRNA differing from the wild-type mRNA by only
a single nucleotide, i.e., these siRNAs represent allelespecific gene silencing agents. Following a battery of
preclinical studies in cells and animal models to show
efficacy, the K6a mutation-specific siRNA was manufactured to Good Manufacturing Practice standards
Chapter 9 :: Racial Considerations: Skin of Color

:: K
avitha K. Reddy, Yolanda M. Lenzy,
Katherine L. Brown, & Barbara A. Gilchrest
SKIN OF COLOR AT A GLANCE
Race and ethnicity are closely related but
distinct factors that may influence skin
disease prevalence or presentation.
The Fitzpatrick skin phototype classification
was developed to convey risk of photodamage
in white skin and is often less useful in
describing skin of color.
The complex polygenic basis for variation
in human skin, hair, and eye color has been
partially elucidated.
The structure and function of skin of color
is similar or identical to that of white
(Caucasian) skin, other than differences
related to pigmentation.
Differences in the character of hair among

whites, Asians, and Africans relate to shape
of the hair follicle and thickness of the cuticle
layer.
African hair displays low tensile strength
and easy breakage. This fragility may
be compounded by chemical or heat
application, apparently predisposing to
several types of alopecia.
Postinflammatory hyper- or hypopigmentation
is often prominent and long lasting in skin of
color; preventive and therapeutic measures
should be considered in the plan of care.
91
Figure 9-1 A spectrum of human pigmentary variation observed among Boston medical trainees. (Photograph by
Michael Krathen, MD.)
Section 3
RACIAL AND ETHNIC INFLUENCES

ON SKIN DISEASE AND THERAPY
::
In the United States and worldwide, myriad cutaneous phenotypes characterize mankind. Most striking is
the range of skin and hair color (Fig. 9-1). The Census
Bureau estimates that half of the US population will be of
non-European descent by the year 2050.1 There are currently more than 95 million persons in the United State2
and billions of individuals worldwide categorized as
having skin of color. There has been increasing awareness of racial and ethnic influences (see Table 9-1) on skin
biology and on diagnosis and treatment of skin disease.
The literature regarding skin of color primarily
focuses on promoting awareness of normal and abnormal skin conditions in a patient regardless of skin
phenotype. It seeks to identify risks and benefits of
treatments in diverse skin types, to develop effective
treatments for common dermatoses in skin of color,
recognizing the importance of individualized therapy,
and to avoid stereotyping and generalization.
DEFINING SKIN OF COLOR

In defining skin of color, it is important to consider
the reasons for doing so. Many have questioned the
common propensity of medical practitioners to state a

patients race among the first few words, as a primary
identifier. The skin type, color, or ethnic background
of most patients may be better suited to the physical
examination or to relevant points in the history. The
International Committee of Medical Journal Editors
Uniform Requirements for Manuscripts Submitted to Biomedical Journals recommends that authors using variables such as race or ethnicity should define how they
measured the variables and justify their relevance.6
The Journal of the American Academy of Dermatology similarly suggests that authors inclined to submit racial,
ethnic, or skin color descriptors in manuscripts ask
themselves a series of questions regarding whether
such identification is important to the understanding
or pedagogical value of the manuscript, whether the
patient would self-identify in the same way and how
this is known, whether the descriptor used could be
open to racist interpretation, and what the evidence is
that the descriptor plays a role in the entities described.7
Most would argue that nonwhite skin is skin
of color. However, there is a diverse array of phenotypes within the nonwhite and white spectra, and two
categories are inadequate to describe them. The most
commonly used classification system in dermatologic practice is the Fitzpatrick phototype,8,9 designed
to provide an estimate of skin cancer and photoaging risk, in which individuals are assigned a number
TABLE 9-1
Race Versus Ethnicity
92
Term
Derivation
Current Usage or Implication
Race
<Latin, root
A population distinguished as a more or less distinct group by genetically transmitted

physical characteristics; originally geographically segregated
Groups increasingly blurred by interracial offspring
Determined at conception, immutable
May influence disease predilection/susceptibility
Ethnicity
<Greek, race
or distinct
population
with its own
customs
A social construct in which a group of individuals shares a language, cultural

practices, or customs
Self-assigned and somewhat mutable
Often but not always associated with race
May influence treatment choices and exposure to disease-promoting or diseasepreventing factors
Stein J, Urdang L, eds.: Derivations from the Random House Dictionary of the English Language. New York, Random House, 1967. Usage or implication is the authors distillation of a large and contradictory literature.35
oxyhemoglobin and deoxyhemoglobin also play a

role in observed color along with capillary blood flow,
dietary pigments carotene and lycopene, collagen, the
spectrum of ambient light, reflection, refraction, and
absorption of light by the skin, and transparency of the
stratum corneum and epidermis.15 Endocrine, inflammatory, neural, and pharmacologic factors also influence skin color.
Melanosome size and distribution vary in skin of
differing colors (Fig. 9-2). In individuals of African
descent, the melanosomes are typically large and dispersed singly in the keratinocytes. In white individuals, melanosomes are smaller and grouped within a
membrane. In Asian skin, a combination of individual and clustered melanosomes is found.16 Melanin
may also be degraded more slowly in skin of color.17
Increasing melanin provides higher natural photoprotection, due to a greater absorption of UV photons, but
also typically increases risk of pigmentary disorders
including hypopigmentation or hyperpigmentation as
a result of physiologic responses to trauma or inflammation.18 For further discussion, see Chapter 72.
Structural or functional differences in white versus nonwhite human skin beyond those related to
photoprotection19 and pigmentary alterations are not
known. Conflicting data have been presented on variations in lipid content, sebum content, and the number
of stratum corneum layers and compaction.20 Histologic sections of normal skin generally appear identical
aside from the difference in melanin. Whether there are
genetically determined functional differences of the
skin associated with skin color is the subject of study
and debate.15
The perceived skin color is the result of the spectrum

of incident light and its absorption and reflection by
chromophores in the skin. It is largely determined by
melanin amount, type (ratio of black/brown eumelanin to red/yellow pheomelanin), and intracellular
distribution and location within the layers of the skin.
The number of melanocytes in a given area of skin
is similar among all individuals. Vascular pigments
Figure 9-2 Variation in melanosome packaging within

the keratinocyte of skin of differing colors. White skin
(right) typically shows spherical melanosomes clustered
within a membrane, black skin has larger elliptical melanosomes dispersed singly, and Asian or golden brown skin
typically has a combination of the two (middle). (Used with
permission from Jag Bhawan, MD.)
::
STRUCTURE AND FUNCTION

IN SKIN OF COLOR
Variation in melanosome packaging
Chapter 9
based on their ability to burn and tan after a single,

rather modest sun exposure. The original Fitzpatrick
system consisted of types IIV; types V and VI were
soon added with the goal of representing individuals of Asian/Indian and African/Aboriginal origin,
respectively. Skin of color is now commonly regarded
as encompassing types IV through VI,10 but many
patients and physicians would argue that the spectrum
is broader. For example, Japanese women not infrequently describe themselves as having type II skin.
In any case, for the purpose of studying nonwhite
skin, the Fitzpatrick system has several limitations.
Although intended to utilize patient-reported characteristics, in practice a patient is commonly assigned
to a type without benefit of a history. Also, the Fitzpatrick type has been shown in studies not to correspond well to constitutive skin color and to correlate
poorly with minimal erythema dose (MED) values.11
Interestingly, the physician-assigned skin phototype
has been shown to correlate moderately with race, and
race assignment does not correlate well with objective
measures of pigmentation or self-reported skin phototype, suggesting that assignment of Fitzpatrick types is
often based on perceived race rather than either objective skin color or response to ultraviolet (UV) light.12
Other scales have been developed with a goal of more
accurately defining skin pigmentation and corresponding to defined clinical features. It has been suggested that
for skin of color a scale based on propensity to postinflammatory hyperpigmentation, for example, might be
more useful than one based on burning and tanning
responses to UV exposure.10 A variety of visual scales
seek to convey skin color more accurately and precisely
and to measure changes over time. These include the
physicians global assessment, melasma area and severity index (MASI), visual hyperpigmentation scale,13 and
skin tone color scale.14 Skin photometers employing UV
light, polarized light, reflectance spectroscopy, tristimulus colorimetry, and spectrophotometry are also available
and can provide an objective skin color score.13 However,
it is possible that, parallel to the Fitzpatrick phototype
classification for white skin, a classification system based
on patient perceptions of desirable or adverse responses
to environmental challenges would be most useful in
managing dermatologic patients with skin of color. For
example, asking the patient about the frequency, severity, and duration of postinflammatory hyperpigmentation in the past may provide critical guidance when
considering a skin care or treatment regimen.
GENETICS OF PIGMENTATION
There is a polygenic basis for human pigmentation.
Genes already implicated in pigmentary variation
93
TABLE 9-2
Genes with Polymorphisms that Influence Human Pigmentary Variation
Section 3
Gene Product
Recognized Function
Pigmentary Variation Effect
TYR
Tyrosinase
Rate-limiting enzyme in melanin

biosynthesis
Europeans and South Asians: lighter/

darker skin within group; little
variation among races
TYRP1 (TRP1)
5,6-Dihydroxyindole-2carboxylic acid oxidase or

tyrosinase related protein 1
Enzyme in melanin biosynthesis
Europeans: lighter/darker skin and eye

color
OCA2 (HERC2)
P protein
l-Tyrosine transmembrane
transporter
Blond/brown hair, blue/nonblue eyes;

East Asians, Africans: lighter/darker
skin
Loss of function causes
oculocutaneous albinism type 2
SLC45A2 (MATP)
Membrane-associated
transporter protein
Transmembrane transport
Black/nonblack hair; dark/light skin;

dark/light eyes
SLC 24A4
Sodium/potassium/calcium
exchanger 4
Transmembrane potassiumdependent sodium/calcium

exchanger
Blond/brown hair; blue/green eyes
SLC24A5
Sodium/potassium/calcium
exchanger 5
Transmembrane potassiumdependent sodium/calcium

exchanger
Africans and Asians: ancestral form

(111Ala), darker skin; Europeans:
variant (111Thr), lighter skin
MC1R
Melanocortin 1 receptor
Receptor for melanocytestimulating hormone (MSH) and

ASIP
Red hairfair skin: R151C, R160W,

D294H mutations; loss of function
increases pheomelanin
ASIP
Agouti-signaling protein
Ligand for MC1R; antagonist for

MSH that increases pheomelanin
Inactivating mutations associated with

dark hair/eyes
KITLG
KIT ligand (steel factor, stem

cell factor, mast cell growth
factor)
Ligand of KIT tyrosinekinase

receptor (cell-migration effects)
Blond/brown hair; lighter/darker skin
IRF4
Interferon regulatory
factor 4
Regulator of RNA polymerase II

transcription factor activity
Light/dark hair
TPCN2
Two-pore calcium channel 2
Lysosomal membrane calcium

channel
Blond/brown hair
::
Gene
94
of human skin, hair, and iris include TYR, TYRP1,

OCA2/HERC2, SLC45A2 (OCA4/MATP), SLC24A5,
SLC24A4, MC1R, ASIP, KITLG, IRF4, and TPCN221,22
(Table 9-2).
Examination of mitochondrial DNA and Y chromosome analysis suggests that all humans descended
from three African females and three African males.22,23
It is believed that some of these descendants stayed
in Africa, while others migrated to Europe and Asia
and from Asia across the polar land bridge to the
Americas. West Africans with the ancestral variant of
the SLC24A5 gene expressing alanine at amino acid
111 have dark brown skin. East Asians also have this
form of SLC24A5.24 A variant of the SLC24A5 gene
with threonine at amino acid 111 is nearly constant in
those of European ancestry, determining lighter skin
types, and is believed to have resulted from natural
selection.24 SLC24A5 encodes a potassium-dependent
sodium/calcium exchanger that is hypothesized to
play a role in melanosome morphogenesis and melanogenesis through changes in intraorganellar cal-
cium concentration and pH. The SLC24A5 variation is

believed to explain 2538% of the melanin difference
between Africans and Europeans.24 Polymorphisms of
SLC45A2, OCA2, and KITLG have also been shown to
contribute to pigmentation differences between European and African populations.25
Within European-derived populations, TYR, OCA2,
MC1R, ASIP, and IRF4 polymorphisms account for
much of the observed pigmentary variation.25 The
best studied concerns the highly polymorphic MC1R,
a melanocyte surface receptor that when activated by
its ligand aMSH increases intracellular cAMP levels,
induces the microphthalmia transcription factor MiTF
and ultimately increases black/brown eumelanin synthesis. A number of loss-of-function variant alleles of
MC1R have been identified and shown to result in a
fair-skinned red-hair phenotype.26 Other MC1R variant alleles result in blond or light brown hair and fair
skin.26 Conversely, dark brown or black hair and dark
skin are observed in individuals expressing the wild
type MC1R. Risk of skin cancer, including melanoma,
BIOCHEMICAL COMPOSITION
Initially, the cross-sectional shape of the hair shaft was

thought to determine the macroscopic appearance
of hair and to distinguish people of different genetic
backgrounds.40 The round cross-section of Asian hair
was thought to result in straight hair, the elliptical
or flattened cross-section of African hair to result in
curly hair and an intermediate to round and elliptical
cross-section results in wavy to straight European hair
(Table 9-3). However, three-dimensional computeraided reconstructions of scalp biopsy cross-sections
suggest that the shape of the hair follicles (helical or
curved in Africans vs. straight and perpendicular to
the skin surface in Asians) also play an important role.
The finding that Caucasians can have hair follicles
that are elliptical in cross-section and yet have straight
hair shafts further implies that the three-dimensional
African or black hair is known to be more affected by

breakage, with easily observed fragility in vivo.31 There
are no known chemical differences in black versus
Caucasian or Asian hair to explain this observed fragility. The biochemical composition of hair in people
from different geographic regions and racial groups
has been shown to be virtually identical in terms of
keratin and amino acid content,32,33 despite significant differences in tensile strength, combability, and
moisture content. In contrast, numerous studies have
described the physical differences in hair from people
of different races.3437 As well, African-Americans have
a significantly lower hair density (number of follicles
per unit area) than whites (22.4 vs. 35.5 follicles); and a
study examining Asian scalp biopsies found lower hair
density than in Caucasians.38 Such differences must be
taken into account in the interpretation of scalp biopsy
specimens.39
HAIR SHAPE
Human hair is typically categorized into three major

distinct groups: (1) Asian, (2) Caucasian, and (3) African.28 However, the worlds population encompasses
people of multiple and mixed backgrounds, resulting
in the existence of multiple hair types.29 All hair exhibits common characteristics of morphology, chemical
makeup, and molecular structure. There are nevertheless differences in hair morphology and physical properties that contribute to the unique features of the hair
fiber, response to hair treatments, and development of
disease processes in different groups.30 Understanding
the biology and the differences in physical properties
of various hair types can assist clinicians in managing
hair and scalp problems. A variety of terms are used
in the dermatologic literature to describe different hair
::
VARIATION IN HAIR
CHARACTERISTICS
types based upon an authors personal preference,

country of origin, or current trends. To date, most studies have focused on African hair, which presents the
greatest array of clinical disorders.
Chapter 9
is also affected by the inherited MC1R alleles and is

generally correlated with fair skin color.26 However,
some variant alleles appear to confer an increased risk
independent of their effect on pigmentation.26
No genetic basis for the different pigmentary phenotypes of Africans compared with Asians has yet been
identified. Both have the ancestral form of SLC24A5
and MC1R, suggesting that evolution to lighter skin
colors may have occurred independently in Europe
and in Asia. The genes regulating pigmentation differences among Asians are not adequately characterized,
although OCA2 variant alleles have been associated
recently with some East Asian skin pigmentation variations. South Asian skin pigmentation shows considerable variation; variants of SLC24A5, SLC45A2, and
TYR have been associated with these pigmentary differences.27
The Hispanic skin color group is least well
defined. It is genotypically and phenotypically variable, representing mixtures of European (largely Spanish), African, and Central and South American Native
origins. The Hispanic phenotype often differs on average in different geographic areas. Perhaps because of
these challenges, genetic determinants of Hispanic
skin color remain virtually unstudied.
TABLE 9-3
Comparison of Physical Properties of Hair

Racial Group
African
Caucasian
Asian
Cross-sectional shape
Elliptical
Ovoid
Round
Hair follicle shape
Curved
Variable
Straight
Tensile strength
Low
High
High
Work of combing
High
Low
Low
Moisture content
Low
High
High
Average number of cuticle layers
Highly variable (68 along the major

axis, 12 along the minor axis)
Constant (45)
Constant (67)
95
structure of the hair follicle is responsible for the shape

of the hair shaft. In vitro experiments comparing the
growth of curly and straight hair found that follicles
producing curled hairs, when dissected out of the
scalp and placed in culture, continue to grow curled
hair shafts.41 This suggests that the shape of the hair
may be genetically programed by the bulb, with or
without the usual dermal environment.42
HAIR STRUCTURE
Section 3
::
96
Recent studies have identified Asian-specific alleles of

the EDAR and FGFR2 genes that are associated with
thick, straight hair.43,44 Likewise, a recent genomewide association scan for hair morphology (straight,
wavy, curly) in Australians of European descent suggested that polymorphisms of the trichohyalin gene
(TCHH), which is expressed in the developing inner
root sheath of the hair follicle, contributes to the
variance in hair morphology.45 A quantitative study
examining hair formation in seven populations demonstrated African hair to have the highest amount
of curvature and kinking and a periodic widening
and narrowing of the cuticle layer. The cuticle layer
of curly hair averages 68 layers thick at the end of
the major axis but only 12 layers at the ends of the
minor axis, a weak point susceptible to hair damage
from mechanical and chemical forces.46 A study of
cuticle differences between Asian (Koreans specifically) and Caucasian hair revealed a 40% larger mean
hair diameter, an increased number of cuticle layers,
and a thicker cuticle layer in Asian compared to Caucasian hair (Table 9-3).47 Cuticle thickness may play
a role in determining the different characteristics of
hair, such as chemical reactivity to hair coloring or
perms, resistance to UV radiation, and mechanical
resilience.
Differences have also been observed in the rate of
hair growth. Although hair from individuals of European descent has been observed to grow an average
of 1 cm a month,48 African hair grows an average of
0.77cm a month.4951 In a comparative light and scanning electron-microscopic study of African, European,
and Asian hair, African subjects who did not have a
hair cut for over 1 year had hair lengths significantly
shorter than would be expected at a growth rate of 1
cm per month. Possible contributors to the differences
in hair length, other than a slower growth rate, could
include a significantly shorter anagen phase of the hair
cycle or perhaps repeated breakage of African hair. In
the same comparative study of African, European,
and Asian hair, the African hair appeared as a tightly
coiled spring-like structure. Compared with shafts
from other ethnic groups, many shafts contained
trichonodosis or knots (1016% vs. 0.15%) and other
shafts appeared broken (eFig. 9-2.1 in online edition).
The study found a lower incidence (<40%) of hairs
with attached roots in the African hair samples compared with more than 75% and approximately 90%,
respectively, for the Caucasian and Asian samples;
and a greater incidence of tips with frayed or serrated
appearance when compared to Asian and Caucasian
hair that had cut tips. These data suggest that most of
the African hair collected from combing in this study
was broken and not shed.51 This raises the question of
whether African hair is breaking off during grooming
because of increased fragility.
TENSILE STRENGTH
Hair fragility is measured using tests of tensile
strength, and it has been suggested that the force
needed to break African hair fibers is less than that
for other population groups. In a review of tensile
strength tests obtained from four different private
laboratories, two showed no difference between African hair and that of Caucasian and Asian hair and the
other two found African hair to be weaker. Others
found a lower tensile strength of both wet and dry
curly African hair compared to wet and dry Caucasian hair.
The strength of hair has been shown to be dependent upon the integrity of its sulfur-rich proteins and
disulfide bonds. In a study of trichothiodystrophy
(TTD), a condition characterized by reduced sulfurrich proteins and increased hair fragility, control
hairs from African, Asian, and Caucasian subjects
had statistically comparable sulfur staining using
transmission electron microscopy and specific sulfur
stains, while hair of patients with TTD was distinct.52
Examination of cultured curly hairs in vitro showed
a variable thickness of the outer root sheath, which
was thicker on the concave side of the follicle, indicating some alteration in the differentiation process of
hair compartments. It is unclear whether the lack of
symmetry of the African hair bulb increases the tendency to mechanical damage, but it is likely that the
shape of African hair makes it susceptible to physical damage as a result of certain grooming practices.
In addition, intraracial variation in the degree of curl
may influence mechanical properties. In a comparative study of African-American hair with different
degrees of curl, from a loose to a tight curl pattern,
mechanical fragility of hair increased with a tighter
curl pattern.53 Certain ethnic hair care practices, such
as repeatedly subjecting hair to extremely high temperatures or processing with chemical straighteners,
may further damage African hair.
COMBING PROPERTIES
In a study examining the amount of work required
(measured in joules) to pass a comb through locks
of hair, it was found that the work of combing wet
African-American hair is almost five times that of
combing wet straight hair. For dry hair, the work is
50 times greater. The teeth of a comb and method of
combing can influence the extent of resulting damage. Broken hairs from combing are more numerous
and of shorter length in curly African-American hair
compared to straight Caucasian and Asian hair. Knots
or trichonodes that are commonly seen in tightly
curled hair are sites especially susceptible to damage
by comb teeth.
MOISTURE CONTENT AND

STATIC ELECTRICITY
No clear difference has been found between the

structure and function of skin of varying colors aside
from the visible pigmentary changes and associated
variation in photoprotection.15 Skin often responds to
trauma or inflammation with hyperpigmentation; and
this is often more prominent and long lasting in darker
skin (Fig. 9-4). Hypopigmentation may similarly be
more common and more apparent in skin of darker
color. Treatment of skin disorders may also affect pigmentation, either positively or negatively (Fig. 9-5).
Finally, epidermal melanin may alter disease presentation by masking erythema. Hypertrophic scarring and
keloids are more frequent in black and Asian skin than
white skin, a major problem for which the pathogenesis remains unknown. There are also some variations
in the prevalence and presentation of certain skin diseases in patients with skin of color (Table 9-5). Not all
of these can be attributed to pigmentation differences,
but other contributing factors are as yet unidentified.
The differences in physical properties and hair care

practices may explain certain dermatologic disorders
DIAGNOSIS AND TREATMENT

OF SKIN DISEASE
::
HAIR DISORDERS MORE COMMON

IN SKIN OF COLOR
Chapter 9
African-American hair demonstrated a slightly lower

water content than Caucasian hair.37 The spiraling of
the hair shaft may be another reason for increased hair
dryness in African-American hair, as sebum from sebaceous glands cannot effectively navigate the twist and
turns of the hair shaft, leading to a drier, more brittle
hair. The relative dryness of African-American hair
is worsened by the cumulative effect of environmental
forces. Features of such weathering include a damaged
cuticle, longitudinal fissures known as split ends,
and transverse fissures resembling the nodes of trichorrhexis nodosa.
When combing untreated curly hair, a highly negative electrostatic charge develops, in contrast to the low
positive electrostatic charge for untreated straight hair.
The highly negative charge on African-American hair
may be the result of decreased moisture content and
increased pulling force from combing. Also, the higher
electrostatic charges in African-American hair can produce flyaway hair and can lead to difficulty in styling.
in patients with skin of color. These include central

centrifugal cicatricial alopecia (CCCA) (Fig. 9-3), traction alopecia (TA), pseudofolliculitis barbae (PFB), and
acne keloidalis nuchae (AKN) (Table 9-4). The curved
African hair follicle has been proposed to contribute to
the pathogenesis of PFB and AKN,54,55 though this has
been debated.56,57
Figure 9-3 Central centrifugal cicatrizing alopecia (CCCA) early (A) and late (B) in the disease course. (Photographs used
with permission from Lynne Goldberg, MD.)
97
Section 3
::
98
TABLE 9-4
Hair Disorders that Commonly Affect Persons of African Descent

Disorder
Alternative Names
Presumed Pathophysiology Clinical Features
Preventive Measures Treatmenta
Central centrifugal
cicatricial
alopecia (CCCA)58
Hot comb alopecia

Follicular59 Degeneration
syndrome60
Genetic predisposition
Heat injury
Chemical relaxers
Traction with rollers,61 tight
sewn-in and glued-in hair
weaves, braids with extension
hair62
Progressive: begins on
the scalp vertex and
advances centrifugally
(Figs. 9-3A and 9-3B);
noninflamed late
stage; smooth patch
of alopecia with loss of
follicular orifices
Minimize use of heat,

braids, weaves
Discontinue or decrease
chemical relaxer
frequency
Aimed at symptoms and halting

progression
Intralesional triamcinolone, topical
steroids (in vehicle of patients
choice)
Antiseborrheic shampoos
Oral tetracyclines or
hydroxychloroquine63,64
Minoxidil for miniaturized or
regrowing hairs65
Hair transplantation (for stable
disease)66,67
Traction alopecia (TA)
Traumatic alopecia
Associated with traction
folliculitis68,69
Hairstyles that place chronic

traction on the hair follicle:
ponytails,70 tight braids
and cornrows,71,72 nylon
hairbrushes,73 elastic hair
bands,74 rollers,75,76 and tight
knotting (Sikh men77,78)
Highest risk of TA seen in women
who attach extensions to relaxed
hair79
Distribution of hair loss

reflects that of maximal
traction, but is most
commonly seen at the
scalp margins (eFig 9-5.1
in online edition)
Avoid the chronic use of

styles that place traction
on the follicles
Rotate hairstyles more
frequently
Remove offending source

Trial of intralesional triamcinolone
(if caught early)
Minoxidil for miniaturized or
regrowing hairs54
Hair transplantation (for individuals
no longer placing traction on the
hair)55,66
Pseudofolliculitis barbae
(PFB) and acne keloidalis
(nuchae) (AKN)56,57
Razor bumps
Curved nature of the hair shaft

resulting in ingrown hairs80,81
Primary scarring alopecia,
AKN.82,83
Presents as multiple
keloidal papules or
plaques most commonly
in the beard area in PFB
and occipital scalp/neck
in AKN (eFigs. 9-5.2 and
9-5.3 in online edition)
Avoid shaving
Depilation
Laser hair removal
Intralesional triamcinolone for
keloids
There have been no clinical trials for the treatment of patients with CCCA or TA or, so little evidence-based data exist regarding treatment regimens.
Cutaneous melanoma merits particular attention in

skin of color because of the trend toward poorer prognosis. Lesions are more often of the acral or subungual
subtype than the more common superficial spreading type seen in whites and present at more advanced
stages. Some estimate that 20% of the worlds mela-
Figure 9-5 Perioral hyperpigmentation secondary to

retinoid dermatitis in an African-American man treated for
acne. (Used with permission from RM Halder, MD and reproduced with permission from Halder RM: Dermatology
and Dermatologic Therapy of Pigmented Skins. Boca Raton,
CRC Press, 2006.)
SKIN CANCER
::
Treatment choices often affect pigmentation

(Table 9-6). For example, topical corticosteroids may
produce unwanted hypopigmentation in treated skin
but may also speed resolution of postinflammatory
hyperpigmentation. Cryotherapy, which preferentially
damages melanocytes, may produce striking and/or
irreversible pigment loss. Conversely, the irritation
associated with many topical therapies and dermatologic procedures may produce unwanted hyperpigmentation. Awareness of these possibilities, careful
choice of therapies and detailed patient education can
avoid these iatrogenic problems.
Chapter 9
Figure 9-4 Acne with postinflammatory hyperpigmentation on the cheek of an African-American woman.
noma cases occur in skin of color.119 The incidence rates

have remained relatively stable in Asians and blacks,
while a large increase in melanoma incidence in the
past century, attributed to increased UV exposure, has
occurred in white populations.120 Not surprisingly,
lightly pigmented Hispanic skin has a risk similar to
that of whites, while darkly pigmented Hispanic skin
has a risk similar to Asians and blacks.121
Acral and subungual melanomas are associated with
higher mortality than nonacral melanoma.122 While the
absolute incidence of acral melanomas is nearly identical for black and white Americans (1.7 vs. 2.0 per 100,000,
respectively),123 acral melanomas in darker populations
tend to present later with large surface areas (>3 cm)
and more advanced disease. According to SEER data
(19861991), US blacks were 3-fold more likely to have
distant metastases compared to US whites (12% vs. 4%,
respectively).120 Similarly, a study of subungual melanomas showed blacks had a 3.5-fold higher mortality
rate than whites, even after controlling for Clarks level
and stage.124 However, existing data are inadequate to
determine whether race is an independent risk factor for
biologic aggressiveness in melanoma or whether the differences are instead a function of delayed diagnosis due to
darker background pigmentation, the higher prevalence
of benign palmar and plantar lentigines and pigmented
bands on nails with which melanomas may be confused,
or socioeconomic factors that affect the care received.
Public education and melanoma screening campaigns typically target Caucasians and often do not
provide relevant information or convey the risk to those
with skin of color, and in fact may even provide false
reassurance. Development of education campaigns
directed toward skin of color may aid in improving
detection and prognosis, but until then individualized
patient counseling and education remain important.
Nonmelanoma skin cancers (NMSC) also occur in skin
of color, though far less commonly than in whites. Basal
and squamous cell carcinomas (BCC and SCC) tend not
to occur in sun-exposed areas, but rather at sites of nonhealing ulcers or other chronic proliferative stimulation.
The incidence rate of SCC in blacks is reported as 3.4
per 100,000 and 1.83.2 in Asians. One series showed a
rate of 5.86.4 BCC per 100,000 in Asians.125 Gorlins syndrome (basal cell nevus syndrome) occurs in all populations and may demonstrate few BCCs in skin of color, so
careful observation of other findings including palmar
pits, frontal bossing, and odontogenic cysts are important in screening for the disease, which has increased risk
of internal malignancy and should prompt referral for
genetic counseling. Immunosuppressed patients with
skin of color, like whites, are at increased risk for NMSC
and should be screened for malignancy. Cutaneous
T-cell lymphoma has a 1.22-fold increased incidence
and a higher mortality rate in blacks than in whites.126128
COSMETIC AND PROCEDURAL

DERMATOLOGY
It is important for providers to be cognizant of the
options, effectiveness, and potential adverse effects
99
TABLE 9-5
Dermatologic Diseases with Special Considerations in Skin of Color

Dermatologic Disease
Normal Findings and Nevi
Pigmentary demarcation lines
Melanonychia striata
Palmoplantar melanosis
Circumscribed dermal melanocytosis
Section 3
Nevus of Ito/Ota
::
Scars
Hypertrophic scars and keloids
Inflammatory Disease
Confluent and reticulate papillomatosis
Lichen planus
Lichen nitidus
Lichen striatus
Pseudofolliculitis barbae
Acne keloidalis nuchae
Scarring alopecias
Acquired Pigmentary Disorders
Idiopathic guttate hypomelanosis
Melasma
Periorbital hypermelanosis
Pityriasis alba
Postinflammatory hyper- and hypopigmentation
Tinea versicolor
Vitiligo
Considerations
Six types recognized84
Most prominent on the arms
Common, increases with age
A single nail affected with >6 mm width lesion and variegation in color
should prompt consideration of malignancy in appropriate setting
Common, increases with age
Consider acral lentiginous melanoma in large, changing, or raised lesions
Blue-gray macules and patches present at birth
Occur in all skin colors, more common in darker skin
Typically resolve in childhood
Term Mongolian Spot not preferred
Nevoid form of dermal melanocytosis
More frequent in Asian populations
Blacks affected 516 times more often than Caucasians85
Coiffure keloid can result from tightly braided hair styles86
More prevalent in darker-skinned individuals and young women
Certain subtypes such as lichen planus pigmentosus and lichen planus
actinicus have a predilection for darker-skinned individuals.87,88
May be hypo- or hyperpigmented in darker skin89
Can present as hypopigmented (rather than erythematous) papules
lesions followed by hypopigmented macules.90
Curled shaved hairs penetrate inwards inciting inflammatory response
Commonly leads to scarring and postinflammatory hyperpigmentation
Laser hair removal, chemical delapitories, increased beard length with less
frequent shaving, single-blade razors, and gentle lifting of ingrown hair
loops out of skin provide improvement
Mostly in males with skin of color
Etiology poorly understood
Avoid close cutting or shaving and friction
Treatment includes medical anti-inflammatory therapies and surgical
options
More common in skin of color (See Table 9-4)
Affects 50% of African-Americans over 50 years of age
No effective treatment available
Women with darker skin types have a higher incidence91,92; Hispanics seem
particularly at risk
Can be more striking in darker-skinned individuals
While estimated to affect 15% of all children, some reports indicate up to
25% of African-American children and 35% of Hispanic children
Often more apparent and more persistent in darker-skinned individuals
Preventive and therapeutic measures warranted
More common in tropical climates
Higher incidence rates reported in black individuals93,94
Often more striking in darker-skinned individuals
Trichrome lesions more common in darker skin types95
VogtKoyanagiHarada syndrome tends to be more severe in Asians
Evidence shows linkage to chromosome 4q13-q21 in Chinese families96
(continued)
100
TABLE 9-5
Dermatologic Diseases with Special Considerations in Skin of Color (Continued)

Dermatologic Disease
Congenital Pigmentary Disorders
Piebaldism
Oculocutaneous albinism (OCA)
Other
Sarcoidosis
Lichen amyloidosis
Dermatosis papulosa nigra
Ashy dermatosis
Can present as hypopigmented macules or patches in a central, rather

than acral, distribution.103
Differences in anatomic distribution and type
More often at advanced stage at presentation
Poorer overall prognosis even for same risk factors
Occurs uncommonly but not rarely in skin of color, usually in the context
of chronic proliferation, as at the site of a nonhealing wound
Ten times more likely in blacks than in whites104
Hypopigmented lesions more common in persons of color105,106
Morbidity and mortality higher in African-Americans than in Caucasians107
Increased prevalence in Asians, Middle Easterners, and South
Americans108111
Incidence as high as 70% in African-Americans112
Scattering of incident light by an irregular dry stratum corneum;
management as for xerosis with emollients and gentle skin care
of cosmetic treatments for conditions affecting darker

skin types. The cosmetic procedure literature has
focused primarily on white skin, and often does not
discuss outcomes in dark-skinned patients. However,
this is changing as greater numbers of patients with
skin of color seek cosmetic and procedural treatments.
PREVENTIVE MEASURES
Photoaging has been a prevalent issue for Caucasians,
but nonwhites also demonstrate changes associated
with photoaging, particularly facial lentigines and
other forms of dyspigmentation that often appear up
to two decades earlier in women with skin of color,
after controlling for latitude of residence. Hence, sun
protection is recommended for optimal prevention of
age-associated changes, regardless of skin color. However, dyschromia (irregular pigmentation) unrelated
to photoaging is perhaps the most frequent complaint
for patients with skin of color. Prevention and minimization of postinflammatory pigmentary changes
due to trauma and irritation, whenever possible, are
paramount. Avoidance of melanogenic stimulation
by direct sun exposure is also critical in this context,
Nonmelanoma skin cancer
::
Melanoma
Often more striking in darker-skinned individuals

Although OCA affects all racial groups (1:17,000 persons worldwide),97
regional incidence depends on gene pools, social customs, and other
environmental factors.
Particularly high rates of OCA have been noted in Cuna Moonchild Indians
in Panama (1:160)98, Native Americans of the Hopi and Zuni tribes (1:227
and 1:240, respectively), Mayans in Guatemala (1:6500), South Africa
(OCA2, 1:3900; OCA3, 1:8500), Nigeria (1:1100), Tanzania (OCA2, 1:1429),
Zimbabwe (OCA2, 1:2833)97,99,100
HermanskyPudlak syndrome is a rare form of tyrosinase-positive OCA
found almost exclusively in Puerto Ricans (1:1800 Puerto Ricans)101
In Japan, 24% of albino patients have OCA type 4102
Chapter 9
Neoplastic Disease
Mycosis fungoides
Considerations
although care must be taken to assure adequate vitamin D levels through oral supplementation if vitamin
D photosynthesis is minimized (see Chapter 90).
TOPICAL THERAPIES FOR

HYPERPIGMENTATION
In treating hyperpigmentation, it is important to consider the location of deposited pigment. Dermal pigmentation retained in melanophages is not affected
by topical therapies and is highly resistant to all treatment modalities. However, increased epidermal melanin can often be improved with topical therapy that
reduces melanogenetic stimulation, tyrosinase activity, or melanin transfer to keratinocytes (Table 9-6).
Topical therapies generally produce slow and subtle
improvements, and treatment expectations should be
discussed with patients.
COSMETIC CAMOUFLAGE
Camouflage makeups that hide dyschromic areas continue to represent a significant aid for some patients,
101
TABLE 9-6
Topical Therapies for Hyperpigmentation

Therapeutic Agent(s), by Category
UV Protection
Sunscreens
Tyrosinase Inhibitorsa
Azelaic acid
Hydroquinone
Section 3
Arbutin
Licorice extract
::
Paper Mulberry
Vitamin C
Tretinoin
Kojic acid
N-Acetylglucosamine
Pycnogenol
Melanosome Transfer Inhibitiona
Niacinamide
Soy
Increased Cellular Turnover
-Hydroxy and -hydroxy acids
Prevent UV-induced tanning and may hasten resolution of

postinflammatory hyperpigmentation; recommended for
most patients with hyperpigmentation concerns, can be used
concomitantly with other therapies
Dicarboxylic acid derived from Plasmodium ovale cultures
Higher concentrations may lead to irritation; low risk of
permanent depigmentation and ochronosis (typically seen at
concentrations >6%); shows increased efficacy in combination
therapy with 0.01% fluocinonide cream and 0.05% tretinoin
Hydroquinone derivative; inhibits tyrosinase and DHICA113
Active ingredient glabridin decreases tyrosinase activity and has
anti-inflammatory effects114
Potent tyrosinase inhibition115
Product should be stable for efficacy
Also provides anti-inflammatory effect
Inhibits tyrosinase transcription and glycosylation; normalizes
epidermal melanin distribution
Fungal derivative; inhibits tyrosinase
Inhibits conversion of protyrosinase to tyrosinase116
Flavanoid compounds with antioxidant activity; oral treatment
(25 mg TID) may improve melasma117
Amide of niacin (B3), inhibits melanosome transfer to
keratinocytes118
Soybean trypsin inhibitor (STI) and Bowman-Birk inhibitor (BBI)
inhibit cleavage of PAR-2, reducing melanosome transfer
Reduce corneocyte adhesion
Reported mechanism of action, based on data of varying strength.
and can be less expensive than other options. Branded

products include Veil Cover Cream, Keromask, Dermacolor, and Dermablend. These and the many other
marketed formulations must be judged by the user on
the basis of esthetics, cost, and other factors of importance to the individual. Referral to a professional
makeup artist or camouflage makeup therapist for
application demonstration and education regarding
proper use can provide significant benefit.
PROCEDURAL DERMATOLOGY IN SKIN OF

COLOR. Superficial and medium depth chemical peels,
102
Special Considerations
when appropriately selected and performed, are appropriate for Fitzpatrick skin types IVVI. Specific choices
regarding chemical agent depend on the efficacy, safety,
desired depth of peel, and the physicians preference
and experience. Microdermabrasion is appropriate for
all skin types, is often used for acne and other types of
facial scarring, and is a good option for those unable to
tolerate peels or extensive recovery times.
Laser treatment in patients with skin of color should
be selected with the knowledge that epidermal mela-
nin can act as a competitive chromophore. Inadvertent

absorption of laser energy by epidermal melanin can
lead to scarring and dyspigmentation.
PATIENT INDIVIDUALIZATION
The spectrum of human phenotypes results from a
combination of genetic and environmental influences.
Complexities of racial and ethnic contributors to disease susceptibility, clinical presentation, and therapeutic response are still poorly understood. Because
there is on average greater genetic diversity between
any two individuals (8590%) than between races
(1015%),129 and because genes determining pigmentation make up an exceedingly small proportion of the
genome, it is desirable that race not be overemphasized in determining a dermatologic plan of care. The
welcome movement toward considering skin types as
a continuous spectrum rather than dichotomously as
white and nonwhite may one day render obsolete the
term skin of color.
KEY REFERENCES
Chapter 9
::
1. US Interim Projections by Age, Sex, Race and Hispanic

Origin, 20002050. US Census Bureau, http://www.
census.gov/population/www/projections/usinterimproj/
natprojtab01a.pdf, accessed August 30, 2011
10. Taylor SC: Skin of color: Biology, structure, function, and
implications for dermatologic disease. J Am Acad Dermatol 46(2 Suppl. Understanding):S41-S62, 2002
21. Sturm RA: Molecular genetics of human pigmentation
diversity. Hum Mol Genet 18(R1):R9-R17, 2009
24. Lamason RL et al: SLC24A5, a putative cation exchanger,
affects pigmentation in zebrafish and humans. Science
(New York, N.Y.) 310(5755):1782-1786, 2005
26. Rees JL. Genetics of hair and skin color. Ann Rev Genet
37:67-90, 2003
30. Wolfram LJ: Human hair: A unique physicochemical composite. J Am Acad Dermatol 48(Suppl. 6):S106-S114, 2003
31. McMichael AJ: Hair breakage in normal and weathered

hair: Focus on the Black patient. J Investig Dermatol Symp
Proc/Soc Investig Dermatol, Inc. 12(2):6-9, 2007
41. Bernard BA: Hair shape of curly hair. J Am Acad Dermatol
48(Suppl. 6):S120-S126, 2003
42. Thibaut S et al: Human hair shape is programmed from
the bulb. Br J Dermatol 152(4):632-638, 2005
57. Kelly AP: Pseudofolliculitis barbae and acne keloidalis
nuchae. Dermatol Clin 21(4):645-653, 2003
120. Ries L, Eisner M, Kosary C: SEER Cancer Statistics Review, 19752001. Bethesda, MD, National Cancer Institute, 2004
123. Stevens NG, Liff JM, Weiss NS: Plantar melanoma: Is
the incidence of melanoma of the sole of the foot really
higher in blacks than whites? Int J Cancer 45(4):691-693,
1990
126. Criscione VD, Weinstock MA: Incidence of cutaneous
T-cell lymphoma in the United States, 19732002. Arch
Dermatol 143(7):854-859, 2007
129. Myles S et al: Identifying genes underlying skin pigmentation differences among human populations. Hum
Genet 120(5):613-621, 2007
103
Disorders Presenting PA RT
in Skin and Mucous
Membranes
Inflammatory Disorders Based on T-Cell
Reactivity and Dysregulation
Chapter 10 :: I nnate and Adaptive Immunity

in the Skin

:: Robert L. Modlin, Lloyd S. Miller,
Christine Bangert, & Georg Stingl
Innate And Adaptive Immunity At a Glance
Innate immune responses
are used by the host to immediately
defend itself;
determine the quality and quantity of
many adaptive immune responses;
include cells such as monocytes/

macrophages, dendritic cells, natural killer
cells, and polymorphonuclear leukocytes.
Adaptive immune responses
have memory;
are short lived;
have specificity;
have no memory;
are long lasting;
include physical barriers (skin and

mucosal epithelia);
in skin, are initiated by dendritic antigenpresenting cells in the epidermis (Langerhans

cells) and by dermal dendritic cells;
include soluble factors such as

complement, antimicrobial peptides,
chemokines, and cytokines;
The human immune system is comprised of two distinct functional parts: (1) innate and (2) adaptive.
These two components have different types of recognition receptors and differ in the speed in which they
respond to a potential threat to the host (Fig. 10-1).
are executed by T lymphocytes and antibodies

produced by B lymphocytes/plasma cells.
Cells of the innate immune system, including macrophages and dendritic cells (DCs), use pattern recognition receptors encoded directly by the germ line DNA,
respond to biochemical structures commonly shared
by a variety of different pathogens, and elicit a rapid
The immune response
Innate response
Foreign
pathogen
Section 4
Rapid response
Pattern recognition receptorsgerm-line encoded
- CD14, mannose and scavenger
Cytokines, costimulatory
molecules-instructive role for
adaptive response
Direct response for host defense
- Phagocytosis
- Antimicrobial activity
Adaptive response
Slow response
Recognition - initially low affinity
receptors
Gene rearrangement
Clonal expansion
Response - T and B cells with
receptors encoded by fully
rearranged genes
Memory
::
Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation
106
Figure 10-1 The immune system of higher vertebrates uses both innate and adaptive immune responses. These immune
responses differ in the way they recognize foreign antigens and the speed with which they respond; yet, they complement
each other in eradicating foreign pathogens.
response against these pathogens, although no lasting

immunity is generated. In contrast, cells of the adaptive immune system, T and B lymphocytes, bear specific antigen receptors encoded by rearranged genes,
and in comparison to the innate response, adaptive
immunity develops more slowly. A unique feature of
the adaptive immune response is its ability to generate and retain memory; thus, it has the capability of
providing a more rapid response in the event of subsequent immunologic challenge. Although the innate
and adaptive immune responses are distinct, they
interact and can each influence the magnitude and type
of their counterpart. Together, the innate and adaptive
immune systems act in synergy to defend the host
against infection and cancer. This chapter describes the
roles of the innate and adaptive immune response in
generating host defense mechanisms in skin.
INNATE IMMUNE RESPONSE

Immune mechanisms that are used by the host to
immediately defend itself are referred to as innate
immunity. These include physical barriers such as the
skin and mucosal epithelium; soluble factors such as
complement, antimicrobial peptides, chemokines, and
cytokines; and cells, including monocytes/macrophages, DCs, natural killer cells (NK cells), and polymorphonuclear leukocytes (PMNs) (Fig. 10-2).
Our present understanding of innate immunity
is based on the studies of Elie Metchnikoff who, in
1884, published studies on the water flea Daphnia and
its interaction with a yeast-like fungus.1 He demonstrated that cells of the water flea, which he termed
phagocytes, were attracted to and engulfed the
foreign spores, which were subsequently killed and
destroyed. Thus, Metchnikoff described the key
direct functions of cells of the innate immune system:
(1) rapid detection of microbes, (2) phagocytosis, and

(3) antimicrobial activity. In addition to this direct role
in host defense, the innate immune system has an indirect role in instructing and determining the type of
adaptive T and B cell responses. Finally, by inducing
inflammation, the innate immune response can also
induce tissue injury.
PHYSICAL AND CHEMICAL BARRIERS2

Physical structures prevent most pathogens and environmental toxins from harming the host. The skin and
the epithelial lining of the respiratory, gastrointestinal,
and the genitourinary tracts provide physical barriers
between the host and the external world. Skin, once
thought to be an inert structure, plays a vital role in
protecting the individual from the external environment. The epidermis impedes penetration of microbial
organisms, chemical irritants, and toxins; absorbs and
blocks solar and ionized radiation; and inhibits water
loss (see Chapter 47).
MOLECULES OF THE INNATE

IMMUNE SYSTEM
COMPLEMENT.3 (See eFig. 10-2.1 in online edition;
see also Chapter 37). One of the first innate defense

mechanisms that awaits pathogens that overcome the
epithelial barrier is the alternative pathway of complement. Unlike the classical complement pathway that
requires antibody triggering, the lectin-dependent
pathway as well as the alternative pathway of complement activation can be spontaneously activated
by microbial surfaces in the absence of specific antibodies (see eFig. 10-2.1 in online edition). In this way,
the host defense mechanism is activated immediately
The innate immune response in skin
Pathogens
UV radiation
Irritants
1. Antimicrobial response:
defensins
cathelicidins/psoriasin
reactive oxygen intermediates
KC
NK cell
T cell response
(Th1, Th2, Treg, Th17)
Figure 10-2 The innate immune response in skin. In response to exogenous factors, such as foreign pathogens, ultraviolet (UV) radiation, and chemical irritants, innate immune cells [granulocytes, mononuclear phagocytes, natural killer (NK)
cells, keratinocytes] mount different types of responses including (1) release of antimicrobial agents; (2) induction of inflammatory mediators, such as cytokines, chemokines, neuropeptides, and eicosanoids; and (3) initiation and modulation
of the adaptive immune response. DDC = dermal dendritic cell; KC = keratinocyte; LC = Langerhans cell; MHC II = major
histocompatibility complex class II; Th1 = type I T cells; Th2 = type II T cells; Th17 = type 17 T cells; T reg = regulatory T cells.
after encountering the pathogen without the 57 days

required for antibody production.
Antimicrobial Peptides.4 Antimicrobial pep-
tides serve as an important evolutionarily conserved

innate host defense mechanism in many organisms.
They typically are positively charged and are amphipathic, possessing both hydrophobic and hydrophilic
surfaces. The antimicrobial activity of these peptides
is thought to relate to their ability to bind membranes
of microbes (through their hydrophobic surface) and
form pores in the membrane, leading to microbial killing. There are numerous antimicrobial peptides identified in various human tissues and secretions. This
section will focus on antimicrobial peptides identified
in resident skin cells, including human b-defensins
(HBD-1, HBD-2, HBD-3), cathelicidin (LL-37), psoriasin, and RNase 7, which have all been demonstrated to
be produced by keratinocytes, and dermcidin, which is
secreted in human sweat. In addition, there are numer-
ous other antimicrobial peptides that are produced by

cells that infiltrate the skin and may participate in cutaneous innate immune responses.5
b-Defensins are cysteine-rich cationic low-molecular-weight antimicrobial peptides. The first human
b-defensin, HBD-1, is constitutively expressed in the
epidermis and is not transcriptionally regulated by
inflammatory agents. HBD-1 has antimicrobial activity against Gram-negative bacteria and appears to play
a role in keratinocyte differentiation. A second human
b-defensin, HBD-2, was discovered in extracts of
lesions from psoriasis patients.6 Unlike HBD-1 expression, HBD-2 expression is inducible by components of
microbes, including Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans.6 Not only can
components of microbes stimulate expression of HBD2, but proinflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interleukin 1 (IL-1) can also
induce HBD-2 transcription in keratinocytes.6 When
tested for antimicrobial activity, HBD-2 was effective
Innate and Adaptive Immunity in the Skin
Macrophage
::
LC/DDC
3. influence adaptive immune

response:
activation of T cells
Chapter 10
2. Inflammatory response:
cytokines
chemokines
neuropeptides
eicosanoids
MHC II
107
Section 4
::
108
against Gram-negative bacteria such as Escherichia coli

and P. aeruginosa and has a weak bacteriostatic effect
against Gram-positive bacteria such as S. aureus.6
HBD-3 is another b-defensin that was first isolated
from extracts of lesions from psoriasis patients.7 Contact with TNF-a and with bacteria was found to induce
HBD-3 messenger RNA expression in keratinocytes.
In addition, HBD-3 demonstrated potent bactericidal
activity against S. aureus and vancomycin-resistant
Enterococcus faecium. Therefore, HBD-3 is among the
first human b-defensins in skin to demonstrate effective antimicrobial activity against Gram-positive bacteria. The localization of human b-defensins to the
outer layer of the skin and the fact the b-defensins have
antimicrobial activity against a variety of microbes
suggest that human b-defensins are an essential part
of cutaneous innate immunity. Furthermore, evidence
indicating that human b-defensins attract DCs and
memory T cells via CC chemokine receptor 6 (CCR6)8
provides a link between the innate and the adaptive
immunity in skin.
Cathelicidins are cationic peptides with a structurally variable antimicrobial domain at the C-terminus.
Whereas in mammals like pigs or cattle a variety of cathelicidin genes exists, men (and mice) possess only one
gene. The human precursor protein hCAP18 (human
cathelicidin antimicrobial protein 18) is produced by
skin cells, including keratinocytes, mast cells, neutrophils, and ductal cells of eccrine glands. Neutrophil
proteases (i.e., proteinase 3) process hCAP18 into
the effector molecule LL-37 (named LL-37 for the
37-amino acid active antimicrobial peptide liberated
from the C-terminus of the protein), which plays an
important role in cutaneous host defense because of
its pronounced antibacterial,9,10 antifungal,11 and antiviral12,13 activities. LL-37 further contributes to innate
immunity by attracting mast cells and neutrophils via
formyl peptide receptor-like 1 and by inducing mediator release from the latter cells via a G protein-dependent, immunoglobulin (Ig) E-independent mechanism.14 It has now been shown that LL-37 is secreted
into human sweat, where it is cleaved by a serine
protease-dependent mechanism into its peptides
RK-31 or KS-30. Interestingly, these components display an even more potent antimicrobial activity than
intact LL-37.15 One of the most important inducers of
LL-37 expression is vitamin D, which can be triggered
by Toll-like receptor (TLR) activation of the vitamin D
receptor and vitamin D-1-hydroxylase genes, leading
to enhanced antimicrobial killing.16,17
In atopic dermatitis (see Chapter 14), LL-37 is downregulated, probably due to the effect of the T2 cytokines IL-4 and IL-13, which renders atopic skin more
susceptible to skin infections with, for example, S.
aureus, vaccinia virus (eczema vaccinatum), or herpes simplex virus (HSV) (eczema herpeticum).10,12,13
Furthermore, patients with rosacea have been found
to possess high levels of aberrantly processed forms
of cathelicidin peptides (due to posttranslational processing by stratum corneum tryptic enzyme), which
contributes to the increased inflammation in the skin.18
Cathelicidin can also form complexes with self-DNA,
which promotes activation of TLR9 on plasmacytoid
dendritic cells in the dermis, resulting in enhanced

cutaneous inflammation that contributes to psoriasis
pathogenesis.19
Another important human antimicrobial peptide
has now been identified, psoriasin (S100A7),20 which
elicits its antimicrobial effect by permeabilization of
bacterial membranes.21 It is secreted predominantly by
keratinocytes and plays a major role in killing the common gut bacterium E. coli. In fact, in vivo treatment of
human skin with antipsoriasin antibodies results in the
massive growth of E. coli.20 Furthermore, expression of
psoriasin by keratinocytes has been shown to occur via
TLR5 stimulation by E. coli flagellin.22 In addition to
antimicrobial activity, psoriasin also functions as a chemoattractant for CD4 cells and neutrophils.23
RNase 7 was originally isolated from the stratum
corneum from healthy human skin.24 RNase 7 has
potent ribonuclease activity but also broad-spectrum
antimicrobial activity against S. aureus, P. acnes, P. aeruginosa, E. coli, and C. albicans. RNase 7 production can
be induced in cultured human keratinocytes by IL-1b,
IFN-g, and bacterial challenge. Interestingly, high
expression of RNase 7 in human skin confers protection against S. aureus cutaneous infection.25
Dermcidin is an antimicrobial peptide that is
expressed by human sweat glands.26 Dermcidin goes
through postsecretory proteolytic processing in sweat
that gives rise to anionic and cationic dermcidin peptides that are secreted onto the skin surface. These
dermcidin peptides have broad antimicrobial activity against S. aureus, E. coli, E. faecalis, and C. albicans.
Although the mechanism of action of dermcidin activity is unknown, it does not involve pore formation like
other antimicrobial peptides.27
PATTERN RECOGNITION RECEPTORS. How

do the cells of the innate immune system recognize
foreign pathogens? One way that pathogens can be
recognized and destroyed by the innate immune system is via receptors on phagocytic cells. Unlike adaptive immunity, the innate immune response relies on
a relatively small set of germ line-encoded receptors
that recognize conserved molecular patterns that are
shared by a large group of pathogens. These are usually molecular structures required for survival of the
microbes and therefore are not subject to selective
pressure. In addition, pathogen-associated molecular
patterns are specific to microbes and are not expressed
in the host system. Therefore, the innate immune system has mastered a clever way to distinguish between
self and nonself and relays this message to the adaptive immune system.
Of key importance was the discovery of the Tolllike receptors (TLRs), named after the Drosophila Toll
gene whose protein product, Toll, participates in
innate immunity and in dorsoventral development
in the fruit fly.30,31 The importance of Toll signaling in
mammalian cells was confirmed by the demonstration
that the transmembrane leucine-rich protein TLR4 is
involved in lipopolysaccharide (LPS) recognition.32
In addition to TLRs, there exist a variety of other
molecules that sense the presence of pathogens. These
include the NOD proteins (see below), triggering
Toll-Like Receptors.38 There is now substan-
SsRNA
LPS
CpG DNA
ds RNA
Flagellin
Profilin (?)
Lipoproteins
X?
TLR9
TLR5
TLR7
TLR8
TLR4
TLR3
TLR 2/6
TLR11
TLR 1/2
TLR10
TRIF
IRF3
NF-B pathway
Influence adaptive response

Cytokine production
Costimulatory molecules
Cell mediated immunity

Humoral immunity
Toll-like receptors and host defense
::
tial evidence to support a role for mammalian TLRs

in innate immunity (Fig. 10-3). First, TLRs recognize
pathogen-associated molecular patterns present in a
variety of bacteria, fungi, and viruses. Second, TLRs
are expressed at sites that are exposed to microbial
threats. Third, the activation of TLRs induces signaling
pathways that, on the one hand, stimulate the produc-
tion of antimicrobial effector molecules, and, on the

other, promote the expression of costimulatory molecules and the release of cytokines and, as a result, the
augmentation of the adaptive response. Fourth, TLRs
directly activate host defense mechanisms that then
combat the foreign invader.
Experiments performed in the Modlin laboratory39
and others40 led to the exciting finding that microbial
lipoproteins trigger host responses via TLR2, requiring the acyl functions for activity. Subsequently, triacylated lipoproteins were found to activate TLR2/1
heterodimers,41 whereas diacylated lipoproteins were
found to activate TLR2/6 heterodimers.42 For recognition of bacteria, the TLR system is redundant: TLR9
is activated by unmethylated DNA sequences (CpG
dinucleotides) found in bacterial DNA43 and TLR5
activated by bacterial flagellin.44 Specific TLRs are
involved in viral recognition: TLR3 is activated by
viral derived double-stranded RNA45 and TLR7 and
TLR8 by virus-derived single-stranded RNA.46 The
finding that different TLRs have distinct patterns of
expression, particularly on monocytes, macrophages,
dendritic cells, B cells, endothelia, and epithelia,
suggests that each TLR could trigger a specific host
response. Furthermore, TLRs are expressed in specific
Chapter 10
receptors expressed on myeloid cell (TREM) proteins,33

the family of Siglec molecules,34 and a group of C-type
lectin receptors.35 The latter are prominently expressed
on antigen-presenting cells (APCs) as, for instance,
dectin-1 and DC-SIGN [DC-specific intercellular adhesion molecule 3 (ICAM-3) grabbing nonintegrin], which
is actually expressed on tissue macrophages.36 They are
able to mediate efficient binding of microorganisms;
facilitate phagocytosis; and induce activation of signaling pathways that result in antimicrobial activity.
Members of the TREM protein family function as
amplifiers of innate responses. Extreme examples of
the consequences of microbe activation of TREM proteins are life-threatening septicemia and the deadly
hemorrhagic fevers caused by Marburg and Ebola
virus infection.37
Immunomodulatory
genes
Tissue injury
Apoptosis
Septic shock
Direct antimicrobial response

Reactive oxygen intermediates
Figure 10-3 Toll-like receptors (TLRs) mediate innate immune response in host defense. Activation of TLRs by specific
ligands induces (1) cytokine release and costimulatory molecules that instruct the type of adaptive immune response; (2)
direct antimicrobial response; and (3) tissue injury. CpG DNA = immunostimulatory cytosine- and guanine-rich sequences
of DNA; dsRNA = double-stranded RNA; LPS = lipopolysaccharide; NF-kB = nuclear factor kB; ssRNA = single-stranded RNA;
X = ligand unknown.
109
Section 4
::
subcellular compartments: TLR7, 8, and 9 are located

in endosomes, where they encounter microbial pathogens in the endocytic pathway. The other TLRs are
expressed on the cell surface and detect microbial
ligands in the extracellular environment.
The expression of TLRs on cells of the monocyte/
macrophage lineage is consistent with the role of TLRs
in modulating inflammatory responses via cytokine
release. Because these cells migrate into sites that interface with the environmentlung, skin, and gutthe
location of TLR-expressing cells would situate them to
defend against invading microbes. TLR expression by
adipocytes, intestinal epithelial cells, and dermal endothelial cells supports the notion that TLRs serve a sentinel role with regard to invading microorganisms. The
regulation of TLR expression is critical to their role in
host defense, yet few factors have been identified that
modulate this process. IL-4 acts to downregulate TLR
expression,47 which suggests that T helper 2 (T2) adaptive immune responses might inhibit TLR activation.
DETAILED STUDIES OF TLR

Tlr-Induced Cytokine Release. TLR activation of a variety of cell types has been shown to trigger
release of both proinflammatory and immunomodulatory cytokines.4852 TLR activation of monocytes and
DC induces IL-12 and IL-18, required for generation
of a Th1 response, and IL-1b, IL-6, IL-23, involved
in the generation of a Th17 response, as well as the
anti-inflammatory IL-10.5356 The relative induction of
specific cytokine patterns determines the type of adaptive T-cell response (see Chapter 11).
MF and DC Differentiation. TLRs can regulate
phagocytosis either through enhancing endosomal

fusion with the lysosomal compartment57 or through
induction of a phagocytic gene program including
multiple scavenger receptors.58 Activation of TLRs
on monocytes leads to the induction of IL-15 and IL15R, triggering differentiation into CD209+ MF36 with
microbicidal activity.59 Activation of TLRs on monocytes also induces GM-CSF and GM-CSFR, triggering
differentiation into immature DC with the capacity to
release cytokines and efficiently present antigen to T
cells.36 In addition, activation of TLRs on immature
DC leads to further maturation with enhanced T-cell
stimulatory capacity.60
TLR-Induced Antimicrobial Activity. In Dro-
110
sophila, Toll is critical for host defense. The susceptibility of mice with spontaneous mutations in TLRs to bacterial infection indicates that mammalian TLRs play a
similar role. Activation of TLR2 by microbial lipoproteins induces activation of the inducible nitric oxide
(NO) synthase (NOS-II or iNOS) promoter,39 which
leads to the production of NO, a known antimicrobial
agent. There is strong evidence that TLR2 activation
leads to killing of intracellular Mycobacterium tuberculosis in both mouse and human macrophages.54 In mouse
macrophages, bacterial lipoprotein activation of TLR2
leads to a NO-dependent killing of intracellular tubercle bacilli. In human monocytes and alveolar macro-
phages, bacterial lipoproteins similarly activate TLR2

to kill intracellular M. tuberculosis; however, this occurs
by an antimicrobial pathway that is NO-independent.
Instead, a key antimicrobial mechanism for TLR-activated human monocytes involves induction of the
25-hydroxyvitamin D3-1a-hydroxylase (CYP27b1),
which converts the 25D into the active 1,25D form,
upregulation and activation of the vitamin D receptor
(VDR), and downstream induction of the antimicrobial
peptide cathelicidin.16,59,6163 The ability of TLR2/1 activation to upregulate expression of CYP27b1 and the
VDR is IL-15 dependent.36 Simultaneous triggering of
IL-1b activity and activation of the VDR induces HBD2, also required for antimicrobial activity.
Activation of TLRs 3, 4, 7, 8, and 9 leads to induction
of antiviral activity, dependent on type I IFN secretion and involving specific signaling pathways.64 Two
TLR-mediated pathways have been identified: type I
IFN production occurs through a MyD88-independent
pathway in response to TLR3 and TLR4 activation,65
and, following stimulation with agonists of TLRs 7, 8,
and 9, through a MyD88-dependent pathway.66
The activation of TLRs can also be detrimental, leading to tissue injury. The administration of LPS to mice
can result in manifestations of septic shock, which is
dependent on TLR4.32 Evidence suggests that TLR2
activation by Propionibacterium acnes induces inflammatory responses in acne vulgaris, which lead to tissue
injury.67 Aliprantis et al demonstrated that microbial
lipoproteins induce features of apoptosis via TLR2.40
Thus, microbial lipoproteins have the ability to elicit
both TLR-dependent activation of host defense and
tissue pathology. This dual signaling pathway is similar to TNF receptor and CD40 signaling, which leads
to both nuclear factor-kB activation and apoptosis.68,69
In this manner, it is possible for the immune system
to use the same molecules to activate host defense
mechanisms and then, by apoptosis, to downregulate
the response from causing tissue injury. Activation of
TLR can lead to the inhibition of the major histocompatibility complex (MHC) class II antigen presentation
pathway, which can downregulate immune responses
leading to tissue injury but may also contribute to
immunosuppression.70 Finally, Toll activation has been
implicated in bone destruction.52
The critical biologic role of TLRs in human host
defense can be deduced from the finding that TLR4
mutations are associated with LPS hyporesponsiveness in humans.71 By inference, one can anticipate that
humans with genetic alterations in TLR may have
increased susceptibility to certain microbial infections.
Furthermore, it should be possible to exploit the pathway of TLR activation as a means to endorse immune
responses in vaccines and treatments for infectious diseases as well as to abrogate responses detrimental to
the host.
Cells of the Innate

Immune System
PHAGOCYTES. Two key cells of the innate immune
system are characterized by their phagocytic function:
Effector Functions of Phagocytes. Activation
influence macrophage differentiation: IFN-g treatment results in classically activated macrophages,

with antimicrobial activity, whereas in contrast IL-4
or IL-13 triggers differentiation into alternatively
activated macrophages, which contribute to humoral
and antiparasite immunity.82,83 Cytokines produced
by the innate immune response also induce distinct
macrophage differentiation programs.84 IL-10 induces
the phagocytic program in macrophages, leading to
the uptake of lipids and bacteria. In contrast, IL-15
induces a macrophage antimicrobial program. These
data establish that the innate immune response, by
selectively inducing IL-10 versus IL-15, differentially
programs macrophages for phagocytosis versus antimicrobial responses that largely determines the outcome of infection.
Phagocytic cells of the innate immune system can
also be activated by cells of the adaptive immune system. CD40 is a 50-kDa glycoprotein present on the surface of B cells, monocytes, DCs, and endothelial cells.
The ligand for CD40 is CD40L, a type II membrane
protein of 33 kDa, preferentially expressed on activated
CD4+ T cells and mast cells. CD40CD40 ligand interaction plays a crucial role in the development of effec-
How Do NK Cells Discriminate Between

Normal and Transformed or PathogenInfected Tissue? All nucleated cells express the
MHC class I molecules. NK cells have receptors,

termed killer inhibitory receptors, which recognize the
self-MHC class I molecules. This recognition results
in the delivery of a negative signal to the NK cell that
paralyzes it. If a nucleated cell loses expression of its
MHC class I molecules, however, as often happens
after malignant transformation or virus infection, the
NK cell, on encountering it, will become activated and
kill it.
In addition, NK cells have activating receptors that
bind MHC-like ligands on target cells. One such receptor is NKGD2, which binds to the human nonclassic
MHC class I chain-related A and B molecules, MICA
and MICB.87 MICA and MICB are not expressed in
substantial amounts on normal tissues, but are overexpressed on carcinomas.88 NK cells are able to kill
MICA/MICB-bearing tumors, which suggests a role
for NKGD2 in immune surveillance.
Another cell type that, at least in mice, could serve a
similar function is the IFN-producing killer DC, which
shares several features with DCs and NK cells.89,90
Their human equivalent has yet to be identified.
KERATINOCYTES. Once thought to only play a

role in maintaining the physical barrier of the skin,
keratinocytes, the predominant cells in the epidermis, can participate in innate immunity by mounting
Macrophage Subsets and Functional Programs. Cytokines of the adaptive T-cell response
86
Natural Killer Cells. NK cells appear

as large granular lymphocytes. In humans, the vast
majority of these cells exhibit the CD3, CD56+, CD16+,
CD94+, and CD161+ phenotype. Their function is
to survey the body looking for altered cells, be they
transformed or infected with viruses (e.g., cytomegalovirus), bacteria (e.g., Listeria monocytogenes), or parasites (e.g., Toxoplasma gondii). These pathogens are then
killed directly via perforin/granzyme- or Fas/Fas
ligand (FasL)-dependent mechanisms or indirectly via
the secretion of cytokines (e.g., IFN-g).
::
of phagocytes by pathogens induces several important

effector mechanisms, for example, triggering of cytokine production. A number of important cytokines
are secreted by macrophages in response to microbes,
including IL-1, IL-6, TNF-a, IL-8, IL-12, and IL-10 (see
also Chapter 11).
Another important defense mechanism triggered
in phagocytes in response to pathogens is the induction of direct antimicrobial responses. Phagocytic cells
such as PMNs and macrophages recognize pathogens,
engulf them, and induce antimicrobial effector mechanisms to kill the pathogens. The induction and/or
release of toxic oxygen radicals, lysosomal enzymes,
and antimicrobial peptides leads to direct killing of
microbial organisms.4 Similarly, activation of TLRs
on macrophages induces these various antimicrobial
pathways as already discussed above.
tor functions. CD4+ T cells activate macrophages and

monocytes to produce TNF-a, IL-1, IL-12, interferon-g
(IFN-g), and NO via CD40CD40L interaction. CD40L
has also been shown to rescue circulating monocytes
from apoptotic death, thus prolonging their survival
at the site of inflammation. In addition, CD40CD40L
interaction during T-cell activation by APCs results in
IL-12 production. Therefore, it can be concluded that
CD40CD40L interactions between T cells and macrophages play a role in maintenance of T1-type cellular
responses and mediation of inflammatory responses.
Other studies have established a role for CD40CD40L
interactions in B-cell activation, differentiation, and
Ig class switching.85 In addition, CD40CD40L interaction leads to upregulation of B7.1 (CD80) and B7.2
(CD86) on B cells. This costimulatory activity induced
on B cells then acts to amplify the response of T cells.
These mechanisms underscore the importance of the
interplay between the innate and the adaptive immune
system in generating an effective host response.
Chapter 10
macrophages and PMNs. These cells have the capacity to take up pathogens, recognize them, and destroy
them. Some of the functions of these cells are regulated
via TLRs and complement receptors as outlined earlier.
PMNs are normally not present in skin; however,
during inflammatory processes, these cells migrate
to the site of infection and inflammation, where they
are the earliest phagocytic cells to be recruited. These
cells have receptors that recognize pathogens directly
(see Pattern Recognition Receptors), and due to their
expression of FcgRIII/CD16 and C3bR/CD35, can
phagocytose microbes coated with antibody and with
the complement component C3b. As a consequence,
granules (containing myeloperoxidase, elastase, lactoferrin, collagenase, and other enzymes) are released,
and microbicidal superoxide radicals (O2) are generated (see Chapter 30).
111
Section 4
::
112
an immune and/or inflammatory response through

secretion of cytokines and chemokines, arachidonic
acid metabolites, complement components, and antimicrobial peptides.
Keratinocytes of unperturbed skin produce only a
few of these mediators, such as the cytokines IL-1, IL-7,
and transforming growth factor-b (TGF-b), constitutively. Resident keratinocytes contain large quantities
of preformed and biologically active IL-1a as well as
immature IL-1b in their cytoplasm.91 The likely in vivo
role of this stored intracellular IL-1 is that of an immediate initiator of inflammatory and repair processes
after epidermal injury. IL-7 is an important lymphocyte growth factor that may have a role in the survival
and proliferation of the T lymphocytes of human skin.
Some evidence exists for the IL-7-driven propagation
of lymphoma cells in Szary syndrome.
TGF-b, in addition to its growth-regulating effects
on keratinocytes and fibroblasts, modulates the inflammatory as well as the immune response92 and is important for LC development (see in Langerhans Cells).93
On delivery of certain noxious, or at least potentially
hazardous, stimuli (e.g., hypoxia, trauma, nonionizing
radiation, haptens, or other rapidly reactive chemicals
like poison ivy catechols, silica, LPS, and microbial toxins), the production and/or release of many cytokines
is often dramatically enhanced. The biologic consequences of this event are manifold and include the initiation of inflammation (IL-1, TNF-a, IL-6, members of
the chemokine family), the modulation of LC phenotype and function (IL-1, GM-CSF, TNF-a, IL-10, IL-15),
T-cell activation (IL-15, IL-18),94,95 T-cell inhibition (IL10, TGF-b),96 and skewing of the lymphocytic response
in either the type 1 (IL-12, IL-18),97 type 2 (thymic
stromal lymphopoietin),98 or Th17 (IL-23) direction.99
In some cases, keratinocytes may also play a role in
amplifying inflammatory signals in the epidermis originating from numerically minor epidermal cell subsets.
One prominent example is the induction of proinflammatory cytokines such as TNF-a in keratinocytes by
LC-derived IL-1b in the initiation phase of allergic contact dermatitis.100 In the presence of a robust stimulus,
keratinocyte-derived cytokines may be released into
the circulation in quantities that cause systemic effects.
During a severe sunburn reaction, for example, serum
levels of IL-1, IL-6, and TNF-a are clearly elevated
and probably responsible for the systemic manifestations of this reaction, such as fever, leukocytosis, and
the production of acute-phase proteins.101 There is also
evidence that the ultraviolet (UV) radiation-inducible
cytokines IL-6 and IL-10 can induce the production of
autoantibodies and thus be involved in the exacerbation of autoimmune diseases such as lupus erythematosus. The fact that secreted products of keratinocytes
can reach the circulation could conceivably also be
used for therapeutic purposes. The demonstration by
Fenjves et al102 that grafting of apolipoprotein E genetransfected human keratinocytes onto mice results in
the detection of apolipoprotein E in the circulation of
the mouse supports the feasibility of such an approach.
Some of the innate functions of keratinocytes can be
elicited by TLR activation, since keratinocytes express
TLRs 16 and 9. Thus, by sensing microbial pathogens
via TLRs, keratinocytes may act as first-responders in

cutaneous innate immunity. Activation of TLRs leads
to keratinocyte production of proinflammatory cytokines (including TNF-a and IL-8), antimicrobial peptides (HBD-2 and HBD-3), and reactive oxygen mediators (iNOS).103105 Activation of TLR3 and TLR9 on
keratinocytes induces production of type I interferon
(IFN-a/b), which may be important in promoting antiviral immune responses.105 Lastly, these TLR-mediated
responses can be enhanced via danger signals such
as toxins, irritants, UV light, purines generated during an infection (P27 receptor activation), and activation of other pattern-recognition receptors (NOD1
and NOD2), which all promote inflammasome-mediated activation of caspase-1 that results in cleavage of
pro-IL1b into its active form.106
Another important function of keratinocytes is the
production/secretion of factors governing the influx
and efflux of leukocytes into and out of the skin. Two
good examples are the chemokines thymus and activation-regulated chemokine (TARC; CC chemokine
ligand 17, or CCL17) and cutaneous T cell-attracting
chemokine (CTACK)/CCL27 and their corresponding receptors CCR4 and CCR10, selectively expressed
on skin-homing T lymphocytes. Blocking of both chemokines drastically inhibits the migration of T cells to
the skin in a murine model of contact hypersensitivity
(CHS).107 KC-derived macrophage inflammatory protein 3a (MIP-3a)/CCL20 also plays an important role
in leukocyte recruitment to the epidermis. Its secretion
is triggered or enhanced by IL-17 and its counterreceptor CCR6 is present on LC precursors and certain
T cells.108110 The T17 cytokines, IL-17, IL-21, and IL-22
also modulate other keratinocyte innate immune functions. For example, IL-17 and IL-22 promote keratinocyte production of antimicrobial peptides, including
HBD-2, cathelicidin, and psoriasin.111,112 In addition,
IL-21 and IL-22 induce keratinocyte proliferation, leading to epidermal hyperplasia and acanthosis as seen in
psoriasis.113,114
The demonstration of cytokine receptors on and
cytokine responsiveness of keratinocytes established
that the functional properties of these cells can be subject to regulation by cells of the immune system. As
a consequence, keratinocytes express, or are induced
to express, immunologically relevant surface moieties
that can be targeted by leukocytes for stimulatory or
inhibitory signal transduction.
In addition to cytokines, keratinocytes secrete other
factors such as neuropeptides, eicosanoids, and reactive oxygen species. These mediators have potent
inflammatory and immunomodulatory properties and
play an important role in the pathogenesis of cutaneous inflammatory and infectious diseases as well as in
aging.
Keratinocytes synthesize complement and related
receptors including the C3b receptor [complement
receptor 1 (CR1), CD35], the Epstein-Barr virus receptor CR2 (C3d receptor, CD21), the C5a receptor (CD88),
the membrane cofactor protein (CD46), the decayaccelerating factor (CD55), and complement protectin
(CD59). CD59 may protect keratinocytes from attack
by complement. Its engagement by CD2 stimulates the
secretion of proinflammatory cytokines from keratinocytes. Membrane cofactor (CD46) is reported to be a

receptor for M protein of group A Streptococci and for
measles virus.115 Its ligation induces proinflammatory
cytokines in keratinocytes such as IL-1a, IL-6, and GMCSF.
ADAPTIVE IMMUNE RESPONSE
LYMPHOCYTES
T-Cell Antigen Receptor (TCR). The T-cell anti-
gen receptor (TCR) is a complex of molecules consisting

of an antigen-binding heterodimer (a/b or g/d chains)
that is noncovalently linked with five CD3 subunits [(1)
g, (2) d, (3) e, (4) , or (5) h). The TCR chains have amino
acid sequence homology with structural similarities to
Ig heavy and light chains. The genes encoding TCR
molecules are encoded as clusters of gene segments
(V, J, D, C, or constant) that rearrange during T-cell
maturation (eFig. 10-3.1 in online edition). Together
with the addition of nucleotides at the junction of rearranged gene segments, this recombinatorial process,
which involves the enzymes recombinase activating
gene 1 and 2, results in a heterogeneity and diversity
of the antigen recognition unit that is broad enough to
allow for a successful host defense. TCR a/b or TCR
g/d molecules must be paired with CD3 molecules to
be inserted into the T-cell surface membrane117 (see
Fig. 10-4). The TCR chains form the actual antigenbinding unit, whereas the CD3 complex mediates signal transduction, which results in either productive
activation or nonproductive silencing of the T lymphocyte. Most T cells express a/b TCRs, which typically
bind antigenic peptides presented by MHC molecules.
/b T cells includes Th1, Th2,
Immunity provided by a
Th17 and T reg responses (see Section Functionality).
B CELLS. B cells mature in the fetal liver and adult

bone marrow. They produce antibody-protein complexes that bind specifically to particular molecules
defined as antigens. As a consequence of recombinatorial events in different Ig gene segments (V or variable; D or diversity; J or joining), each B cell produces a
different antibody molecule (eFig. 10-3.1 in online edition). Some of this antibody is present on the surface
of the B cell, conferring the unique ability of that B cell
to recognize a specific antigen. B cells then differentiate into plasma cells, the actual antibody-producing
and -secreting cells. Plasma-cell secreted Ig comprise
the dimer IgA, the monomers IgD, IgE, and IgG as well
as the pentamer IgM that mediate humoral immune
responses. In general, antibodies bind to microbial
agents and neutralize them or facilitate uptake of the
pathogen by phagocytes that destroy them. Briefly, IgA
can be found in mucosal tissues, saliva, tears, or breast
milk and prevents colonization by various pathogens. IgD functions mainly as an antigen receptor on
B cells and, as recently discovered, activates mast cells
and basophils to produce antimicrobial factors.116 IgE
binds to allergens on mast cells and basophils and can
thereby trigger histamine release and allergic reactions
including anaphylaxis and urticaria. In addition, some
evidence exists that it can protect against parasitic and
helminthic infections. IgG provides the majority of antibody responses that contribute to the immune defense
against extracellular pathogens. It is the only antibody
that is capable of crossing the placenta in order to protect
the fetus. Finally, IgM is available either surface-bound
on B cells or as secreted form and eliminates microbes
::
Three subsets of lymphocytes exist in the human

immune system: B cells, T cells, and NK cells (see Section Cells of the Innate Immune System). The adaptive immune response is mediated by T and B lymphocytes. The unique role of these cells is the ability
to recognize antigenic specificities in all their diversity.
All lymphocytes derive from a common bone marrow
stem cell. This finding has been exploited in various
clinical settings, with attempts to restore the entire
lymphocyte pool by bone marrow or stem cell transplantation.
T CELLS. T cells mature in the thymus, where they

are selected to live or to die. Those T cells that will
have the capacity to recognize foreign antigens are
positively selected and can enter the circulation. Those
T cells that react to self are negatively selected and
destroyed. T cells have the unique ability to direct
other cells of the immune system. They do this, in part,
by releasing cytokines. For example, T cells contribute
to cell-mediated immunity (CMI), required to eliminate intracellular pathogens, by releasing cytokines
that activate macrophages and other T cells. T cells
release cytokines that activate NK cells and permit the
growth, differentiation, and activation of B cells.
T cells can be classified and subdivided in different
ways: (1) on the basis of the T cell receptor; (2) on the
basis of the accessory molecules CD4 and CD8; (3) on
the basis of their virginity, i.e., their activation status
(naive, memory, effector T cells); and (4) on the basis
of their functional role in the immune response, which
is often linked to the cytokine secretion property of the
respective cell population. We have used the abbreviations Th1 and Th2 to distinguish CD4+ helper T cell
subtypes but, as discussed below, many of the functional attributes, including cytokine production, of Th
cells are not as clearly defined as previously thought
and some cytokine profiles are also attributable to CD8+
cytotoxic T cells (Tc) (see Section Functionality).
Chapter 10
The strength and the type of the innate response determines both the quantity and quality of an adaptive
response initiated by dendritic APCs in the epidermis
(LCs) and dermis (dermal DCs or DDCs) and executed
by T lymphocytes and antibodies.
in the early stages of humoral immunity before there is

sufficient IgG production. Antibodies are also responsible for mediating certain pathologic conditions in skin.
In particular, antibodies against self-antigens (mostly
IgG, but also IgA) lead to autoimmune disease, typified
in the pathogenesis of pemphigus and bullous pemphigoid (see Chapter 37 for more details about B cells and
antibody production).
113
T-cell differentiation
Antigen
Dendritic cell
Naive T-cell
IFN-
IL-2
LY-
Th1
IFNs, IL-12
IL-6, IL-21
Bcl-6
IL-2, IL-4
Section 4
IL-4
IL-5
IL-6
IL-13
TFH
TGF-, IL-2
TGF-
IL-4
Th2
GATA-3
IL-1- IL-23
TGF- IL-6
Th9
IL-9
IL-10
IL-21
IL-17
TNF-
IL-6
Treg
FoxP3
TGF-
IL-10
IL-35
Th22
IL-22
Th17
RORC
::
114
IL-17A
IL-17F
IL-22
IL-26
Figure 10-4 Schematic view of events governing and occurring in T-cell differentiation. Depending on the type and activation status of the antigen-presenting dendritic cells (DCs) and on the type and amounts of cytokines secreted by these
and/or other cells, naive T cells will expand and differentiate into various directions, i.e., Th1 cells, Th2 cells, Th9 cells, Th17
cells, Th22 cells, T reg cells, and Tfh cells. They exhibit different types of transcription factors (e.g., T-bet, GATA-3, RORC,
FoxP3, Bcl-6) and secrete different types of cytokines.
In contrast, only a small subset of T cells express g/d

TCRs. These T cells have the capacity to directly bind
pathogen-derived glycoproteins or nonclassical MHC
molecules. It has been shown that g/d T cells in men
and mice predominantly display a tissue-associated
TCR repertoire as well as a memory phenotype, both
probably due to chronical stimulation by nonpeptide
antigens within the tissue. Importantly, they act early
during immune response and are therefore termed
innate-like effectors. Previous studies conducted in
mice infected with Listeria monocytogenes or Nippostrongylus brasiliensis revealed that g/d T cells discriminate
early between these pathogens and react by IFN-g
/b T-cell responses
versus IL-4 production, skewing a
in a Th1 or Th2 direction, respectively.118 Meanwhile,
growing evidence exists that human and murine g/d
T cells also have the capacity to produce IL-17 during
bacterial or viral infections and thereby significantly
contribute to the early innate immune defense.119121
CD4+ Helper T Cells. The original observation that
CD4+ T cells are critical for helping B cells to produce
antibodies by triggering their differentiation into plasma cells in the humoral response coined the term T
helper cells (Th cells). During the past years these
lymphocytes have been characterized extensively. To
our current knowledge, CD4+ T cells represent a heterogeneous cell population with diverse function depending on environmental requirements that play a
central role in humoral and cell-mediated immunity.
Effector CD4+ T cells protect against pathogens mainly
by their production of Th1, Th2, or Th17 cytokines (i.e.,
IFN-g, IL-4, IL-17) and influence immune responses
through both helper and effector functions. In
contrast, regulatory CD4+ T cells have the capacity to

downregulate disproportionate effector responses to
(self-) antigen (see Section Functionality).
CD8+ Cytotoxic T Cells. In responding to an intracellular pathogen (e.g., a virus) the T cell must lyse the
infected cell. To do so, it must be able to recognize
and respond to antigenic peptides encoded by this
pathogen and displayed on the cell surface. For this
to occur, antigens arising in the cytosol are cleaved
into small peptides by a complex of proteases, called
the proteasome. The peptide fragments are then transported from the cytosol into the lumen of the endoplasmic reticulum, where they associate with MHC
class I molecules. These peptideclass I complexes are
exported to the Golgi apparatus and then to the cell
surface (see Section General Principles of Antigen
Presentation). The maturation of a CD8+ T cell to a
killer T cell requires not only the display of the antigenic signal but also the delivery of helper signals
from CD4+ T cells, for which the functional interaction between CD40 on the APC and CD40L on the
CD8+ T cell can substitute.
VIRGINITY
Naive T Cells. After
positive selection in the thymus, mature T cells with low affinity for self-peptide/
MHC molecules are released into the blood stream and
form the long-lived pool of naive T cells. In order to
survive, naive T cells require IL-7 signaling and a low
level of self-reactivity entertained by constant TCR
engagement with self-p/MHC molecules.145
T Helper 1/T Helper 2 Paradigm. T cells

that produce IL-2, IFN-g, and TNF are termed Th1
cells. They are the main carriers of cell-mediated
immunity (CMI). Other T cells produce IL-4, IL-5,
IL-6, IL-13, and IL-15. These are termed Th2 cells and
are primarily responsible for extracellular immunity
(see below).160,161 Many factors influence whether an
uncommitted T cell develops into a mature Th1 or Th2
cell. The cytokines IL-12 and IL-4, acting through signal transducer and activator of transcription (STAT) 4
and 6, respectively, are key determinants of the outcome, as are antigen dose, level of costimulation, and
genetic modifiers. Certain transcription factors have
causal roles in the gene-expression programs of Th1
and Th2 cells. For example, the T-box transcription
factor T-bet is centrally involved in Th1 development,
inducing both transcriptional competence of the IFN-g
locus and selective responsiveness to the growth factor IL-12.162 By contrast, the zinc-finger transcription
factor GATA-3 seems to be crucial for inducing certain
key attributes of Th2 cells, such as the transcriptional
competence of the Th2 cytokine cluster, which includes
the genes encoding IL-4, IL-5, and IL-13.163,164
In murine models of intracellular infection, resistant
versus susceptible immune responses appear to be
regulated by these two T-cell subpopulations.165167 Th1
cells, primarily by the release of IFN-g, activate macrophages to kill or inhibit the growth of the pathogen
and trigger cytotoxic T-cell responses, which results in
mild or self-curing disease. In contrast, Th2 cells facili-
Th17 Cells. Not every T-cell-mediated immune

response and/or disease can be easily explained by
the T1/T2 paradigm. Certain T-cell subpopulations are
characterized by the secretion of IL-17. These cells are
therefore termed Th17 cells. It was originally assumed
that Th1 and Th17 cells arise from a common T1 precursor, but it now appears that Th17 cells are a completely separate and early lineage of effector CD4+ T
cells produced directly from naive CD4+ T cells. This
was proven by the identification of the Th17-specific
transcription factor ROR (RAR-related orphan nuclear
receptor) that regulates the expression of IL-17, IL-23R,
and CCR6 in Th17 cells.170 The expression of CCR6 is
unique for Th17 cells amongst T cells and regulates
their migration into epithelial sites depending on its
ligand CCL20.171 Recently, it has been demonstrated
that Th17 cells may originate from a small subset of
CD4+ T cells bearing the NK-cell-associated C-type lectin NKP-1A (CD161), which are present in cord blood
and newborn thymus.172 Differentiation of human
Th17 cells strongly depends on IL-23, a member of the
IL-12 family, as well as on IL-1b, IL-6, and low doses
of TGF-b173,174; murine Th17-lineage commitment is
mainly induced by IL-6 and TGF-b. Importantly, the
induction of Th17 cells from naive precursors may be
inhibited by IFN-g and IL-4, using a cross-regulatory
mechanism between Th1, Th2, and Th17 cells. One of
the main physiological roles of Th17 cells is to promote
protection against fungi, protozoa, viruses, and various extracellular bacteria, but Th17 cells have also been
169
tate humoral responses and inhibit some cell-mediated

immune responses, which results in progressive infection. These cytokine patterns are cross-regulatory. The
Th1 cytokine IFN-g downregulates Th2 responses. The
Th2 cytokines IL-4 and IL-10 downregulate both Th1
responses and macrophage function. The result is that
the host responds in an efficient manner to a given
pathogen by making either a Th1 or Th2 response.
Sometimes, the host chooses an inappropriate cytokine
pattern, which results in clinical disease.
Of particular interest to immunologists is the delineation of factors that influence the T-cell cytokine pattern. The innate immune response is one important
factor involved in determining the type of T-cell cytokine response.
The ability of the innate immune response to induce
the development of a Th1 response is mediated by
release of IL-12, a 70-kDa heterodimeric protein.168
For example, in response to various pathogens, APCs
including DCs and macrophages release IL-12, which
acts on NK cells to release IFN-g. The presence of IL-12,
IL-2, and IFN-g, with the relative lack of IL-4, facilitates
Th1 responses. In contrast, in response to allergens or
extracellular pathogens, mast cells or basophils release
IL-4, which in the absence of IFN-g leads to differentiation of T cells along the Th2 pathway. It is intriguing
to speculate that keratinocytes may also influence the
nature of the T-cell cytokine response. Keratinocytes
can produce IL-10, particularly after exposure to UVB
radiation.96 The released IL-10 can specifically downregulate T1 responses, thus facilitating the development of Th2 responses.
::
With regard to the functional

capacities of various T-cell subsets, it was originally
assumed that CD4+ cells predominantly subserve
helper functions and that CD8+ cells act as killer cells.
Many exceptions to this rule are now known to exist;
for example, both CD4+ and CD8+ regulatory cells are
found, but CD4+ cells are still commonly referred to as
helper T cells (Th cells) and CD8+ cells as cytotoxic T
cells (Tc cells).
During an immune response, naive Th/Tc cells can
differentiate into several functional classes of cells: (1)
Th1 cells (type 1 T cells); (2) Th2 cells (type 2 T cells);
(3) Th17 cells; (4) natural killer T cells (NKT); (5) regulatory T cells (T reg); and (6) T follicular helper (Tfh)
cells (Fig. 10-4). Originally, all these T-cell subsets have
mainly been defined as CD4+ Th cells. In the meantime
we have learned that both CD4+ Th and CD8+ Tc cells
can produce cytokines allowing their classification into
these distinct T-cell subsets. The functional commitment of effector T-cell populations is controlled by the
expression of lineage-specific transcription factors, but
individual T cells can also express cytokines that are
not lineage-specific. It therefore remains to be determined whether T cells display heterogeneity within a
lineage or whether each distinct cytokine-expression
pattern already reflects a separate lineage. It seems that
T cells, although already polarized, still possess a high
degree of functional plasticity that allows further differentiation depending on various factors such as the
strength of antigenic signaling, cytokines, or interactions with other cells encountered in their microenvironment.155
Chapter 10
Functionality.
115
Section 4
::
116
linked to a growing list of autoimmune and inflammatory diseases such as neuroinflammatory disorders,
asthma, lupus erythematosus, rheumatoid arthritis,
Crohns disease and, most notably, psoriasis.99,175 Very
recent evidence exists that Th17 cells might also play
a role in antitumor immunity.176 Importantly, IL-17
expression is not restricted to CD4+ cells only, but has
also been detected in CD8+ T cells.177 Th17 cells exert
their function by producing effector cytokines including IL-17A, IL-17F, IL-22, and IL-26. Whereas IL-17 is
believed to contribute to the pathogenesis of these diseases by acting as potent proinflammatory mediator,
IL-22 has been described as a multifunctional cytokine
with inflammatory as well as protective properties. In
vitro stimulation of normal keratinocytes with IL-22,
for example, results in inhibition of keratinocyte differentiation followed by epidermal hyperplasia and
upregulated expression of proinflammatory genes in
these cells.178
Regulatory T Cells. An important type of

immunomodulatory T cells that controls immune
responses are the so-called regulatory T cells (T reg cells),
formerly known as T suppressor cells.181 T reg cells are
induced by immature APCs/DCs and play key roles in
maintaining tolerance to self-antigens in the periphery.
Loss of T reg cells is the cause of organ-specific autoimmunity in mice that results in thyroiditis, adrenalitis,
oophoritis/orchitis, etc. T reg cells are also critical for
controlling the magnitude and duration of immune
responses to microbes. Under normal circumstances,
the initial antimicrobial immune response results in
the elimination of the pathogenic microorganism and
is then followed by an activation of T reg cells to suppress the antimicrobial response and prevent host
injury. Some microorganisms (e.g., Leishmania parasites, mycobacteria) have developed the capacity to
induce an immune reaction in which the T reg component dominates the effector response. This situation prevents elimination of the microbe and results in
chronic infection.
The best-characterized T reg subset is the CD4+/
CD25+/CTLA-4+/GITR+ (glucocorticoid-induced TNF
receptor family-related gene)/FoxP3+ lymphocytes.182
The transcription factor FoxP3 is specifically linked to
the suppressor function, as evidenced by the findings
that mutations in the FoxP3 gene cause the fatal autoimmune and inflammatory disorder of scurfy in mice
and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) in humans. The cytokines
TGF-b and IL-10 are thought to be the main mediators
of suppression.
During the past years the situation has become
even more complicated, because, at least under certain conditions, subsets with different phenotypes
have been associated with regulatory functions such
as CD4+, CD8+, and NKT cells. Accordingly, the existence of T reg cells coexpressing IL-17 and FoxP3 has
been described.183 CD8+ cells can also be activated to
become suppressor cells by antigenic peptides that are
presented in the context of an MHC class Ib molecule
[Qa1 in mice; human leukocyte antigen E (HLA-E) in
humans]. CD8+ T reg cells suppress T cells that have
intermediate affinity for self or foreign antigens and

are primarily involved in selfnonself discrimination.
In addition, recent data provides evidence for a suppressive function of human FoxP3-, TGf-b-producing
g/d T cells.184
T Follicular Helper (Tfh) Cells. Tfh cells

represent a distinct subset of CD4+ T cells found in limited numbers, especially in B-cell areas of lymph nodes
and spleen.
Homing and long-term residency in B-cell follicles
of these newly described T cells is secured by their surface expression of CXCR5. They have a crucial role in
orchestrating T-cell-dependent effector and memory
B-cell responses, produce IL-21 and express inducible
T-cell costimulator (ICOS) and programed cell death
1 (PD-1) as costimulatory and coinhibitory molecules,
respectively. Specific differentiation of Tfh cells was
associated to the transcription factor Bcl6 as well as to
the cytokines IL-6 and IL-21.185187
Lymphocytes in Normal and Diseased Skin. As opposed to normal mouse skin,
in which a resident population of dendritic epidermal

T cells uniformly equipped with a nonpolymorphic,
canonical gd TCR exists, the lymphocytes of normal
human skin are mainly located in the dermis and predominantly express the ab TCR rather than the g/d
TCR. While the majority of epidermal T cells exhibit
the CD8+/CD4 phenotype, dermal T cells are mainly
CD4+/CD8, belong to the CD45RO memory population, express the addressins CLA (cutaneous lymphocyte antigen) and CCR4 which they use for skinhoming purposes,188 and are largely devoid of CCR7
and L-selectin, i.e., addressins promoting the homing
of lymphocytes to the lymphoid organs.152,189 This situation is true also for homeostatic conditions which
means that a cutaneous pool of effector memory cells
is already in place when danger is imminent. Some of
these effector memory T cells have a rather long life
span and have been found in different skin conditions,
for example, at sites of HSV infection of mice 190,191
and men192 as well as in clinically resolved, hyperpigmented fixed drug eruptions.193
Normal human skin contains approximately 1 million T cells per cm2, 2%3% of which reside within the
epidermis,194 primarily in the basal and suprabasal layers. The T cells of the dermis are preferentially clustered around postcapillary venules of the superficial
plexus high in the papillary dermis and are often situated just beneath the dermalepidermal junction and
within, or in close proximity to, adnexal appendages
such as hair follicles and eccrine sweat ducts.
The process of T-cell trafficking to the skin is guided
by a series of receptorligand interactions between
cells. It is of note that DCs are capable of imprinting
homing receptor expression on T cells,195 which means
that T cells programed by skin and/or skin-derived
DCs will preferentially return to the skin. One such
moiety is the glycoprotein cutaneous lymphocyte antigen (CLA) that defines a subset of memory T cells that
home to skin. It is a glycosylated form of P-selectin
glycoprotein ligand 1 that is expressed constitutively
on all human peripheral blood T cells. The level of

CLA on cells is regulated by an enzyme, a (1,3)-fucosyltransferase VII, which modifies P-selectin glycoprotein ligand 1. In this manner, CLA+ cells bind to both
E-selectin and P-selectin, whereas CLA cells bind
P-selectin, but not E-selectin.196,197 The chemokine
chemokine receptor system is the other major regulator and coordinator of leukocyte migration to the skin
(see Chapter 12).
While lymphocytes are the only cells capable of recognizing antigenic moieties, the recognition process per se, at least as far as T cells are concerned, is
dependent on the presence of antigen-presenting cells
(APC). Unlike B cells, T cells cannot recognize soluble
protein antigen per se; their antigen receptor (TCR) is
designed to recognize antigen-derived peptides bound
to MHC locus-encoded molecules expressed by APCs.
Most CD8+ T cells, destined to become cytotoxic T cells,
recognize the endogenous antigen in association with
MHC class I molecules.216 Because most nucleated cells
transcribe and express MHC class I genes and gene
products, it is evident that many cell types can serve
as APCs for MHC class I-restricted antigen presentation and/or as targets for MHC class I-dependent
attack by T cells. For the antigen-specific activation
of CD4+ T cells, exogenous antigen-derived peptides
are usually presented in the context of MHC class II
molecules.216 In this situation, peptides are generated
in the endocytic, endosomal/lysosomal pathway and
are bound to MHC class II molecules. The resulting
MHC-peptide complex is expressed at the APC surface
for encounter by the TCR of CD4+ T cells. In the MHC
class II-dependent antigen presentation pathway, dendritic cells (DCs), including Langerhans cells (LCs) and
dermal dendritic cells (DDCs), B cells, and activated
monocytes/macrophages are the major APC populations. Among these, DCs act as professional APC,
i.e., are capable of migration and stimulating antigenspecific responses in naive, resting T cells.
::
Antigen Presenting Cells
Chapter 10
Skin Homing of Memory T Cells. Of particular importance for skin homing of memory T cells,
independent of their polarization, is the interaction
of CCL17 and CCL22 with CCR4 and of CCL27 with
its counterreceptor CCR10 on CLA+ T cells. CCL17
is synthesized by activated keratinocytes, DCs and
endothelial cells of the skin, while CCL22 is mainly
of macrophage and DC origin. The CCR10 ligand,
CCR27, appears to be exclusively produced by epidermal keratinocytes.198 Although it was originally
assumed that functionally different T-cell subsets can
be distinguished from each other by their chemokine
receptor expression pattern and their responsiveness
to the respective chemokines, the situation is less clear
now. Reportedly, T1 cells selectively bear CXCR3 and
CCR5, T2 cells preferentially exhibit CCR8 and CCR3,
and T17 as well as T reg express CCR6, allowing them
to respond to the keratinocyte- and endothelial cellderived chemokine CCL20.199,200
From all that has been said so far, one can surmise
that the accumulation of T cells in skin is not stochastic. This is indeed the case as exemplified by the
dominance of CD8+ T cells in skin lesions, but not in
the peripheral blood of patients with lepromatous leprosy201 as well as by the clonality of the T-cell population in cutaneous T-cell lymphoma, in which a single
V gene usage is found to predominate in different skin
lesions from the same individual.202,203 A limited TCR
V gene usage has also been reported to be present in
skin lesions of leprosy,204 psoriasis,205 basal cell carcinoma, and countless other reactions in which T cells
are present.
The most direct indication of relevant T-cell populations in skin is determination of the number of antigenspecific T cells. It has been documented that 1 in 1,000
to 1 in 10,000 T cells in the peripheral blood, but only
1 in 50 to 1 in 100 T cells recognize the antigen causing
the disease at sites of inflammation.206,207 Thus, there is
as much as a 100-fold enrichment of antigen-reactive T
cells at the site of cutaneous inflammation.
With regard to survival and/or expansion of T cells
of human skin/epidermis, it appears that IL-2, IL-7,
and IL-15 play important roles.208 Notably, the latter
two T-cell growth factors can be produced by human
epidermal cells, and all of them are frequently overexpressed in T cell-rich skin lesions, for example, in
patients with tuberculoid leprosy. For a long period of
time, the Th1/Th2 paradigm was used to explain the
pathogenesis and, more often, the course of infectious,
inflammatory and, even, neoplastic skin diseases.
Leprosy and leishmaniasis are outstanding examples
of diseases in which the clinical manifestations are
decisively determined by the dominance of either Th1
or Th2 cells. With the identification of new functionbased T-cell subpopulations (e.g., T0 cells, Th17 cells,
Th22 cells), this classification is too rigid and no longer tenable. In fact, we come to realize that the T-cell
pathogenesis of certain diseases that we had originally
considered to belong into either the Th1 (e.g., psoriasis, allergic contact dermatitis) or the Th2 world (atopic
dermatitis) is very complex and sometimes even stagespecific. Th17 and/or Th22 cells are apparently major
players in psoriasis158 and allergic contact dermatitis.177
In atopic dermatitis, the acute lesions harbor not only
Th2, but also Th17 and Th22 cells; in the chronic stage,
however, Th1 cells seem to predominate. In syphilis,
perhaps not only Th1 cells, but also CD8+IFN-g-producing Th17 cells do confer immunologic resistance to
T. pallidum.209,210 Th17 cells may also be important in
the pathogenesis of Borrelia burgdorferi-induced Lyme
arthritis, which was long attributed to be a solely Th1
cell-mediated response.211,212 In patients with cutaneous T cell lymphoma (CTCL), Th2 responses dominate the inflammatory infiltrate of the skin, especially
at late stages.213 In early lesions, however, infiltrating
CD3+CD45RO+CLA+CCR4+ T cells also express IFN-g
and IL-17 (see Chapter 145). In basal cell carcinomas
the presence of a Th2-dominated environment with
an increased expression of IL-4 and IL-10 as well as
tumor-surrounding T reg cells may be responsible for
tumor growth214 (see Chapter 115). In alopecia areata,
recent data suggest a role for Th1 cells.215
117
4
CD8+
T cell
CD8
Lipid
antigen
TCR
V24
Proteasome
Section 4
::
118
NKT cell/
DNT cell
TCR
MHC Class I
pathway
CD1
pathway
CD4+
T cell
TAP
Endosome
TCR
MHC class I
ER
CD4
MHC class II
pH < 5
Golgi
MHC Class II
pathway
Endosome
Figure 10-5 Antigen-processing pathways. The intracellular antigen-processing pathways for major histocompatibility
complex (MHC) class I, MHC class II, and CD1 presentation are shown. The MHC class I pathway involves the processing of
cytoplasmic proteins, whereas the MHC class II pathway involves the processing of exogenous proteins. The CD1 pathway
regulates the processing and presentation of self-glycosphingolipids and bacterial lipoglycans. DN T cell = double-negative (CD4/CD8) T cell; ER = endoplasmic reticulum; MIIC = MHC class II lysosomal peptide-loading compartment; NKT cell
= natural killer T cell; TAP = transporter associated with antigen processing; TCR = T-cell receptor.
General Principles of Antigen Presentation. (Fig. 10-5)

Major Histocompatibility Complex Class
I-Restricted
Antigen Presentation: Classic
Pathway.217,218 Immediately after their biosynthesis,
MHC class I heavy and light (b2-microglobulin) chains

are inserted into the membranes of the endoplasmic
reticulum. The third subunit of the functional MHC
class I complex is the peptide itself. The major sources
of peptides for MHC class I loading are cytosolic proteins, which can be targeted for their rapid destruction
through the catalytic attachment of ubiquitin. These
cytosolic proteins can be self-proteins, viral particles,
or neoantigens (altered self-proteins). Cytosolic proteinaceous material undergoes enzymatic digestion by
the proteasome to yield short peptide chains of 812
amino acids, an appropriate length for MHC class I
binding. In its basic conformation, the proteasome is a
constitutively active factory for self-peptides. IFN-g,

by replacing or adding certain proteasomal subunits,
induces immunoproteasomes, presumably to finetune the degradation activity and specificity to the
demands of the immune response. The processed peptides are translocated to the endoplasmic reticulum
by the transporter associated with antigen processing
(TAP), an MHC-encoded dimeric peptide transporter.
With the aid of chaperons (calnexin, calreticulin, tapasin), MHC class I molecules are loaded with peptides,
released from the endoplasmic reticulum, and transported to the cell surface. Several infectious agents
with relevance to skin biology have adopted strategies
to subvert MHC class I presentation, and thus the surveillance of cell integrity, by interfering with defined
molecular targets. Important examples of such interference are the inhibition of proteasomal function by
the EpsteinBarr virus-encoded EBNA-1 protein, the
competition for peptideTAP interactions by a herpes
simplex virus protein, and the retention or destruction

of MHC class I molecules by adenovirus- and human
cytomegalovirus-encoded products.
Alternative Pathway (Cross-Presentation).
Dendritic Cells. DCs are the only APC capable

of interacting with naive T cells. Depending on the
DC activation status (i.e., mature versus immature),
this cellular contact will result in either productive or
nonproductive T-cell responses. Originally, DCs were
identified in peripheral lymphoid organs in mice (lymphoid DC).227 A few years later the presence of DC in
nonlymphoid tissue (nlDC) was first demonstrated as
evidenced by the expression of Fc and C3 receptors as
well as MHCII antigens on epidermal LC.228230 This
finding anchored LC as cells of the immune system.
DCs populate nearly every mammalian tissue
under homeostatic (indigenous DC) and inflammatory
(inflammatory DC) conditions (Fig. 10-6). Both indigenous and inflammatory DCs ultimately derive from
119
Besides peptides, self-glycosphingolipids and bacterial

lipoglycans may also act as T-cell-stimulatory ligands.
Molecules that bind and present these moieties belong
to the family of nonpolymorphic, MHC class I- and IIrelated CD1 proteins. CD1 molecules are structurally
close to MHC class I molecules, but functionally related
to MHC class II molecules. In the skin, members of the
CD1 family are expressed mainly by LCs and DDCs. The
CD1 isoforms CD1a, CD1b, CD1c, and CD1d sample
both recycling endosomes of the early endocytic system
and late endosomes and lysosomes to which lipid antigens are delivered. Unlike in the MHC class II pathway,
antigen loading in the CD1 pathway occurs in a vacuolar acidification-independent fashion. T cells expressing
a Va24-containing canonic TCR, NKT cells, and CD4/
CD8 T cells include the most prominent subsets of
CD1-restricted T cells. CD1-restricted T cells play important roles in host defense against microbial infections.
Accordingly, human subjects infected with M. tuberculosis showed stronger responses to CD1c-mediated presentation of a microbial lipid antigen than control subjects,
and activation of CD1d-restricted NKT cells with a synthetic glycolipid antigen resulted in improved immune
responses to several infectious pathogens. Thus, the CD1
pathway of antigen presentation and glycolipid-specific
T cells may provide protection during bacterial and parasite infection, probably by the secretion of proinflammatory cytokines, the direct killing of infected target cells,
and B cell help for Ig production.
class II molecules predominantly bind peptides within

endosomal/lysosomal compartments. Sampling peptides in these subcellular organelles allow class II
molecules to associate with a broad array of peptides
derived from proteins targeted for degradation after
internalization by fluid phase or receptor-mediated
endocytosis, macropinocytosis, or phagocytosis. One
of the striking structural differences between MHC
class I and class II molecules is the conformation of
their peptide-binding grooves. Whereas MHC class
I molecules have binding pockets to accommodate
the charged termini of peptides and thus selectively
associate with short peptides, the binding sites of
MHC class II molecules are open at both ends. Thus,
MHC class II molecules bind peptides with preferred
lengths of 1522 amino acids but can also associate
with longer moieties. An important chaperone for
MHC II molecules and responsible for the correct folding and the functional stability of MHC II molecules
is the type II transmembrane glycoprotein invariant
chain (Ii; CD74). Ii also prevents class II molecules
from premature loading by peptides intended for
binding to MHC class I molecules in the endoplasmic
reticulum and participates in the sorting of MHC II
toward the endocytic pathway.222 Depending on the
cell type and the activation status of a cell, the half-life
CD1-Dependent Antigen Presentation.225,226
::
Major Histocompatibility Complex216Class

II-Restricted Antigen Presentation. MHC
Chapter 10
Under certain conditions, exogenous antigen can reach

the MHC class I presentation pathway. Significant
evidence for this cross-presentation first came from
in vivo experiments in mice demonstrating that viral,
tumor, and MHC antigens can be transferred from
MHC-mismatched donor cells to host bone marrowderived APCs to elicit antigen-specific cytotoxic T-cell
responses that are restricted to self-MHC molecules.219
In vitro studies have defined that exosomes (i.e., small
secretory vesicles of approximately 100 nm in diameter secreted by various cell types, including tumor
cells), heat shock proteins, immune complexes, and
apoptotic cells (taken up via CD36 and avb3 or avb5
integrins) can all serve as vehicles for the delivery of
antigen to DCs in a manner that permits the cross-presentation of antigen. In all in vitro systems in which
a direct comparison has been made, DCs, including
LCs, but not monocytes/macrophages, were capable
of cross-presentation.220,221 Three distinct pathways are
currently exploited by which antigen can access MHC
class I molecules of DCs: (1) a recycling pathway for
MHC class I in which antigen is loaded in the endosome; (2) a pathway by which retrograde transport
of the antigen from the endosome to the endoplasmic
reticulum facilitates entry into the classic MHC class
I antigen presentation pathway; and (3) an endosome
to the cytosol transport pathway, which again allows
antigen processing via the classic MHC class I antigen
presentation pathway.
of class IIpeptide complexes varies from a few hours

to days. It is particularly long (more than 100 hours)
on DCs that have matured into potent immunostimulatory cells of lymphoid organs on encounter with an
inflammatory stimulus in nonlymphoid tissues. The
very long retention of class IIpeptide complexes on
mature DCs ensures that only the peptides generated
at sites of inflammation will be displayed in lymphoid
organs for T cell priming. Cytokines have long been
known to regulate antigen presentation by DCs. In
fact, proinflammatory (TNF-a, IL-1, IFN-g) and antiinflammatory (IL-10, TGF-b1) cytokines regulate presentation in MHC class II molecules in an antagonistic
fashion. Mechanistically, regulatory effects include the
synthesis of MHC components and proteases, and the
regulation of endolysosomal acidification.223,224
4
Unperturbed skin
Dermis
Epidermis
Perturbed skin
Section 4
::
120
KEY
CD8+ T cell
LC
IDSC
Mast cell
CD4+ T cell
DDC
pDC
Granulocyte
Mononuclear phagocytes
Granzyme B
perforin
NK cell
KC
Figure 10-6 Resident and passenger leukocytes of the skin. Unperturbed skin: under homeostatic, steady-state conditions, the skin harbors only limited numbers of leukocytes. They consist mainly of dendritic cells (Langerhans cells in the
epidermis and dermal dendritic cells in the dermis) and, to a lesser extent, of T cells in the epidermis (largely CD8+) and
dermis (largely CD4+) and a few mononuclear phagocytes and mast cells. Granulocytes, NK cells, B cells, and inflammatory
dendritic cells are essentially absent. Perturbed skin: upon delivery of exogenous (e.g., microorganisms, chemical irritants,
ultraviolet radiation) and perhaps endogenous danger signals, resident skin cells such as keratinocytes become activated
and, as a consequence, initiate an inflammatory tissue response arising mainly from circulating, but probably also resident
leukocytes. KC = keratinocyte; LC = Langerhans cells; DDC = dermal dendritic cells; pDC = plasmacytoid dendritic cells;
IDSC = inflammatory dendritic skin cells; NK cell = natural killer cells.
hematopoietic stem and progenitor cells (HSPC) in
the bone marrow. HSPCs give rise to progenitor cells
that can further differentiate into one or more DC subsets.231,232 DC precursors can be found in multiple locations throughout the body such as the bone marrow,
the thymus as well as the peripheral lymphoid organs
including the blood.233235 These blood-derived DC
precursors populate nonlymphoid tissues and organs
using specific chemokine receptorligand pathways
(e.g., CCR2-CCL2, CCR5-CCL5, CCR6-CCL20).236239
Upon arrival in the periphery, they either undergo a
process of differentiation or maintain their density by
self-renewal.234 Inflammatory DCs are mainly mobilized into the tissues from peripheral blood precursors
upon receipt of danger signals. They probably do not
constitute a DC subpopulation per se, but rather represent an activated state of a given DC.
Within the periphery, differentiated DCs accumulate
in extravascular areas and survey their surroundings
for microbial invasion, always prepared for antigen
capture. Under homeostatic conditions, the overwhelming majority of DCs are in an immature state that
allows them to efficiently take up antigen (e.g., serum
proteins, extracellular matrix components, dead cells)
with the help of specific receptor sites (e.g., Langerin,
macrophage mannose receptor, C-type lectin receptor DEC-205, low-affinity IgG receptor CD32/FcgRII,
high-affinity IgE receptor FceRI, the thrombospondin

receptor CD36, DC-SIGN), but does not endow them
with immunostimulatory properties for naive resting T
cells. DCs apparently increase their efficacy in antigenuptake by repetitively extending and retracting their
dendrites through intercellular spaces (dSEARCH:
dendrite surveillance extension and retracting cycling
habitude).240 Antigen-engulfment triggers DC maturation, which is followed by DC detachment from neighboring cells and trafficking to draining lymph nodes
dependent on CCR7 signaling.241243
DC trafficking from nonlymphoid to lymphoid tissues
occurs, in a limited fashion, also under homeostatic conditions,244,245 but is much more enhanced upon the delivery of danger signals. During this journey, DCs have to
overcome several obstacles such as vessel walls, connective tissue, basement membranes, or other anatomical
barriers. To be capable of traveling, DCs are equipped
with distinct proteolytic enzymes such as matrix metalloproteinase 2 (MMP-2) and MMP-9 that lead to the
degradation of extracellular matrix proteins.246248 Interstitial DC migration is partly controlled by tissue inhibitors of metalloproteinases (TIMPs), which inhibit MMP
activity under nondanger conditions. However, upon
maturation of DCs, TIMP expression is downregulated
and MMPs exert their function.249 In the LN, DCs rapidly extend their dendrites in a probing way thereby
we find several APC including epidermal Langerhans cells (LC) and dermal dendritic cells278 (DDC). LCs
and DDCs are lineage-negative (Lin), bone marrowderived leukocytes, which phenotypically and functionally resemble other DCs present in most, if not all,
lymphoid and nonlymphoid tissues.279 As gatekeepers of the immune system, they control the response
to events perturbing tissue/skin homeostasis. In other
species such as mice an additional DC subset has been
described recently, namely CD103+CD207+ cells, which
in humans have yet to be identified.280282 Healthy
skin also harbors other cells which at least theoretically could subserve APC function, such as basophils
and mast cells. While these cells have been shown to
play a role in the modulation of cutaneous immune
responses, their functions as APC remain to be defined.
Under inflammatory conditions, DC types that are
not residents of the normal cutaneous environment
appear in the skin. These include DCs from the plasmacytoid lineage, so-called plasmacytoid DC (pDCs)
and inflammatory dendritic skin cells (IDSC), which
originate from myeloid precursors and phenotypically
resemble myeloid DCs (mDC) of the peripheral blood.
Dendritic Cells of Normal and Diseased

Skin. In essentially unperturbed normal human skin
::
Mechanisms responsible for the tolerance-inducing

property of nonactivated DCs, although not entirely
understood, include (1) a reduced expression of MHCantigen complexes263 and costimulatory molecules264
on the cell surface; (2) expression of the coinhibitory
receptor ligands programed cell death-ligand 1 (PDL1/B7-H1) and, to a lesser extent, PD-L2 (B7-DC)265267;
(3) the secretion of immunosuppressive cytokines such
as IL-10,268 which fits well to the finding of T reg induction by UV-irradiated, IL-10-producing T reg cells269;
(4) the expression of immunoinhibitory enzymes
such as indoleamine 2,3-dioxygenase270; and (5) the
receipt of signals interfering with the maturation and
migration of DCs, for example, neuropeptides such
as CGRP271 and vasoactive intestinal peptide,272 or the
engagement of the CD47/SHPS-1 signal transduction
cascade.273,274 It appears that these different factors are
not equally operative in all situations. LCs, for example, can activate self-antigen-specific CD8 T cells in
the steady state, which leads to chronic skin disease,275
and, at the same time, LCs are dispensable for276 or can
even downregulate277 the induction of CHS.
Chapter 10
establishing physical contacts with adjacent T cells, as

in vivo two-photon intravital microscopy of inguinal
lymph nodes of mice has revealed.250,251 The display of
MHC-peptide complexes on the DC surface delivers
the first signal to T cells thereby starting communication, i.e., the triggering of the TCR by the APC-bound
peptide-MHC complex. Upon activation, DCs display
an upregulated and prolonged surface expression of
MHCII as compared with nonactivated APC. Although
this event may be sufficient to induce the proliferation
of primed T cells, it is insufficient for the productive
activation of naive T cells. The occurrence of the latter
requires the receipt of second signals, which are also
delivered by professional APCs. In fact, antigen-specific
T cells that encounter MHC-expressing cells that cannot deliver second signals (e.g., MHC class II-induced
keratinocytes, endothelial cells, fibroblasts) enter a state
of anergy.252 Second signals, which include secreted
cytokines and membrane-bound costimulatory molecules, determine the magnitude and quality of primary
and secondary T-cell responses. Upon contact with the
DC-derived cytokine IL-12, for example, T cells turn
into type 1 IFN-g-producing cells, whereas DC-derived
IL-23 may skew T-cell responses in the type 17 direction (see Section Functionality). Upon danger stimuli,
DCs produce a variety of additional cytokines such as
IL-1b, TNF-a, TGF-b, or IL-6 that all have the potential to polarize distinct T-cell responses. Costimulatory
molecules on DCs are upregulated during the process
of maturation induced by surface receptors triggered by
ligands secreted or presented by other somatic cells or,
alternatively, by microbial products (danger signals).253
The best-defined costimulatory molecules are the two
members of the B7 family, B7.1/CD80 and B7.2/CD86.
LCs/DCs in situ do not express or express only minute
amounts of these costimulatory molecules, but greatly
upregulate these moieties during maturation. Other
costimulatory molecules include the ICAM-1 that binds
to LFA-1 and LFA-3, the ligand of T cell-expressed CD2.
Other important ligandreceptor pairs that positively
affect T-cell activation by DCs include heat-stable antigen CD24/CD24L, CD40/CD40L, CD70/CD27L, OX40
(CD134)/OX40L, and receptor activator of nuclear factor kB (RANK)/RANKL. Another costimulatory molecule of great importance is the membrane-bound glycoprotein CD83. It is significantly upregulated during
DC maturation and enhances CD8+ T cell proliferation
upon binding to an as yet unknown CD83 ligand on T
cells whose expression is strictly dependent on CD28mediated costimulation.254,255
Recent evidence suggests that DCs/LCs themselves can actively induce immune tolerance. The
main mechanism to maintain immune tolerance is
deletion of T cells with high affinity to self-peptide/
MHC complexes in the thymus by inducing apoptosis
(negative selection). Another variation of tolerance is
T cell-anergy induced by contact with APC that do not
provide second signals. Finally, DCs, at least in their
immature state, preferentially activate T reg cells.256
When antigen is targeted to these nonactivated DCs in
vivo, antigen-specific hyporesponsiveness occurs.257261
This finding has therapeutic implications for the treatment of autoimmune diseases.262
Langerhans Cells.283
In 1868, the medical

student Paul Langerhans, driven by his interest in the
anatomy of skin nerves, identified a population of dendritically shaped cells in the suprabasal regions of the
epidermis after impregnating human skin with gold
salts.284 These cells, which later were found in virtually
all stratified squamous epithelia of mammals, are now
eponymously referred to as Langerhans cells (Fig. 10-7).
The expression of the Ca2+-dependent lectin Langerin
(CD207) is currently the single best feature discriminating LCs from other cells. Langerin is a transmembrane molecule associated with and sufficient to form
Birbeck granules, the prototypic, and cell type-defining
organelles of LCs (see Fig. 10-7). Birbeck granules are
121
Section 4
::
122
Figure 10-7 A. Langerhans cells in a sheet preparation of murine epidermis as revealed by antimajor histocompatibility complex class II (fluorescein isothiocyanate) immunostaining. B. Electron micrograph of a Langerhans cell in human
epidermis. Arrows denote Birbeck granules. N = nucleus. (From Stingl G: New aspects of Langerhans cell functions. Int J
Dermatol 19:189, 1980, with permission.) Inset: High-power electron micrograph of Birbeck granules. The curved arrows indicate the zipper-like fusion of the fuzzy coats of the vesicular portion of the granule. The delimiting membrane envelops
two sheets of particles attached to it and a central lamella composed of two linear arrays of particles. (From Wolff K: The
fine structure of the Langerhans cell granule. J Cell Biol 35:466, 1967, with permission.)
entilaminar cytoplasmic structures frequently disp
playing a tennis racket shape at the ultrastructural
level. The additional presence of Langerin on the cell
surface coupled with its binding specificity for mannose suggests that Langerin is involved in the uptake of
mannose-containing pathogens by LCs. However, the
disruption of the Langerin gene in experimental animals does not result in a marked loss in LC functionality.285 Additional molecules besides Langerin allow the
identification of LCs within normal unperturbed epidermis. These include CD1a; the MHC class II antigens
HLA-DR, HLA-DQ, and HLA-DP; and CD39, a membrane-bound, formalin-resistant, sulfhydryl-dependent
adenosine triphosphatase (ATPase).
The tissue distribution of LC varies regionally in
human skin. On head, face, neck, trunk, and limb skin,
the LC density ranges between 600 and 1,000/mm2.
Comparatively low densities (approximately 200/mm2)
are encountered in palms, soles, anogenital and sacrococcygeal skin, and the buccal mucosa. The density of
human LCs decreases with age, and LC counts in skin
with chronic actinic damage are significantly lower
than those in skin not exposed to UV light (Fig. 23-7).
HLADR+/ATPase+ DCs can be identified in the human
epidermis by 67 weeks of estimated gestational age.
These cells must originate from hemopoietic progenitor
cells in the yolk sac or fetal liver, the primary sites of

hemopoiesis during the embryonic period. Until week
14 of estimated gestational age (EGA), these cells acquire
the full phenotypic profile of LC in a stepwise fashion.286
The relative numeric stability of LC counts during later
life must be achieved by a delicate balance of LC generation and immigration into the epidermis and LC
death and emigration from the epidermis. Within the
epidermis, LCs are anchored to surrounding keratinocytes by E-cadherin-mediated homotypic adhesion.287
This anchoring and the display of TGF-b1 also prevent
terminal differentiation and migration, thus securing
intraepidermal residence for the cells under homeostatic
conditions. Two nonmutually exclusive pathways of LC
repopulation of the epidermis may exist: (1) LC division
within the epidermis, and (2) the differentiation of LCs
from skin-resident or blood-borne precursors. Evidence
for the first possibility is the demonstration of cycling/
mitotic LCs in the epidermis,288 although it remains to
be established whether this cell division alone suffices
for maintaining the epidermal LC population.
The observation that the half-life of LCs within unperturbed murine epidermis is around 23 months289 suggests a significant turnover of the epidermal LC population even under noninflammatory conditions. In seeming contradiction stands the observation that the LC
::
peptides, have lost their capacity to process and present native protein antigens.298
Upon perturbance of skin homeostasis (e.g., TLR
ligation, contact with chemical haptens, hypoxia), LCs
gain access to antigen/allergen encountering the epidermis by distending their dendrites through epidermal tight junctions, thereby demonstrating strikingly
remarkable cooperation between keratinocytes and
LC.299 After a few hours, LCs begin to enlarge, to display increased amounts of surface-bound MHC class
II molecules, and to migrate downward in the dermis,
where they enter afferent lymphatics and, finally, reach
the T-cell zones of draining lymph nodes.300 During this
process, LCs undergo phenotypic changes similar to
those that occur in single epidermal cell cultures,301 i.e.,
downregulation of molecules or structures responsible
for antigen uptake and processing as well as for LC
attachment to keratinocytes (e.g., Fc receptors, E-cadherin) and upregulation of moieties required for active
migration and stimulation of robust responses of naive
T cells (e.g., CD40, CD80, CD83, CD86). The mechanisms governing LC migration are becoming increasingly clear. TNF-a and IL-1b (in a caspase 1-dependent
fashion) are critical promoters of this process, whereas
IL-10 inhibits its occurrence. Increased cutaneous production and/or release of the proinflammatory cytokines are probably one of the mechanisms by which
certain immunostimulatory compounds applied to or
injected into the skin [e.g., imiquimod, unmethylated
cytosinephosphateguanosine (CpG) oligonucleotides] accelerate LC migration. Another example is the
topical application of contact sensitizers (e.g., dinitrofluorobenzene), which leads to the activation of certain
protein tyrosine kinases, the modification of cellular
content and structure of intracytoplasmic organelles
(increase in coated pits and vesicles, endosomes and
lysosomes, Birbeck granules), and increased in situ
motility of these cells.302 Interestingly, Cumberbatch
et al303 reported that, in psoriasis, LCs are impaired in
their migratory capacity. This was somewhat unexpected in view of the remarkable overexpression of
TNF-a in psoriatic skin. These investigators also found
that the failure of TNF-a and/or IL-1b to induce LC
migration from uninvolved skin was not attributable
to an altered expression of receptors for these cytokines. An important hurdle for emigrating LCs is the
basement membrane. During their downward journey, LCs probably attach to it via a6-containing integrin receptors and produce proteolytic enzymes such
as type IV collagenase (MMP-9) to penetrate it and to
pave their way through the dense dermal network into
the lymphatic system. IL-16 also induces LC mobilization. This process could perhaps be operative in atopic
dermatitis. In this disease, DCs of lesional skin exhibit
surface IgE bound to high-affinity Fc receptors (FceRI),
and allergen-mediated receptor cross-linking results in
enhanced IL-16 production. Evidence is accumulating
that DC migration occurs in an active, directed fashion.
Osteopontin is a chemotactic protein that is essential in
this regard. It initiates LC emigration from the epidermis and attracts LCs to draining nodes by interacting
with an N-terminal epitope of the CD44 molecule.304
The entry into and active transport of cutaneous DCs
Chapter 10
population of human skin grafted onto a nude mouse

remains rather constant for the life of the graft, despite
epidermal proliferation and the absence of circulating
precursors for human LCs. Moreover, epidermal LCs in
mice whose bone marrow was lethally irradiated and
subsequently transplanted are only partially replaced
by LCs of donor origin,290 whereas DCs in other organs
are efficiently exchanged for donor DCs.238 Together,
these observations suggest that a precursor cell population resides in the dermis that is engaged constantly in
the self-renewal of the epidermal LC population under
noninflammatory conditions. The prime candidate LC
precursors are dermal CD14+/CD11c+ cells that have
the potential to differentiate in vitro into LCs in a TGFb1-dependent fashion.291
Under inflammatory conditions (e.g., UV radiation
exposure, graft-versus-host disease), an additional
pathway of epidermal LC recruitment becomes operative. In this situation, LC precursors enter the tissue,
and their progeny populate the epidermis in a fashion dependent on chemoattraction mediated by LCexpressed chemokine receptors CCR2 and CCR6,239
the ligands of which are secreted by endothelial cells
and keratinocytes. Thus, CCR6 and its ligand MIP3a/CCL20 may be essential for epidermal LC localization in vivo, as postulated previously in studies
of LCs differentiated from human progenitor cells in
vitro.108 The action of MIP-3a/CCL20 may be assisted
or replaced under noninflammatory situations by the
chemokine BRAK/CXCL14, which is constitutively
produced by keratinocytes.292 The differentiation stage
of the biologically relevant circulating LC precursors
entering inflamed skin in vivo remains to be resolved.
However, evidence exists that common myeloid progenitors, granulocytemacrophage progenitors, monocytes, and even common lymphoid progenitors can
give rise to the emergence of an epidermal LC population in experimental animals.293,294
Compelling evidence exists from in vitro and in
vivo studies that LCs play a pivotal role in the induction of adaptive immune responses against antigens
introduced into and/or generated in the skin (immunosurveillance). This is best illustrated by the early
observation that LC-containing, but not LC-depleted,
epidermal cell suspensions pulse-exposed to either
soluble protein antigens or haptens elicit a genetically restricted, antigen-specific, proliferative T cell
response.295 Inaba et al296 found that freshly isolated
LCs (immature LCs) can present soluble antigen to
primed MHC class II-restricted T cells but are only
weak stimulators of naive, allogeneic T cells. In contrast, LCs purified from epidermal cell suspensions
after a culture period of 72 hours or LCs purified from
freshly isolated murine epidermal cells and cultured
for 72 hours in the presence of GM-CSF and IL-1
(mature LC) are extremely potent stimulators of primary T cell-proliferative responses to alloantigens,296
soluble protein antigens,297 and haptens.297 Immature
LCs, however, far excel cytokine-activated LCs in their
capacity to take up and process native protein antigens.298 Accordingly, immature rather than mature
LCs express antigen uptake receptors. Mature LCs,
although fully capable of presenting preprocessed
123
within lymphatic vessels appears to be mediated by

MCPs binding to CCR2 and by secondary lymphoidorgan chemokine/CCL21 produced by lymphatic
endothelial cells of the dermis and binding to CCR7
on maturing LCs and DDCs.242,305 Interestingly, CCL21
expression is upregulated in irritant and allergic contact dermatitis, which implicates its regulated impact
on DC emigration from the skin.306
Section 4
::
Dermal Dendritic Cells. Like resident LCs

in the epidermis, dermal dendritic cells (DDCs) constitute another resident DC subpopulation in normal and
inflamed skin that is capable of activating the immune
system upon receipt of danger signals. Located primarily in the vicinity of the superficial vascular plexus,
DDCs have been identified by their surface expression of CD1b, CD1c (BDCA-1), CD11c, CD36, CD205,
MHCII, as well as the subunit A of the clotting proenzyme factor XIII (FXIIIa).307 They can be distinguished
from LCs by the absence of Langerin expression and
lack of Birbeck granules. Based on the positive reactivity
for FXIIIa, DDCs from dermal single-cell suspensions
were originally classified into at least three different
subsets: (1) CD1a/CD14 cells, (2) CD1a/CD14 cells,
and (3) CD1a/CD14+ cells. Many assays conducted
with DDCs during the past years revealed that they
possess functional features of both macrophages and
DCs, i.e., the capacity of efficient phagocytosis on the
one hand as well as antigen-presenting, migratory and
T-cell-stimulating capacities on the other hand.308,309
LC Versus DDC in Skin Immunity. (Fig. 10-8).
What is the function of LCs/DDCs in normal skin? Is there
a natural flux of LCs/DDCs to the regional lymph nodes?
If so, what are the consequences of such an occurrence?
Evidence exists that melanin granules captured in the
skin accumulate in the regional lymph nodes but not
in other tissues. The further observation of only very
few melanin granule-containing cells in TGF-b1/ mice
suggests that, under steady-state conditions, epidermal
and/or dermal antigens are carried to the regional lymph
nodes by TGF-b1-dependent cells (most likely LCs/
DDCs) only. It appears that T lymphocytes encountering
such APCs in vivo are rendered unresponsive in an
antigen-specific manner.259 It is therefore conceivable
that immature resident skin DC, i.e., LCs and DDCs, are
endowed with tolerogenic skills inhibiting inflammatory
T-cell responses in the steady state and, consequently, that
absence of pathogenic T-cell autoimmunity and/or lack
of reactivity against seemingly innocuous environmental
compounds (e.g., aeroallergens) in the periphery is
primarily the consequence of an active immune response
rather than the result of its nonoccurrence.
In the past few years, there has been a heavy debate
about the relative sensitizing capacity of LCs versus
DDCs in skin-derived immune responses. This discussion was initiated by seemingly controversial results
obtained with different types of LC-depleted mice
undergoing contact sensitization.
Inflammatory Dendritic Cells.309 DCs
124
appearing in inflamed skin can be subdivided into

two major subpopulations, i.e., (1) inflammatory den-
dritic epidermal/dermal cells (IDECs/IDDCs) and (2)

plasmacytoid dendritic cells (pDCs). The former ones
will be referred to as inflammatory dendritic skin cells
(IDSCs).
Inflammatory Dendritic Skin Cells (IDSC).
It is still unclear whether IDSCs represent a subpopulation of myeloid DCs which, upon danger stimuli, are
recruited to the sites of inflammation from the blood,
or whether indigenous DDCs are converted into specialized IDSCs that have the capacity to adapt their
function according to the kind of danger signal delivered. Supporting the idea of circulating DC precursors
infiltrating the skin upon danger signals, potential precursor cells including pre-DCs320,321 or hematopoietic
precursor cells234 have been identified.
Much work on the identification and characterization of epidermal and/or dermal inflammatory DC
populations in various skin diseases has lately been
provided by different groups.322325 In the dermis of
psoriatic lesions, the number of CD11c+ DCs is 30-fold
increased as compared to normal skin.325,326 In contrast to steady-state DDC, these dermal CD11c+ DCs
are CD1c, but produce a number of proinflammatory
cytokines (e.g., TNF-a. ) and inducible oxide synthetase
(iNOS) and were therefore termed TIP-DCs (TNF-a
and iNOS-producing DCs). Initially identified in 2003
in a murine model of Listeria monocytogenes infection,327
they have been located in the lamina propria of human
gut328 as well as in imiquimod-treated human basal cell
carcinoma.324 Imiquimod and the other imidazoquinolines as ligands of TLR7/8 induce strong inflammation
and, ultimately, regression of viral acanthomas and
other superficial skin neoplasms.329 Upon treatment,
TIP-DCs are abundantly present around regressing
tumor cell islands330 and, interestingly, can express
molecules of the lytic machinery such as perforin,
granzyme B, and TRAIL, suggesting their cytotoxic
potential. In psoriasis, TIP-DC have the capacity to
prime T cells to become Th1, Th17, and a mixture of
Th1/Th17 cells, which simultaneously produce IFN-g
and IL-17325 and may contribute to the pathogenesis of
the disease. In addition, their pathogenic role is indicated by downregulation of TNF-a, iNOS, and other
cytokines they produce, namely, IL-20 and IL-23, upon
effective psoriasis treatment.331 Recent work also identified TRAIL on CD11c+ CD1c TIP-DCs in psoriasis,
proposing a proinflammatory, cell-damaging interaction with keratinocytes that express activating TRAIL
receptors (death receptor 4 and decoy receptor 2).332
In the epidermis of atopic dermatitis (AD) skin, the
emergence of inflammatory dendritic epidermal cells
(IDECs) has been well documented.333 They are characterized by the expression of CD1a, CD1b, CD1c,
CD11c, FceRI, CD23, HLA-DR, CD11b, CD206 (MMR/
macrophage mannose receptor), and CD36.333,334 In
situ staining of costimulatory molecules on epidermal CD1a+ DC in AD skin showed that mainly cells
with the phenotype of IDEC display CD80 and CD86,
whereas Langerin+ CD1a+ epidermal LC are almost
devoid of these molecules.335 CD86 signaling is critical
for the stimulatory capacity of IDEC. Evidence exists
that, upon engagement of FceRI on IDEC, an immune
The mechanisms operative in the initiation, expression, and downregulation of skin-derived immune responses
Afferent phase
Efferent phase
Perturbation
Ag
Homeostasis
Ag
Danger signals
Ag
Cytokines
Ag
KC
Ag
LC
LC
Epidermis
LC
KC
Dermis
DDC
Anergic T cell
DDC
Ag
Naive T cells
Treg cell
TCR
Lymph node
Endothelial cells
Afferent lymphatic
vessel
Mature
LC/DDC
Naive T cells
Clonal expansion
Effector T cells
Figure 10-8 The mechanisms operative in the initiation, expression, and downregulation of skin-derived immune responses. Induction of T cell immunity via the skin: Antigens administered to or occurring in the skin (microbial products,
haptens, etc.) will be picked up, engulfed, processed and presented by dendritic antigen-presenting cells in the epidermis
(LC = Langerhans cells) and/or the dermis (DDC = dermal dendritic cells). When danger signals, particularly those reaching
beyond the dermalepidermal junction, are present at the time of antigenic exposure, these DC will undergo a process
of maturation as evidenced by an enhanced expression of MHC antigens, costimulatory molecules (CD80, CD86, CD40,
CD83, etc.), and immunostimulatory cytokines (IL-1b, IL-6, IL-12, IL-23) as well as their enhanced emigration from the skin
to the paracortical areas of the draining lymph nodes. At this site, the skin-derived DCs provide activation stimuli to the
naive resting T cells surrounding them. This occurs in an antigen-specific fashion and thus results in the expansion of the
respective clone(s). T cells thus primed begin to express skin-homing receptors (e.g., CLA) as well as receptors for various
chemoattractants that promote their attachment to dermal microvascular endothelial cells of inflamed skin and, ultimately, their entry into this tissue. Elicitation of T-cell-mediated tissue inflammation and pathogen clearance: on receipt
of a renewed antigenic stimulus by activated skin DCs or other APCs, the skin-homed T cells expand locally and display
the effector functions needed for the elimination of the pathogen. Downregulation and prevention of cutaneous T cell
immunity: In the absence of danger signals (tissue homeostasis), antigen-loaded skin DCs leave their habitat and migrate
toward the draining lymph node. These cells or, alternatively, resident lymph node DCs that had picked up antigenic
moieties from afferent lymphatics present this antigen in a nonproductive fashion, i.e., they induce antigen-specific T-cell
unresponsiveness or allow the responding T cell(s) to differentiate into immunosuppressive T regulatory cells. The latter
may limit antigen-driven clonal T-cell expansion during primary immune reactions in lymph nodes and during secondary immune reactions at the level of the peripheral tissue. Such events can result in the downregulation of both desired
(antitumor, antimicrobial) and undesired (hapten-specific, autoreactive) immune responses. Ag = antigen; T = T naive cell;
T* = anergic T cell; TCR = T-cell receptor; T reg = regulatory T cells; EM T cells = effector memory T cells.
response triggered by these cells is skewed into the

Th1 direction.336 Recent work also located a substantial
number of CD1a+ CD11c+ Langerin-DC within the dermis of AD lesions. Interestingly, these cells showed an
upregulation of the chemokines CCL17 and CCL18 and
can thereby provide a Th2 polarizing environment.323
Importantly, this subset of IDSC does not produce
Immature
LC/DDC
::
Cytokines
Chemokines
Chapter 10
DDC
iNOS or TNF-a, thus confirming the presence of different inflammatory DC subsets in different cutaneous
pathologies.
Plasmacytoid Dendritic Cells.337
pDCs are
DCs that are characterized by a highly developed
endoplasmic reticulum, which results in their plasma
125
cell-like appearance.338 Functionally, pDCs display

a unique ability to produce up to 1,000 times more
natural IFNs than any other blood mononuclear cell
in response to TLR ligands and thus were also named
principal type 1 IFN-producing cells.339
KEY REFERENCES
Section 4
::
3. Gasque P: Complement: A unique innate immune sensor

for danger signals. Mol Immunol 41:1089, 2004
5. Schauber J, Gallo RL: Antimicrobial peptides and the
skin immune defense system. J Allergy Clin Immunol
122:261, 2008
38. Akira S et al: Pathogen recognition and innate immunity.
Cell 124:783, 2006
75. Martinon F et al: The inflammasomes: Guardians of the
body. Annu Rev Immunol 27:229, 2009
117. von Boehmer H: Selection of the T-cell repertoire: Receptor-controlled checkpoints in T-cell development. Adv
Immunol 84:201, 2004
151. Surh CD, Sprent J: Homeostasis of naive and memory T
cells. Immunity 29:848, 2008
169. Korn T et al: IL-17 and Th17 cells. Annu Rev Immunol
27:485, 2009
Chapter 11 :: Cytokines

:: Ifor R. Williams & Thomas S. Kupper
CYTOKINES AT A GLANCE
Cytokines are polypeptide mediators
that function in communication between
hematopoietic cells and other cell types.
Cytokines often have multiple biologic
activities (pleiotropism) and overlapping
biologic effects (redundancy).
Primary cytokines, such as interleukin 1 and
tumor necrosis factor-, are sufficient on their
own to trigger leukocyte influx into tissue.
Most cytokines signal through either the
nuclear factor-B or the Jak/STAT signaling
pathways.
126
179. Bendelac A et al: The biology of NKT cells. Annu Rev Immunol 25:297, 2007
182. Shevach EM: Mechanisms of foxp3+ T regulatory cellmediated suppression. Immunity 30:636, 2009
186 Schaerli P et al: CXC chemokine receptor 5 expression
defines follicular homing T cells with B cell helper function. J Exp Med 192:1553, 2000
189. Sallusto F, Mackay CR: Chemoattractants and their receptors in homeostasis and inflammation. Curr Opin Immunol 16:724, 2004
207. Modlin RL et al: Learning from lesions: Patterns of tissue
inflammation in leprosy. Proc Natl Acad Sci U S A 85:1213,
1988
218. Hammer GE et al: The final touches make perfect the
peptide-MHC class I repertoire. Immunity 26:397, 2007
253. Matzinger P: An innate sense of danger. Ann N Y Acad
Sci 961:341, 2002
258. Steinman RM et al: Dendritic cell function in vivo during
the steady state: A role in peripheral tolerance. Ann N Y
Acad Sci 987:15, 2003
274 Seiffert K, Granstein RD: Neuroendocrine regulation of
skin dendritic cells. Ann N Y Acad Sci 1088:195, 2006
283. Romani N et al: Langerhans cells and more: Langerinexpressing dendritic cell subsets in the skin. Immunol Rev
234:120, 2010
309. Zaba LC et al: Resident and inflammatory dendritic
cells in human skin. J Invest Dermatol 129:302, 2009
337. Lande R, Gilliet M: Plasmacytoid dendritic cells: Key
players in the initiation and regulation of immune responses. Ann N Y Acad Sci 1183:89, 2010
Cytokine-based therapeutics now in

use include recombinant cytokines,
inhibitory monoclonal antibodies, fusion
proteins composed of cytokine receptors
and immunoglobulin chains, topical
immunomodulators such as imiquimod, and
cytokine fusion toxins.
THE CONCEPT OF CYTOKINES

When cells and tissues in complex organisms need
to communicate over distances greater than one cell
diameter, soluble factors must be employed. A subset
of these factors is most important when produced or
released transiently under emergent conditions. When
faced with an infection- or injury-related challenge, the
host must orchestrate a complex and carefully choreographed series of steps. It must mobilize certain circulating white blood cells precisely to the relevant injured
area (but not elsewhere) and guide other leukocytes
involved in host defense, particularly T and B cells, to
specialized lymphatic tissue remote from the infectious
lesion but sufficiently close to contain antigens from
the relevant pathogen. After a limited period of time
in this setting (i.e., lymph node), antibodies produced
by B cells and effector-memory T cells, can be released
into the circulation and will localize at the site of infection. Soluble factors produced by resident tissue cells
at the site of injury, by leukocytes and platelets that are
recruited to the site of injury, and by memory T cells
ultimately recruited to the area, all conspire to generate an evolving and effective response to a challenge to
host defense. Most important, the level of this response
must be appropriate to the challenge and the duration
A simple concept that continues to be extremely useful

for discussion of cytokine function is the concept of primary and secondary cytokines.6 Primary cytokines
are those cytokines that can, by themselves, initiate all
the events required to bring about leukocyte infiltration
in tissues. IL-1 (both and forms) and tumor necrosis
factor (TNF; includes both TNF- and TNF-) function
as primary cytokines, as do certain other cytokines that
signal through receptors that trigger the nuclear factor
B (NF-B) pathway. IL-1 and TNF are able to induce
cell adhesion molecule expression on endothelial cells
[selectins as well as immunoglobulin superfamily
members such as intercellular adhesion molecule 1
(ICAM-1) and vascular cellular adhesion molecule 1
(VCAM-1)], to stimulate a variety of cells to produce
a host of additional cytokines, and to induce expression of chemokines that provide a chemotactic gradient
allowing the directed migration of specific leukocyte
subsets into a site of inflammation (see Chapter 12).
Primary cytokines can be viewed as part of the innate
immune system (see Chapter 10), and in fact share signaling pathways with the so-called Toll-like receptors
(TLRs), a family of receptors that recognize molecular
patterns characteristically associated with microbial
products.7 Although other cytokines sometimes have
potent inflammatory activity, they do not duplicate this
full repertoire of activities. Many qualify as secondary
cytokines whose production is induced after stimulation by IL-1 and/or TNF family molecules. The term
secondary does not imply that they are less important or
less active than primary cytokines; rather, it indicates
that their spectrum of activity is more restricted.
Cytokines
The first cytokines described had distinct and easily

recognizable biological activities, exemplified by IL-1,
IL-2, and the interferons (IFNs). The term cytokine was
first coined by Cohen in 1975, to describe several such
PRIMARY AND SECONDARY

CYTOKINES
::
CLASSIFICATIONS OF CYTOKINES
activities released into the supernatant of an epithelial

cell line.2 Prior to this, such activities had been thought
to be the exclusive domain of lymphocytes (lymphokines) and monocytes (monokines) and were considered a function of the immune system. Keratinocyte
cytokines were first discovered in 1981,3 and the list of
cytokines produced by this epithelial cell rivals nearly
any other cell type in the body.4,5 The number of molecules that can be legitimately termed cytokines continues to expand and has brought under the cytokine
rubric molecules with a broad range of distinct biological activities. The progress in genomic approaches has
led to identification of novel cytokine genes based on
homologies to known cytokine genes. Making sense of
this plethora of mediators is more of a challenge than
ever, and strategies to simplify the analysis of the cytokine universe are sorely needed.
Chapter 11
of the response must be transient; that is, long enough

to decisively eliminate the pathogen, but short enough
to minimize damage to healthy host tissues. Much of
the cell-to-cell communication involved in the coordination of this response is accomplished by cytokines.
Cytokines (which include the large family of chemokines, discussed in Chapter 12) are soluble polypeptide
mediators that play pivotal roles in communication
between cells of the hematopoietic system and other
cells in the body.1 Cytokines influence many aspects of
leukocyte function including differentiation, growth,
activation, and migration. While many cytokines are
substantially upregulated in response to injury to allow
a rapid and potent host response, cytokines also play
important roles in the development of the immune system and in homeostatic control of the immune system
under basal conditions. The growth and differentiation effects of cytokines are not limited to leukocytes,
although we will not discuss soluble factors that principally mediate cell growth and differentiation of cells
other than leukocytes in this chapter. The participation
of cytokines in many parts of immune and inflammatory responses has prompted the examination of a variety of cytokines or cytokine antagonists (primarily antibodies and fusion proteins) as agents for pharmacologic
manipulation of immune-mediated diseases. Only a few
classes of effective cytokine drugs have emerged from
the lengthy pathway of clinical trials to achieve FDA
approval and widespread therapeutic use, but some of
these drugs are now valuable therapeutics in dermatology. This chapter discusses these approved drugs and
other promising biological agents still in clinical trials.
General features of cytokines are their pleiotropism
and redundancy. Before the advent of a systematic
nomenclature for cytokines, most newly identified
cytokines were named according to the biologic assay
that was being used to isolate and characterize the
active molecule (e.g., T-cell growth factor for the molecule that was later renamed interleukin 2, or IL-2). Very
often, independent groups studying quite disparate
bioactivities isolated the same molecule that revealed
the pleiotropic effects of these cytokines. For example,
before being termed interleukin 1 (IL-1), this cytokine
had been variously known as endogenous pyrogen, lymphocyte-activating factor, and leukocytic endogenous mediator. Many cytokines have a wide range of activities,
causing multiple effects in responsive cells and a different set of effects in each type of cell capable of responding. The redundancy of cytokines typically means that
in any single bioassay (such as induction of T-cell proliferation), multiple cytokines will display activity. In
addition, the absence of a single cytokine (such as in
mice with targeted mutations in cytokine genes) can
often be largely or even completely compensated for by
other cytokines with overlapping biologic effects.
T-CELL SUBSETS DISTINGUISHED

BY PATTERN OF CYTOKINE
PRODUCTION
Another valuable concept that has withstood the test
of time is the assignment of many T-cell-derived cytokines into groups based on the specific helper T-cell
127
IL-12
Section 4
::
128
IL-4
TGF-1
IL-23
IL-6
TGF-1
C
m yto
at ki
ur ne
e s
CD m
4 ade
T
ce by
lls
Development of CD4 helper T-cell subsets
U
na ndi
ive ffe
CD ren
4 tiat
T ed
ce
ll
Cy
CD to
4 kin
de es
ve in
lo flu
pm en
en cin
t g
Th1
IFN-,LT-
Th2
IL-4, IL-5, IL-13
Th17
IL-17
Treg
TGF-1, IL10
FoxP3
Figure 11-1 Cytokines control the development of specific CD4 helper T-cell subsets. The cytokine milieu at the
time of activation of naive undifferentiated CD4 T cells has
a profound influence on the ultimate pattern of cytokine
secretion adopted by fully differentiated T cells. Subsets
of effector CD4 T cells with defined patterns of cytokine
secretion include T helper 1 (Th1), Th2, and Th17 cells.
Regulatory CD4 T cells (Treg cells) express the FoxP3 transcription factor, and their effects are mediated in part by
their production of transforming growth factor-1 (TGF1) and/or interleukin 10 (IL-10). IFN = interferon; LT = lymphotoxin. (Adapted from Tato CM, OShea JJ: What does it
mean to be just 17? Nature 441:166, 2006.)
subsets that produce them (Fig. 11-1). The original two

helper T-cell subsets were termed Th1 and Th2.8 Commitment to one of these two patterns of cytokine secretion also occurs with CD8 cytotoxic T cells and / T
cells. Dominance of type 1 or type 2 cytokines in a T-cell
immune response has profound consequences for the
outcome of immune responses to certain pathogens
and extrinsic proteins capable of serving as allergens.
Over two decades after the original description of the
Th1 and Th2 subsets, strong evidence has emerged
that there are other functionally significant patterns of
cytokine secretion by T cells. Most prominent among
these newer T-cell lineages are Th17 cells and regulatory
T cells (or Treg cells for short). The Th17 subset is distinguished by production of a high level of IL-17, but
many Th17 cells also secrete IL-21 and IL-22. Th17 cells
promote inflammation, and there is consistent evidence from human autoimmune diseases and mouse
models of these diseases that IL-17-producing cells are
critical effectors in autoimmune disease.9 A subset of
T cells known as Treg cells has emerged as a crucial
subset involved in the maintenance of peripheral self-
tolerance.10 Two of the most distinctive features of Treg

cells are their expression of the FoxP3 transcription
factor and production of transforming growth factor-
(TGF-), a cytokine that appears to be required for Treg
cells to limit the excess activity of the proinflammatory
T-cell subsets.11 IL-10 is also a significant contributor
to the suppressive activity of Treg cells, particularly at
some mucosal interfaces.12 Additional proposed helper
T-cell subsets are follicular helper T cells (Tfh) that specialize in providing B cell help in germinal centers, Th9
cells distinguished by high levels of IL-9 production
that function in antiparasite immunity along with Th2
cells, and Th22 cells associated with skin inflammation that produce Th22, but not other Th17-associated
cytokines. Not only does each of these T-cell subsets
exhibit distinctive patterns of cytokine production,
cytokines are key factors in influencing the differentiation of naive T cells into these subsets. IL-12 is the key
Th1-promoting factor, IL-4 is required for Th2 differentiation, and IL-6, IL-23, and TGF- are involved in
promoting Th17 development.
STRUCTURAL CLASSIFICATION
OF CYTOKINES
Not all useful classifications of cytokines are based
solely on analysis of cytokine function. Structural
biologists, aided by improved methods of generating
homogenous preparations of proteins and establishment of new analytical methods (e.g., solution magnetic
resonance spectroscopy) that complement the classical
X-ray crystallography technique, have determined the
three-dimensional structure of many cytokines. These
efforts have led to the identification of groups of cytokines that fold to generate similar three-dimensional
structures and bind to groups of cytokine receptors
that also share similar structural features. For example,
most of the cytokine ligands that bind to receptors of the
hematopoietin cytokine receptor family are members of
the four-helix bundle group of proteins. Four-helix bundle proteins have a shared tertiary architecture consisting of four antiparallel -helical stretches separated by
short connecting loops. The normal existence of some
cytokines as oligomers rather than monomers was discovered in part as the result of structural investigations.
For example, interferon- (IFN-) is a four-helix bundle
cytokine that exists naturally as a noncovalent dimer.
The bivalency of the dimer enables this ligand to bind
and oligomerize two IFN- receptor complexes, thereby
facilitating signal transduction. TNF- and TNF- are
both trimers that are composed almost exclusively
of -sheets folded into a jelly roll structural motif.
Ligand-induced trimerization of receptors in the TNF
receptor family is involved in the initiation of signaling.
SIGNAL TRANSDUCTION
PATHWAYS SHARED BY CYTOKINES
To accomplish their effects, cytokines must first bind
with specificity and high affinity to receptors on the
cell surfaces of responding cells. Many aspects of the
TABLE 11-1
Major Families of Cytokine Receptors
IL-1R, type I
NF-B activation via TRAF6
TNF receptor family
TNFR1
NF-B activation involving TRAF2 and

TRAF5
Apoptosis induction via death domain
proteins
Hematopoietin receptor family (class I receptors)
IL-2R
Activation of Jak/STAT pathway
IFN/IL-10 receptor family (class II receptors)
IFN-R
Activation of Jak/STAT pathway
Immunoglobulin superfamily
M-CSF R
Activation of intrinsic tyrosine kinase
TGF- receptor family
TGF-R, types I and II
Activation of intrinsic serine/threonine

kinase coupled to Smad proteins
Chemokine receptor family
CCR5
Seven transmembrane receptors coupled

to G proteins
CCR = CC chemokine receptor; IFN = interferon; IL = interleukin; Jak = Janus kinase; M-CSF = macrophage colony-stimulating factor; NF-B =
nuclear factor B; STAT = signal transducer and activator of transcription; TGF = transforming growth factor; TNF = tumor necrosis factor;
TRAF = tumor necrosis factor receptor-associated factor.
pleiotropism and redundancy manifested by cytokines

can be understood through an appreciation of shared
mechanisms of signal transduction mediated by cell
surface receptors for cytokines. In the early years of
the cytokine biology era, the emphasis of most investigative work was the purification and eventual cloning
of new cytokines and a description of their functional
capabilities, both in vitro and in vivo. Most of the cytokine receptors have now been cloned, and many of the
signaling cascades initiated by cytokines have been
described in great detail. The vast majority of cytokine receptors can be classified into a relatively small
number of families and superfamilies (Table 11-1), the
members of which function in an approximately similar fashion. Table 11-2 lists the cytokines of particular
relevance for cutaneous biology, including the major
sources, responsive cells, features of interest, and clinical relevance of each cytokine. Most cytokines send
signals to cells through pathways that are very similar
to those used by other cytokines binding to the same
class of receptors. Individual cytokines often employ
several downstream pathways of signal transduction,
which accounts in part for the pleiotropic effects of
these molecules. Nevertheless, we propose here that
a few major signaling pathways account for most
effects attributable to cytokines. Of particularly central
importance are the NF-B pathway and the Jak/STAT
pathway, described in the following sections.
NUCLEAR FACTOR kB, INHIBITOR

OF kB, AND PRIMARY CYTOKINES
A major mechanism contributing to the extensive
overlap between the biologic activities of the primary
cytokines IL-1 and TNF is the shared use of the NF-B
signal transduction pathway. IL-1 and TNF use completely distinct cell surface receptor and proximal signaling pathways, but these pathways converge at the
activation of the NF-B transcription factor. NF-B is
of central importance in immune and inflammatory
processes because a large number of genes that elicit or
propagate inflammation have NF-B recognition sites
in their promoters.13 NF-B-regulated genes include
cytokines, chemokines, adhesion molecules, nitric oxide
synthase, cyclooxygenase, and phospholipase A2.
In unstimulated cells, NF-B heterodimers formed
from p65 and p50 subunits are inactive because they
are sequestered in the cytoplasm as a result of tight
binding to inhibitor proteins in the IB family (Fig.
11-2). Signal transduction pathways that activate the
NF-B system do so through the activation of an IB
kinase (IKK) complex consisting of two kinase subunits
(IKK and IKK) and a regulatory subunit (IKK).
The IKK complex phosphorylates IB and IB on
specific serine residues, yielding a target for recognition by an E3 ubiquitin ligase complex. The resulting
polyubiquitination marks this IB for rapid degradation by the 26S proteasome complex in the cytoplasm.
Once IB has been degraded, the free NF-B (which
contains a nuclear localization signal) is able to pass
into the nucleus and induce expression of NF-Bsensitive genes. The presence of B recognition sites in
cytokine promoters is very common. Among the genes
regulated by NF-B are IL-1 and TNF-a. This endows
IL-1b and TNF-a with the capacity to establish a positive regulatory loop that favors persistent inflammation. Cytokines besides IL-1 and TNF that activate the
NF-B pathway as part of their signal transduction
mechanisms include IL-17 and IL-18.
Proinflammatory cytokines are not the only stimuli
that can activate the NF-B pathway. Bacterial products
Cytokines
IL-1 receptor family
::
Example
Chapter 11
Receptor Family
Major Signal Transduction

Pathway(s) Leading to Biologic
Effects
129
TABLE 11-2
Cytokines of Particular Relevance for Cutaneous Biology
Section 4
Responsive Cells
Features of Interest
Clinical Relevance
IL-1
Epithelial cells
Infiltrating leukocytes
Active form stored in

keratinocytes
IL-1Ra used to treat

rheumatoid arthritis
IL-1
Myeloid cells
Caspase 1 cleavage required

for activation
IL-1Ra used to treat

IL-2
Activated T cells
Activated T cells, Treg cells
Autocrine factor for activated

T cells
IL-2 fusion toxin targets

CTCL
IL-4
Activated Th2 cells, NKT

cells
Lymphocytes, endothelial
cells, keratinocytes
Causes B-cell class switching

and Th2 differentiation
IL-5
Activated Th2 cells, mast

cells
B cells, eosinophils
Regulates eosinophil
response to parasites
Anti-IL-5 depletes
eosinophils
IL-6
Activated myeloid cells,

fibroblasts, endothelial
cells
B cells, myeloid cells,

hepatocytes
Triggers acute-phase
response, promotes
immunoglobulin synthesis
Anti-IL-6R used to treat

IL-10
T cells, NK cells
Myeloid and lymphoid cells
Inhibits innate and acquired

immune responses
IL-12
Activated APCs
Th1 cells
Promotes Th1 differentiation,

shares p40 subunit with IL-23
Anti-p40 inhibits
Crohns disease and
psoriasis
IL-13
Activated Th2 cells,

nuocytes
Monocytes, keratinocytes,
endothelial cells
Mediates tissue responses to

parasites
IL-17
Activated Th17 cells
Multiple cell types
Mediates autoimmune
diseases
Potential drug target in

autoimmune disease
IL-22
Activated Th17 cells and

Th22 cells
Keratinocytes
Induces cytokines and

antimicrobial peptides
Contributes to psoriasis
IL-23
Activated dendritic cells
Memory T cells, Th17 cells
Directs Th17 differentiation,

mediates autoimmune
disease
Anti-p40 inhibits
Crohns disease and
psoriasis
IL-25
Activated Th2 cells, mast

cells
Th17 cells
Promotes Th2 differentiation,

inhibits Th17 cells
IL-27
Activated APCs
Th1 cells
Promotes Th1 differentiation
IL-35
Treg cells
Th17 cells and Treg cells
Inhibits Th17 cells and

expands Treg cells
TNF-
Activated myeloid,
lymphoid, and epithelial
cells
Mediates inflammation
Anti-TNF- effective in
psoriasis
IFN- and
IFN-
Plasmacytoid dendritic
cells
Most cell types
Major part of innate antiviral

response
Elicited by topical
imiquimod application
IFN-
Activated Th1 cells, CD8

T cells, NK cells, dendritic
cells
Macrophages, dendritic cells,

naive T cells
Macrophage activation,
specific isotype switching
IFN- used to treat

chronic granulomatous
disease
TSLP
Epithelial cells including

keratinocytes
Dendritic cells, B cells, Th2

cells
Promotes Th2 differentiation
Involved in atopic
diseases
::
Cytokine Major Sources
APC = antigen-presenting cell; CTCL = cutaneous T-cell lymphoma; IFN = interferon; IL = interleukin; NK = natural killer; NKT = natural killer T
cell; Th = T helper; TNF = tumor necrosis factor; Treg = T regulatory; TSLP = thymic stromal lymphopoietin.
130
Activation of nuclear factor B (NF-B)
IL-1
TNF
1
Agonist binding
to cell surface
receptor
Receptor
3
Induction of IB
kinase activity
Cytoplasm
Phosphorylation and
ubiquitination of IB
IB
Ub
IB
IB
p65
::
NF-B
Nucleus
NF-B
NF-B release and

nuclear translocation
Gene
GGGRNNYYCC
B site
NF-B
Cytokines
NF-B complex
with IB
Degradation of IB
by 26S proteasome
Chapter 11
p50
Ub
Ub
Transcription of NF-Bresponsive genes
Figure 11-2 Activation of nuclear factor B (NF-B)-regulated genes after signaling by receptors for primary cytokines or
by Toll-like receptors (TLRs) engaged by microbial products. Under resting conditions, NF-B (a heterodimer of p50 and
p65 subunits) is tightly bound to an inhibitor called IB that sequesters NF-B in the cytoplasm. Engagement of one of
the TLRs or the signal transducing receptors for interleukin 1 (IL-1) or tumor necrosis factor (TNF) family members leads
to induction of IB kinase activity that phosphorylates IB on critical serine residues. Phosphorylated IB becomes a substrate for ubiquitination, which triggers degradation of IB by the 26S proteasome. Loss of IB results in release of NF-B,
which permits it to move to the nucleus and activate transcription of genes whose promoters contain B recognition sites.
Ub = ubiquitin.
(e.g., lipopolysaccharide, or LPS), oxidants, activators

of protein kinase C (e.g., phorbol esters), viruses, and
ultraviolet (UV) radiation are other stimuli that can
stimulate NF-B activity. TLR4 is a cell surface receptor for the complex of LPS, LPS-binding protein, and
CD14. The cytoplasmic domain of TLR4 is similar to
that of the IL-1 receptor type 1 (IL-1R1) and other IL-1R
family members and is known as the TIR domain (for
Toll/IL-1 receptor).14 When ligand is bound to a TIR
domain-containing receptor, one or more adapter proteins that also contain TIR domains are recruited to
the complex. MyD88 was the first of these adapters
to be identified; the other known adapters are TIRAP
(TIR domain-containing adapter protein), TRIF (TIR
domain-containing adapter inducing IFN-), and
TRAM (TRIF-related adapter molecule). Engagement
of the adapter, in turn, activates one or more of the

IL-1R-associated kinases (IRAK1 to IRAK4) that then
signal through TRAF6, a member of the TRAF (TNF
receptor-associated factor) family, and TAK1 (TGF-activated kinase) to activate the IKK complex.15
JAK/STAT PATHWAY
A major breakthrough in the analysis of cytokinemediated signal transduction was the identification
of a common cell surface to nucleus pathway used
by the majority of cytokines. This Jak/STAT pathway
was first elucidated through careful analysis of signaling initiated by IFN receptors (Fig. 11-3), but was
subsequently shown to play a role in signaling by all
131
Jak and STAT proteins in interferon- signaling
IFN-
Ligand binding
triggering receptor
oligomerization
Activation of tyrosine
phosphorylation by
Jak kinases
Section 4
::
132
Docking of SH2 domain

proteins including
specific STATs
STAT1 dimer
STAT phosphorylation,
dimerization, and
nuclear translocation
Jak1
Jak2
Y440
P
SH2
Stat1
Stat1
SH2 P
Y
P SH2
Y
Stat1
Nucleus
Figure 11-3 Participation of Jak (Janus kinase) and STAT

(signal transducer and activator of transcription) proteins
in interferon- (IFN-) signaling. Binding of human IFN-
(a dimer) to its receptor brings about oligomerization
of receptor complexes composed of and chains. The
nonreceptor protein tyrosine kinases Jak1 and Jak2 are
activated and phosphorylate critical tyrosine residues in
the receptor such as the tyrosine at position 440 of the
chain (Y440). STAT1 molecules are recruited to the IFN-
receptor based on the affinity of their Src homology 2
(SH2) domains for the phosphopeptide sequence around
Y440. Receptor-associated STAT1 molecules then dimerize
through reciprocal SH2-phosphotyrosine interactions. The
resulting STAT1 dimers translocate to the nucleus and
stimulate transcription of IFN--regulated genes.
cytokines that bind to members of the hematopoietin receptor family.16 The Jak/STAT pathway operates through the sequential action of a family of four
nonreceptor tyrosine kinases (the Jaks or Janus family
kinases) and a series of latent cytosolic transcription
factors known as STATs (signal transducers and activators of transcription). The cytoplasmic portions of
many cytokine receptor chains are noncovalently associated with one of the four Jaks [Jak1, Jak2, Jak3, and
tyrosine kinase 2 (Tyk2)].
The activity of the Jak kinases is upregulated after
stimulation of the cytokine receptor. Ligand binding
to the cytokine receptors leads to the association of
two or more distinct cytokine receptor subunits and
brings the associated Jak kinases into close proximity
with each other. This promotes cross-phosphorylation
or autophosphorylation reactions that in turn fully
activate the kinases. Tyrosines in the cytoplasmic tail
of the cytokine receptor as well as tyrosines on other
associated and newly recruited proteins are also phosphorylated. A subset of the newly phosphorylated
tyrosines can then serve as docking points for attachment of additional signaling proteins bearing Src
homology 2 (SH2) domains. Cytoplasmic STATs possess SH2 domains and are recruited to the phosphorylated cytokine receptors via this interaction. Homodimeric or heterodimeric STAT proteins are phosphorylated by the Jak kinases and subsequently translocate
to the nucleus. In the nucleus they bind recognition
sequences in DNA and stimulate transcription of specific genes, often in cooperation with other transcription factors. The same STAT molecules can be involved
in signaling by multiple different cytokines. The specificity of the response in these instances may depend on
the formation of complexes involving STATs and other
transcription factors that then selectively act on a specific set of genes.
INTERLEUKIN 1 FAMILY OF
CYTOKINES (INTERLEUKINS 1a, 1b,
18, 33)
IL-1 is the prototype of a cytokine that has been discovered many times in many different biologic assays.
Distinct genes encode the and forms of human
IL-1, with only 26% homology at the amino acid level.
Both IL-1s are translated as 31-kDa molecules that lack
a signal peptide, and both reside in the cytoplasm. This
form of IL-1 is biologically active, but 31-kDa IL-1b
must be cleaved by caspase 1 (initially termed interleukin-1b-converting enzyme) in a multiprotein cytoplasmic complex called the inflammasome to generate
an active molecule.17
In general, IL-1 appears to be the dominant form
of IL-1 produced by monocytes, macrophages, Langerhans cells, and dendritic cells, whereas IL-1 predominates in epithelial cells, including keratinocytes. This is
likely to relate to the fact that epithelial IL-1 is stored
in the cytoplasm of cells that comprise an interface with
the external environment. Such cells, when injured,
release biologically active 31-kDa IL-1 and, by doing
so, can initiate inflammation.6 However, if uninjured,
these cells will differentiate and ultimately release
their IL-1 contents into the environment. Leukocytes,
including dendritic and Langerhans cells, carry their
cargo of IL-1 inside the body, where its unregulated
release could cause significant tissue damage. Thus,
biologically active IL-1 release from cells is controlled
at several levels: IL-1 gene transcription, caspase 1 gene
transcription, and availability of the adapter proteins
that interact with caspase 1 in the inflammasome to
allow the generation of mature IL-1. IL-1 stimulates
the egress of Langerhans cells from the epidermis during the initiation of contact hypersensitivity, a pivotal
event that leads to accumulation of Langerhans cells in
skin-draining lymph nodes. Studies of mice deficient
in IL-1 and IL-1 genes suggest that both molecules
are important in contact hypersensitivity, but that
IL-1 is more critical.
Active forms of IL-1 bind to the IL-1R1 or type 1
IL-1 receptor.14 This is the sole signal-transducing
receptor for IL-1, and its cytoplasmic domain has
Cytokines
IL-1RAcP
IL-18R
IL-18RAcP
Toll-like receptor
family (TLR1-11)
IL-1R1
IL-1 receptor
family
::
cell types in skin, including keratinocytes, Langerhans

cells, and monocytes. IL-18 induces proliferation, cytotoxicity, and cytokine production by Th1 and natural
killer (NK) cells, mostly synergistically with IL-12.
The IL-18 receptor bears striking similarity to the IL-1
receptor.14 The binding chain (IL-18R) is an IL-1R1
homolog, originally cloned as IL-1Rrp1. IL-18R alone
is a low-affinity receptor that must recruit IL-18RAcP
(a homolog of IL-1RAcP). As for IL-1, both chains of
the IL-18 receptor are required for signal transduction.
Although there is no IL-18 homolog of IL-1ra, a molecule known as IL-18-binding protein binds to soluble
mature IL-18 and prevents it from binding to the IL18R complex.
More recently, it has become clear that there is a family of receptors homologous to the IL-1R1 and IL-18R
molecules,14 having in common a TIR motif (Fig. 11-4).
All of these share analogous signaling pathways initiated by the MyD88 adapter molecule. One of these
receptors, originally known as ST2, was initially characterized as a gene expressed by Th2 cells, but not by
Th1 cells. The description of a natural ligand for ST2
designated IL-33 has added a new member to the
IL-1 family that shares characteristic features of other
cytokines in the family, such as a requirement for
Chapter 11
little homology with other cytokine receptors, showing greatest homology with the Toll gene product identified in Drosophila. A second cell surface protein, the
IL-1R accessory protein, or IL-1RAcP, must associate
with IL-1R1 for signaling to occur. When IL-1 engages
the IL-1R1/IL-1RAcP complex, recruitment of the
MyD88 adapter occurs, followed by interactions with
one or more of the IRAKs. These kinases in turn associate with TRAF6. Stepwise activation and recruitment of
additional signaling molecules culminate in the induction of IKK activity. The net result is the activation of a
series of NF-B-regulated genes.
A molecule known as the IL-1 receptor antagonist, or
IL-1ra, can bind to IL-1R1 but does not induce signaling through the receptor. This IL-1ra exists in three
alternatively spliced forms, and an isoform produced
in monocytes is the only ligand for the IL-1R1 that
both contains a signal peptide and is secreted from
cells. Two other isoforms of IL-1ra, both lacking signal peptides, are contained within epithelial cells. The
function of IL-1ra seems to be as a pure antagonist of
IL-1 ligand binding to IL-1R1, and binding of IL-1ra to
IL-1R1 does not induce the mobilization of IL-1RAcP.
Consequently, although both IL-1/ and IL-1ra
bind with equivalent affinities to IL-1R1, the association of IL-1R1 with IL-1RAcP increases the affinity for
IL-1/ manyfold while not affecting the affinity for
IL-1ra. This is consistent with the observation that a
vast molar excess of IL-1ra is required to fully antagonize the effects of IL-1. The biologic role of IL-1ra is
likely to be in the quenching of IL-1-mediated inflammatory responses, and mice deficient in IL-1ra show
exaggerated and persistent inflammatory responses.
A second means of antagonizing IL-1 activity
occurs via expression of a second receptor for IL-1,
IL-1R2. This receptor has a short cytoplasmic domain
and serves to bind IL-1/ efficiently, but not IL-1ra.
This 68-kDa receptor can be cleaved from the cell surface by an unknown protease and released as a stable,
soluble 45-kDa molecule that retains avid IL-1-binding
function. By binding the functional ligands for IL-1R1,
IL-1R2 serves to inhibit IL-1-mediated responses. It is
likely that IL-1R2 also inhibits IL-1 activity by associating with IL-1RAcP at the cell surface and removing
and sequestering it from the pool available to associate with IL-1R1. Thus, soluble IL-1R2 binds to free
IL-1, whereas cell surface IL-1R2 sequesters IL-1RAcP.
Expression of IL-1R2 can be upregulated by a number
of stimuli, including corticosteroids and IL-4. However,
IL-1R2 can also be induced by inflammatory cytokines,
including IFN- and IL-1, probably as a compensatory
signal designed to limit the scale and duration of the
inflammatory response. Production of IL-1R2 serves to
make the producing cell and surrounding cells resistant to IL-1-mediated activation. Interestingly, some of
the most efficient IL-1-producing cells are also the best
producers of the IL-1R2.
IL-18 was first identified based on its capacity to
induce IFN-. One name initially proposed for this
cytokine was IL-1, because of its homology with IL-1
and IL-1. Like IL-1, it is translated as an inactive precursor molecule of 23 kDa and is cleaved to an active
18-kDa species by caspase 1. It is produced by multiple
TIR
TIR
TIR
TIR
Leucine rich
repeats
TIR
MyD88
MyD88
IRAK
IRAK
MyD88
IRAK
TRAF6
TRAF6
TRAF6
NF-B activation
Figure 11-4 The interleukin 1 receptor (IL-1R) family and

Toll-like receptors (TLRs) use a common intracellular signaling pathway. Receptors for cytokines in the IL-1 family
(typified by the IL-1 and IL-18 receptors) share a common
signaling domain with the TLRs (TLR1 to TLR11) called
the Toll/IL-1 receptor (TIR) domain. The TIR domain receptors interact with TIR domain-containing adapter proteins
such as MyD88 that couple ligand binding to activation of
IL-1R-associated kinase (IRAK) and ultimately activation
of nuclear factor B (NF-B). IL-1RAcP = IL-1R accessory
protein; TRAF = tumor necrosis factor receptor-associated
factor.
133
Section 4
::
processing by caspase 1 to release a mature form of

the ligand.18 IL-33 stimulation of Th2 cells promotes
their production of the characteristic Th2 cytokines
IL-4, IL-5, and IL-10.19 IL-1R1, IL-18R, IL-33R (ST2), the
TLRs, and their ligands are all best viewed as elements
of the innate immune system that signal the presence
of danger or injury to the host.
When IL-1 produced by epidermis was originally
identified, it was noted that both intact epidermis and
stratum corneum contained significant IL-1 activity,
which led to the concept that epidermis was a shield
of sequestered IL-1 surrounding the host, waiting to be
released on injury. More recently, it was observed that
high levels of the IL-1ra coexist within keratinocytes;
however, repeated experiments show that in virtually all cases, the amount of IL-1 present is sufficient
to overcome any potential for inhibition mediated by
IL-1ra. Studies have now shown that mechanical stress
to keratinocytes permits the release of large amounts
of IL-1 in the absence of cell death. Release of IL-1
induces expression of endothelial adhesion molecules,
including E-selectin, ICAM-1, and VCAM-1, as well as
chemotactic and activating chemokines. This attracts
not only monocytes and granulocytes but a specific
subpopulation of memory T cells that bear cutaneous
lymphocyte antigen on their cell surface. Memory T
cells positive for cutaneous lymphocyte antigen are
abundant in inflamed skin, comprising the majority
of T cells present. Therefore, any injury to the skin, no
matter how trivial, releases IL-1 and attracts this population of memory T cells. If they encounter their antigen in this microenvironment, their activation and subsequent cytokine production will amplify the inflammatory response. This has been proposed as the basis
of the clinical observation of inflammation in response
to trauma, known as the Koebner reaction.
Several biologics that act by inhibiting IL-1 function have been developed for clinical use including
recombinant IL-1Ra (anakinra), antibody to IL-1
(canakinumab), and an IgG Fc fusion protein that
includes the ligand binding domains of the type I
IL-1R and IL-1RAcP (rilonacept, also known as IL-1
Trap). All of these agents are efficacious in countering the IL-1-induced inflammation associated with a
group of rare autoinflammatory diseases called the
cryopyrin-associated periodic syndromes (CAPS).
Anakinra was initially US Food and Drug Administration (FDA) approved as a therapy for adult rheumatoid arthritis. IL-1 inhibition is also being tested as a
therapy for gout, an inflammatory arthritis triggered
by uric acid-mediated activation of inflammasomes
that generate IL-1.
TUMOR NECROSIS FACTOR: THE

OTHER PRIMARY CYTOKINE
134
TNF- is the prototype for a family of related signaling

molecules that mediate their biologic effects through a
family of related receptor molecules. TNF- was initially cloned on the basis of its ability to mediate two
interesting biologic effects: (1) hemorrhagic necrosis
of malignant tumors, and (2) inflammation-associated
cachexia. Although TNF- exerts many of its biologically important effects as a soluble mediator, newly
synthesized TNF- exists as a transmembrane protein
on the cell surface. A specific metalloproteinase known
as TNF--converting enzyme (TACE) is responsible
for most TNF- release by T cells and myeloid cells.
The closest cousin of TNF- is TNF-, also known as
lymphotoxin (LT-). Other related molecules in the
TNF family include lymphotoxin (LT-) that combines with LT- to form the LT-12 heterotrimer; Fas
ligand (FasL); TNF-related apoptosis-inducing ligand
(TRAIL); receptor activator of NF-B ligand (RANKL);
and CD40 ligand (CD154). Although some of these
other TNF family members have not been traditionally
regarded as cytokines, their structure (all are type II
membrane proteins with an intracellular N-terminus
and an extracellular C-terminus) and signaling mechanisms are closely related to those of TNF. The soluble
forms of TNF-, LT-, and FasL are homotrimers, and
the predominant form of LT- is the membrane-bound
LT-12 heterotrimer. Trimerization of TNF receptor
family members by their trimeric ligands appears to
be required for initiation of signaling and expression
of biologic activity.
The initial characterization of TNF receptors led
to the discovery of two receptor proteins capable of
binding TNF- with high affinity. The p55 receptor for
TNF (TNFR1) is responsible for most biologic activities of TNF, but the p75 TNF receptor (TNFR2) is also
capable of transducing signals (unlike IL-1R2, which
acts solely as a biologic sink for IL-1). TNFR1 and
TNFR2 have substantial stretches of close homology
and are both present on most types of cells. Nevertheless, there are some notable differences between the
two TNFRs.
Unlike cytokine receptors from several of the other
large families, TNF signaling does not involve the Jak/
STAT pathway. TNF- evokes two types of responses
in cells: (1) proinflammatory effects, and (2) induction
of apoptotic cell death (Fig. 11-5). The proinflammatory
effects of TNF- that include upregulation of adhesion molecule expression and induction of secondary
cytokines and chemokines, stem in large part from
activation of NF-B and can be transduced through
both TNFR1 and TNFR2. Induction of apoptosis by
signaling through TNFR1 depends on a region known
as a death domain that is absent in TNFR2, as well as
interactions with additional proteins with death
domains within the TNFR1 signaling complex. Signaling initiated by ligand binding to TNFR1, Fas, or other
death domain-containing receptors in the TNF family
eventually leads to activation of caspase 8 or 10 and the
nuclear changes and DNA fragmentation characteristic of apoptosis.
At least two TNFR family members (TNFR1 and the
LT- receptor) also contribute to the normal anatomic
development of the lymphoid system. Mice deficient
in TNF- lack germinal centers and follicular dendritic
cells. TNFR1 mutant mice show the same abnormalities plus an absence of Peyers patches. Mice with null
mutations in LT- or LT- have further abnormalities
in lymphoid organogenesis and fail to develop peripheral lymph nodes.
Contrasting outcomes of signaling through

tumor necrosis factor receptor 1(TNFR1)
TNF-
D.D.
D.D.
D.D.
D.D.
D.D.
D.D.
FADD
D.D.
TNFR1
TRAF
D.E.D.
D.E.D.
RING
TRAF2
NF-B activation
Figure 11-5 Two contrasting outcomes of signaling

through tumor necrosis factor receptor 1 (TNFR1). Engagement of TNFR1 by trimeric tumor necrosis factor- (TNF-)
can trigger apoptosis and/or nuclear factor B (NF-B) activation. Both processes involve the adapter protein TNFRassociated death domain (TRADD), which associates with
TNFR1 via interactions between death domains (D.D.)
on both proteins. For NF-B activation, TNFR-associated
factor 2 (TRAF2) and receptor-interacting protein (RIP) are
required. Induction of apoptosis occurs when the death
domain-containing protein Fas-associated death domain
protein (FADD) associates with TRADD. FADD also contains a death effector domain (D.E.D.) that interacts with
caspase 8 to initiate the apoptotic process. Cys = cysteine. (Adapted from Yuan J: Transducing signals of life and
death. Curr Opin Cell Biol 9:247, 1997; and Nagata S: Apoptosis by death factor. Cell 88:355, 1997.)
TNF- is an important mediator of cutaneous

inflammation, and its expression is induced in the
course of almost all inflammatory responses in skin.
Normal human keratinocytes and keratinocyte cell
lines produce substantial amounts of TNF- after
stimulation with LPS or UV light. Cutaneous inflammation stimulated by irritants and contact sensitizers
is associated with strong induction of TNF- production by keratinocytes. Exposure to TNF- promotes
Langerhans cell migration to draining lymph nodes,
allowing for sensitization of naive T cells. One molecular mechanism that may contribute to TNF--induced
migration of Langerhans cells toward lymph nodes
is reduced expression of the E-cadherin adhesion
molecule after exposure to TNF-. Induction of CC
chemokine receptor 7 on both epidermal and dermal
antigen-presenting cells correlates with movement
Cytokines
Cys protease
TRADD
::
Apoptosis
TRADD
Chapter 11
Caspase-8
D.E.D.
RIP
Kinase
into the draining lymphatics. The predominant TNFR

expressed by keratinocytes is TNFR1. Autocrine signaling loops involving keratinocyte-derived TNF-
and TNFR1 lead to keratinocyte production of a variety of TNF-inducible secondary cytokines.
The central role of TNF- in inflammatory diseases,
including rheumatoid arthritis and psoriasis, has
become evident from clinical studies. Clinical drugs that
target the TNF pathway include the humanized antiTNF- antibody infliximab, the fully human anti-TNF-
antibody adalumimab, and the soluble TNF receptor
etanercept. Drugs in this class are FDA approved for the
treatment of several autoimmune and inflammatory diseases, including Crohns disease and rheumatoid arthritis. These three anti-TNF drugs are also FDA approved
for the treatment of psoriasis and psoriatic arthritis (see
Chapter 234). This class of drugs also has the potential
to be valuable in the treatment of other inflammatory
dermatoses. Paradoxically, they are not effective against
all autoimmune diseasesmultiple sclerosis appears
to worsen slightly after treatment with these agents.
The TNF antagonists are powerful immunomodulating
drugs, and appropriate caution is required in their use.
Cases of cutaneous T-cell lymphoma initially thought
to represent psoriasis have rapidly progressed to fulminant disease after treatment with TNF antagonists. TNF
antagonists can also allow the escape of latent mycobacterial infections from immune control, with a potentially
lethal outcome for the patient.
IL-17 FAMILY OF CYTOKINES

IL-17 (also known as IL-17A) was the first described
member of a family of related cytokines that now
includes IL-17B through F. IL-17A and IL-17F have
similar proinflammatory activities, bind to the same
heterodimeric receptor composed of the IL-17RA and
IL-17RC receptor chains, and act to promote recruitment of neutrophils and induce production of antimicrobial peptides. These IL-17 species normally
function in immune defense against pathogenic species of extracellular bacteria and fungi. Signaling by
IL-17A and IL-17F depends on STAT3; mutations in
STAT3 associated with the hyper-IgE syndrome block
IL-17 signaling and lead to recurrent skin infections
with Staphylococcus aureus and Candida albicans. Less is
currently known about the actions of IL-17B, C, and
D. IL-17E, also known as IL-25, is a product of Th2
cells and mast cells that signals through IL-17RB. A
total of five receptor chains for IL-17 family cytokines
have been identified, but how each of these individual
receptor chains associates to form receptors for all the
members of the IL-17 family remains to be worked out.
These IL-17 receptor chains are homologous to each
other, but display very limited regions of homology to
the other major families of cytokine receptors. Recent
expansion of interest in Th17 cells and the entire
IL-17 family is closely linked to observations that the
immunopathology of autoimmune disease in human
patients and mouse models is often associated with an
inappropriate expansion of Th17 cells. Thus, the cytokines produced by Th17 cells and the receptors that
135
transduce these signals may turn out to be useful targets for therapies designed to dampen autoimmunity.
LIGANDS OF THE CLASS I

(HEMATOPOIETIN RECEPTOR)
FAMILY OF CYTOKINE RECEPTORS
Section 4
::
136
The hematopoietin receptor family (also known as

the class I cytokine receptor family) is the largest of the
cytokine receptor families and comprises a number of structurally related type I membrane-bound
glycoproteins. The cytoplasmic domains of these
receptors associate with nonreceptor tyrosine kinase
molecules, including the Jak kinases and src family
kinases. After ligand binding and receptor oligomerization, these associated nonreceptor tyrosine kinases
phosphorylate intracellular substrates, which leads to
signal transduction. Most of the multiple-chain receptors in the hematopoietin receptor family consist of a
cytokine-specific chain subunit paired with one or
more shared receptor subunits. Five shared receptor
subunits have been described to date: (1) the common
chain (c), (2) the common chain shared between the
IL-2 and IL-15 receptors; (3) a distinct common chain
shared between the granulocyte-macrophage colony
stimulating factor (GM-CSF), IL-3, and IL-5 receptors;
(4) the IL-12R2 chain shared by the IL-12 and IL-23
receptors; and (5) finally the glycoprotein 130 (gp130)
molecule, which participates in signaling by IL-6 and
related cytokines.
CYTOKINES WITH RECEPTORS THAT

INCLUDE THE gc CHAIN
The receptor complexes using the c chain are the
IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, and IL-21 receptors.
Two of these receptors, IL-2R and IL-15R, also use the
IL-2Rc chain. The c chain is physically associated
with Jak3, and activation of Jak3 is critical to most
signaling initiated through this subset of cytokine
receptors.20
INTERLEUKIN 2 AND INTERLEUKIN 15. IL-2

and IL-15 can each activate NK cells and stimulate
proliferation of activated T cells. IL-2 is a product
of activated T cells, and IL-2R is largely restricted
to lymphoid cells. The IL-15 gene is expressed by
nonlymphoid tissues, and its transcription is induced
by UVB radiation in keratinocytes and fibroblasts and
by LPS in monocytes and dendritic cells. Multiple
isoforms of IL-15R are found in various hematopoietic
and nonhematopoietic cells. The IL-2R and IL-15R
complexes of lymphocytes incorporate up to three
receptor chains, whereas most other cytokine receptor
complexes have two. The affinities of IL-2R and IL-15R
for their respective ligands can be regulated, and to
some extent, IL-2 and IL-15 compete with each other.
The highest affinity receptor complexes for each ligand
(approximately 1011 M) consist of the IL-2Rc and c
chains, as well as their respective chains (IL-2R,
also known as CD25, and IL-15R). c and IL-2Rc

without the chains form a functional lower affinity
receptor for either ligand (108 to 1010 M). Although
both ligands transmit signals through the c chain,
those signals elicit overlapping but distinct responses
in various cells. Activation of naive CD4 T cells by
T-cell receptor and costimulatory molecules induces
expression of IL-2, IL-2R, and IL-2Rc, which leads to
vigorous proliferation. Prolonged stimulation of T-cell
receptor and IL-2R leads to expression of FasL and
activation-induced cell death. Although IL-2 signaling
facilitates the death of CD4 T cells in response to
sustained exposure to antigen, IL-15 inhibits IL-2mediated activation-induced cell death as it stimulates
growth. Similarly, IL-15 promotes proliferation of
memory CD8 T cells, whereas IL-2 inhibits it. IL-15 is
also involved in the homeostatic survival of memory
CD8 T cells, NK cells, and NK T cells. These contrasting
biologic roles are illustrated by mice deficient in IL-2 or
IL-2R that develop autoimmune disorders, and mice
deficient in IL-15 or IL-15R, which have lymphopenia
and immune deficiencies. Thus, IL-15 appears to have
an important role in promoting effector functions of
antigen-specific T cells, whereas IL-2 is involved in
reining in autoreactive T cells.21
INTERLEUKIN 4 AND INTERLEUKIN 13. IL-4

and IL-13 are products of activated Th2 cells that
share limited structural homology (approximately
30%) and overlapping but distinct biologic activities.
A specific receptor for IL-4, which does not bind IL13, is found on T cells and NK cells. It consists of IL4R (CD124) and c and transmits signals via Jak1 and
Jak3. A second receptor complex that can bind either
IL-4 or IL-13 is found on keratinocytes, endothelial
cells, and other nonhematopoietic cells. It consists of
IL-13R1 and IL-4R and transmits signals via Jak1
and Jak2. These receptors are expressed at low levels
in resting cells, and their expression is increased by
various activating signals. Curiously, exposure of
monocytes to IL-4 or IL-13 suppresses expression of
IL-4R and IL-13R1, whereas the opposite effect is
observed in keratinocytes. Both signal transduction
pathways appear to converge with the activation of
STAT6, which is both necessary and sufficient to drive
Th2 differentiation. IL-13R2 is a cell surface receptor
homologous to IL-13R1 that specifically binds to IL13 but is not known to transmit any signals.20
The biologic effects of engagement of the IL-4 receptor vary depending on the specific cell type, but most
pertain to its principal role as a growth and differentiation factor for Th2 cells. Exposure of naive T cells
to IL-4 stimulates them to proliferate and differentiate into Th2 cells, which produce more IL-4, which
in turn leads to autocrine stimulation that prolongs
Th2 responses. Thus the expression of IL-4 early in
the immune response can initiate a cascade of Th2
cell development that results in a predominately
Th2 response. The genes encoding IL-4 and IL-13 are
located in a cluster with IL-5 that undergoes structural
changes during Th2 differentiation that are associated with increased expression. Although naive T
cells can make low levels of IL-4 when activated, IL-4
is also produced by activated NK T cells. Mast cells

and basophils also release preformed IL-4 from secretory granules in response to FcRI-mediated signals.
A prominent activity of IL-4 is the stimulation of class
switching of the immunoglobulin genes of B cells.
Nuocytes and natural helper cells are recently identified populations of innate immune effector cells that
provide an early source of IL-13 during helminth infection. As critical factors in Th2 differentiation and effector function, IL-4 and IL-13 are mediators of atopic
immunity. In addition to controlling the behavior of
effector cells they also act directly on resident tissue
cells, such as in inflammatory airway reactions.22
that could act as a growth factor for B- and T-lineage

cells. The TSLP receptor consists of the IL-7R and a
second receptor chain (TSLPR) homologous to but
distinct from the c chain. TSLP has attracted interest
because of its ability to prime dendritic cells to become
stronger stimulators of Th2 cells. This activity may
permit TSLP to foster the development of some types
of allergic diseases.26,27
INTERLEUKIN 9 AND INTERLEUKIN 21. IL-9 is
The receptors for IL-3, IL-5, and GM-CSF consist of

unique cytokine-specific chains paired with a common chain known as IL-3R or c (CD131). Each of
these factors acts on subsets of early hematopoietic
cells.28 IL-3, which was previously known as multilineage colony-stimulating factor, is principally a product
of CD4+ T cells and causes proliferation, differentiation, and colony formation of various myeloid cells
from bone marrow. IL-5 is a product of Th2 CD4+ cells
and activated mast cells that conveys signals to B cells
and eosinophils. IL-5 has a costimulatory effect on B
cells in that it enhances their proliferation and immunoglobulin expression when they encounter their
cognate antigen. In conjunction with an eosinophilattracting chemokine known as CC chemokine ligand 11
or eotaxin, IL-5 plays a central role in the accumulation
of eosinophils that accompanies parasitic infections
and some cutaneous inflammatory processes. IL-5
appears to be required to generate a pool of eosinophil
precursors in bone marrow that can be rapidly mobilized to the blood, whereas eotaxins role is focused
on recruitment of these eosinophils from blood into
specific tissue sites. GM-CSF is a growth factor for
myeloid progenitors produced by activated T cells,
phagocytes, keratinocytes, fibroblasts, and vascular
endothelial cells. In addition to its role in early hematopoiesis, GM-CSF has potent effects on macrophages
and dendritic cells. In vitro culture of fresh Langerhans cells in the presence of GM-CSF promotes their
transformation into mature dendritic cells with maximal immunostimulatory potential for naive T cells.
The effects of GM-CSF on dendritic cells probably
account for the dramatic ability of GM-CSF to evoke
therapeutic antitumor immunity when tumor cells are
engineered to express it.29,30
Cytokines
function of IL-7, IL-7R (CD127), c, or Jak3 in mice

or humans cause profound immunodeficiency as a
result of T- and NK-cell depletion.20 This is principally
due to the indispensable role of IL-7 in promoting
the expansion of lymphocytes and regulating the
rearrangement of their antigen receptor genes. IL-7
is a potent mitogen and survival factor for immature
lymphocytes in the bone marrow and thymus. The
second function of IL-7 is as a modifier of effector
cell functions in the reactive phase of certain immune
responses. IL-7 transmits activating signals to mature
T cells and certain activated B cells. Like IL-2, IL-7 has
been shown to stimulate proliferation of cytolytic T
cells and lymphokine-activated killer cells in vitro and
to enhance their activities in vivo. IL-7 is a particularly
significant cytokine for lymphocytes in the skin and
other epithelial tissues. It is expressed by keratinocytes
in a regulated fashion, and this expression is thought
to be part of a reciprocal signaling dialog between
dendritic epidermal T cells and keratinocytes in
murine skin. Keratinocytes release IL-7 in response to
IFN-, and dendritic epidermal T cells secrete IFN- in
response to IL-7.
An IL-7-related cytokine using one chain of the IL-7
receptor as part of its receptor is thymic stromal lymphopoietin (TSLP). TSLP was originally identified as a
novel cytokine produced by a thymic stromal cell line
::
INTERLEUKIN 7 AND THYMIC STROMAL

LYMPHOPOIETIN. Mutations abrogating the
CYTOKINES WITH RECEPTORS

USING THE INTERLEUKIN 3
RECEPTOR b CHAIN
Chapter 11
a product of activated Th2 cells exposed to TGF- that

acts as an autocrine growth factor as well as a mediator
of inflammation.23 It is also produced by mast cells
in response to IL-10 or stem cell factor. It stimulates
proliferation of T and B cells and promotes expression
of immunoglobulin E by B cells. It also exerts
proinflammatory effects on mast cells and eosinophils.
IL-9-deficient mice exhibit deficits in mast cell and
goblet cell differentiation. IL-9 can be grouped with
IL-4 and IL-13 as cytokines that function as effectors
of allergic inflammatory processes and may play an
important role in asthma and allergic disorders. IL21 is also a product made by the Th2, Th17, and Tfh
lineages that signals through a receptor composed of
a specific chain (IL-21R) homologous to the IL-4R
chain and c.24 Absence of an intact IL-21 receptor is
associated with impaired Th2 responses.25
INTERLEUKIN 6 AND OTHER

CYTOKINES WITH RECEPTORS
USING GLYCOPROTEIN 130
Receptors for a group of cytokines including IL-6,
IL-11, IL-27, leukemia inhibitory factor, oncostatin M,
ciliary neurotrophic factor, and cardiotrophin-1 interact with a hematopoietin receptor family member,
gp130, which does not appear to interact with any
ligand by itself. The gp130 molecule is recruited into
signaling complexes with other receptor chains when
they engage their cognate ligands.
137
Section 4
::
IL-6 is the most thoroughly characterized of the

cytokines that use gp130 for signaling and serves as
a paradigm for discussion of the biologic effects of
this family of cytokines. IL-6 is yet another example
of a highly pleiotropic cytokine with multiple effects.
A series of different names (including IFN-2, B-cell
stimulatory factor 2, plasmacytoma growth factor, cytotoxic
T cell differentiation factor, and hepatocyte-stimulating factor) were used for IL-6 before it was recognized that a
single molecular species accounts for all of these activities. IL-6 acts on a wide variety of cells of hematopoietic origin. IL-6 stimulates immunoglobulin secretion
by B cells and has mitogenic effects on B lineage cells
and plasmacytomas. IL-6 also promotes maturation of
megakaryocytes and differentiation of myeloid cells.
Not only does it participate in hematopoietic development and reactive immune responses, but IL-6 is also a
central mediator of the systemic acute-phase response.
Increases in circulating IL-6 levels stimulate hepatocytes to synthesize and release acute-phase proteins.
There are two distinct signal transduction pathways
triggered by IL-6. The first of these is mediated by the
gp130 molecule when it dimerizes on engagement by
the complex of IL-6 and IL-6R. Homodimerization
of gp130 and its associated Jak kinases (Jak1, Jak2,
Tyk2) leads to activation of STAT3. A second pathway
of gp130 signal transduction involves Ras and the
mitogen-activated protein kinase cascade and results
in phosphorylation and activation of a transcription
factor originally designated nuclear factor of IL-6.
IL-6 is an important cytokine for skin and is subject
to dysregulation in several human diseases, including
some with skin manifestations. IL-6 is produced in a
regulated fashion by keratinocytes, fibroblasts, and
vascular endothelial cells as well as by leukocytes infiltrating the skin. IL-6 can stimulate the proliferation of
human keratinocytes under some conditions. Psoriasis
is one of several inflammatory skin diseases in which
elevated expression of IL-6 has been described. Human
herpesvirus 8 produces a viral homolog of IL-6 that
may be involved in the pathogenesis of human herpes
virus-8-associated diseases, including Kaposi sarcoma
and body cavity-based lymphomas.
The other cytokines using gp130 as a signal transducer have diverse bioactivities. IL-11 inhibits production of inflammatory cytokines and has shown some
therapeutic activity in patients with psoriasis. Exogenous IL-11 also stimulates platelet production and has
been used to treat thrombocytopenia occurring after
chemotherapy. IL-27 is discussed in the next section
with the IL-12 family of cytokines.
INTERLEUKIN 12, INTERLEUKIN 23,

INTERLEUKIN 27, AND INTERLEUKIN
35: PIVOTAL CYTOKINES REGULATING
T HELPER 1 AND T HELPER 17
RESPONSES
138
IL-12 is different from most other cytokines in that

its active form is a heterodimer of two proteins, p35
and p40. IL-12 is principally a product of antigen-
presenting cells such as dendritic cells, monocytes,

macrophages, and certain B cells in response to bacterial components, GM-CSF, and IFN-. Activated
keratinocytes are an additional source of IL-12 in skin.
Human keratinocytes constitutively make the p35
subunit, whereas expression of the p40 subunit can be
induced by stimuli including contact allergens, phorbol esters, and UV radiation.
IL-12 is a critical immunoregulatory cytokine that
is central to the initiation and maintenance of Th1
responses. Th1 responses that are dependent on IL-12
provide protective immunity to intracellular bacterial
pathogens. IL-12 also has stimulatory effects on NK
cells, promoting their proliferation, cytotoxic function,
and the production of cytokines, including IFN-. IL-12
has been shown to be active in stimulating protective
antitumor immunity in a number of animal models.31
Two chains that are part of the cell surface receptor for IL-12 have been cloned. Both are homologous
to other chains in the hematopoietin receptor family
and are designated 1 and 2. The 1 chain is associated with Tyk2 and the 2 chain interacts directly with
Jak2. The signaling component of the IL-12R is the 2
chain. The 2 chain is expressed in Th1 but not Th2
cells and appears to be critical for commitment of T
cells to production of type 1 cytokines. IL-12 signaling
induces the phosphorylation of STAT1, STAT3, and
STAT4, but it is STAT4 that is essential for induction of
a Th1 response.
IL-23 is a heterodimeric cytokine in the IL-12 family that consists of the p40 chain of IL-12 in association with a distinct p19 chain. IL-23 has overlapping
activities with IL-12, but also induces proliferation of
memory T cells. Interest in IL-23 has been sparked by
the observation that IL-23 promotes the differentiation of T cells producing IL-17 (Th17 subset). The IL-23
receptor consists of two chains: (1) the IL-12R1 chain
that forms part of the IL-12 receptor and (2) a specific
IL-23 receptor.32
The third member of the IL-12 family to be discovered was IL-27. IL-27 is also a heterodimer and consists
of a subunit called p28 that is homologous to IL-12 p35
and a second subunit known as EBI3 that is homologous to IL-12 p40. IL-27 plays a role in the early induction of the Th1 response. The IL-27 receptor consists of
a receptor called WSX-1 that associates with the shared
signal-transducing molecule gp130.32,33
The newest member of the IL-12 family is IL-35. The
IL-35 heterodimer is composed of the p35 chain of
IL-12 associated with the IL-27 chain EBI3. In contrast
to the other IL-12 family cytokines, IL-35 is selectively
made by Treg cells, promotes the growth of Treg cells,
and suppresses the activity of Th17 cells.34
The IL-12 family of cytokines has emerged as a
promising new target for anticytokine pharmacotherapy. The approach that has been developed the
furthest to date is targeting both IL-12 and IL-23 with
monoclonal antibodies directed against the p40 subunit that is part of both cytokines. Ustekinumab is an
antihuman p40 monoclonal antibody that has shown
therapeutic activity against psoriasis comparable to
that of TNF inhibitors and has received FDA approval
for the treatment of psoriasis.35 The development of
anti-p40 therapies is several years behind anti-TNF-

drugs, but development of additional anti-p40 biologics for clinical use is anticipated.
LIGANDS OF THE CLASS II FAMILY

OF CYTOKINE RECEPTORS
A second major class of cytokine receptors with common features includes two types of receptors for IFNs,
IL-10R, and the receptors for additional IL-10- related
cytokines including IL-19, IL-20, IL-22, IL-24, and
IL-26.
::
Cytokines
IFNs were one of the first families of cytokines to be

characterized in detail. The IFNs were initially subdivided into three classes: (1) IFN- (the leukocyte IFNs),
(2) IFN- (fibroblast IFN), and (3) IFN- (immune IFN).
The and IFNs are collectively called type I IFNs,
and all of these molecules signal through the same
two-chain receptor (the IFN- receptor).36 The second
IFN receptor is a distinct two-chain receptor specific
for IFN-. Both of these IFN receptors are present on
many cell types within skin as well as in other tissues.
Each of the chains comprising the two IFN receptors is
associated with one of the Jak kinases (Tyk2 and Jak1
for the IFN-R, and Jak1 and Jak2 for the IFN-R).
Only in the presence of both chains and two functional
Jak kinases will effective signal transduction occur
after IFN binding. A new class of IFNs known as IFN-
or type III IFNs has now been identified that has a low
degree of homology with both type I IFNs and IL-10.37
The current members of this class are IL-28A, IL-28B,
and IL-29. Although the effects of these cytokines are
similar to those of the type I IFNs, they are less potent.
These type III IFNs use a shared receptor that consists
of the chain of the IL-10 receptor associated with an
IL-28 receptor chain.
Viruses, double-stranded RNA, and bacterial products are among the stimuli that elicit release of the type
I IFNs from cells. Plasmacytoid dendritic cells have
emerged as a particularly potent cellular source of type
I IFNs. Many of the effects of the type I IFNs directly or
indirectly increase host resistance to the spread of viral
infection. Additional effects mediated through IFNR are increased expression of major histocompatibility complex (MHC) class I molecules and stimulation
of NK cell activity. Not only does it have well-known
antiviral effects, but IFN- also can modulate T-cell
responses by favoring the development of a Th1 type
of T-cell response. Finally, the type I IFNs also inhibit
the proliferation of a variety of cell types, which provides a rationale for their use in the treatment of some
types of cancer. Forms of IFN- enjoy considerable use
clinically for indications ranging from hairy cell leukemia, various cutaneous malignancies, and papillomavirus infections (see Chapter 196). Some of the same
conditions that respond to therapy with type I IFNs
Chapter 11
INTERFERONS: PROTOTYPES OF
CYTOKINES SIGNALING THROUGH A
JAK/STAT PATHWAY
also respond to topical immunomodulatory agents like

imiquimod. This synthetic imidazoquinoline drug is an
agonist for the TLR7 receptor, whose natural ligand is
single-stranded RNA. Imiquimod stimulation of cells
expressing TLR7 elicits local release of large amounts
of type I IFNs from plasmacytoid dendritic cells, which
can trigger clinically useful antiviral and tumor inhibitory effects against genital warts, superficial basal
cell carcinoma, and actinic keratoses. Resiquimod is a
related synthetic compound that activates both TLR7
and TLR8, eliciting a slightly different spectrum of
cytokines.38
Production of IFN- is restricted to NK cells, CD8
T cells, and Th1 CD4 T cells. Th1 cells produce IFN-
after engagement of the T-cell receptor, and IL-12 can
provide a strong costimulatory signal for T-cell IFN production. NK cells produce IFN- in response to
cytokines released by macrophages, including TNF-,
IL-12, and IL-18. IFN- has antiviral activity, but it is a
less potent mediator than the type I IFNs for induction
of these effects. The major physiologic role of IFN-
is its capacity to modulate immune responses. IFN-
induces synthesis of multiple proteins that play essential roles in antigen presentation to T cells, including
MHC class I and class II glycoproteins, invariant chain,
the Lmp2 and Lmp7 components of the proteasome,
and the TAP1 and TAP2 intracellular peptide transporters. These changes increase the efficiency of antigen presentation to CD4 and CD8 T cells. IFN- is also
required for activation of macrophages to their full antimicrobial potential, enabling them to eliminate microorganisms capable of intracellular growth. Like type
I IFNs, IFN- also has strong antiproliferative effects
on some cell types. Finally, IFN- is also an inducer of
selected chemokines (CXC chemokine ligands 9 to 11)
and an inducer of endothelial cell adhesion molecules
(e.g., ICAM-1 and VCAM-1). Because of the breadth
of IFN-s activities, it comes the closest of the T-cell
cytokines to behaving as a primary cytokine.
INTERLEUKIN 10: AN ANTIINFLAMMATORY CYTOKINE

IL-10 is one of several cytokines that primarily exert
regulatory rather than stimulatory effects on immune
responses. IL-10 was first identified as a cytokine produced by Th2 T cells that inhibited cytokine production after activation of T cells by antigen and antigenpresenting cells. IL-10 exerts its action through a cell
surface receptor found on macrophages, dendritic
cells, neutrophils, B cells, T cells, and NK cells. The
ligand-binding chain of the receptor is homologous
to the receptors for IFN-/ and IFN-, and signaling
events mediated through the IL-10 receptor use a Jak/
STAT pathway. IL-10 binding to its receptor activates
the Jak1 and Tyk2 kinases and leads to the activation
of STAT1 and STAT3. The effects of IL-10 on antigenpresenting cells such as monocytes, macrophages,
and dendritic cells include inhibition of expression of
class II MHC and costimulatory molecules (e.g., B71,
B72) and decreased production of T cell-stimulating
cytokines (e.g., IL-1, IL-6, and IL-12). At least four viral
139
Section 4
::
140
genomes harbor viral homologs of IL-10 that transmit

similar signals by binding to the IL-10R.39
A major source of IL-10 within skin is epidermal
keratinocytes. Keratinocyte IL-10 production is upregulated after activation; one of the best-characterized
activating stimuli for keratinocytes is UV irradiation.
UV radiation-induced keratinocyte IL-10 production
leads to local and systemic effects on immunity. Some
of the well-documented immunosuppressive effects
that occur after UV light exposure are the result of the
liberation of keratinocyte-derived IL-10 into the systemic circulation. IL-10 also plays a dampening role in
other types of cutaneous immune and inflammatory
responses, because the absence of IL-10 predisposes
mice to exaggerated irritant and contact sensitivity
responses.
NOVEL INTERLEUKIN 10-RELATED

CYTOKINES: INTERLEUKINS 19,
20, 22, 24, AND 26
A series of cytokines related to IL-10 have been identified and shown to engage a number of receptor complexes with shared chains.40 IL-19, IL-20, and IL-24
transmit signals via a complex consisting of IL-20R
and IL-20R. IL-22 signals through a receptor consisting of IL-22R and IL-10R. The receptors for these IL-20
family cytokines are preferentially expressed on epithelial cells including keratinocytes. Increased expression of these cytokines and their receptors is associated
with psoriasis. The IL-20 family cytokines have profound effects on the proliferation and differentiation
of human keratinocytes in culture.41 Transgenic mice
overexpressing IL-20, IL-22, or IL-24 develop epidermal hyperplasia and abnormal keratinocyte differentiation.42 All of these findings point to a significant role
for these cytokines in the epidermal changes associated with cutaneous inflammation. T cells producing
IL-22 that elaborate a distinct set of cytokines from
Th1, Th2 and Th17 cells have been isolated from the
epidermis of patients with psoriasis and other inflammatory skin disorders. The IL-22 produced by these T
cells promotes keratinocyte proliferation and epidermal acanthosis.43,44
TRANSFORMING GROWTH
FACTOR-b FAMILY AND ITS
RECEPTORS
TGF-1 was first isolated as a secreted product of virally
transformed tumor cells capable of inducing normal
cells in vitro to show phenotypic characteristics associated with transformation. Over 30 additional members
of the TGF- family have now been identified. They
can be grouped into several families: the prototypic
TGF-s (TGF-1 to TGF-3), the bone morphogenetic
proteins, the growth/differentiation factors, and the
activins. The TGF name for this family of molecules
is somewhat of a misnomer, because TGF- has anti-
proliferative rather than proliferative effects on most

cell types. Many of the TGF- family members play an
important role in development, influencing the differentiation of uncommitted cells into specific lineages.
TGF- family members are made as precursor proteins
that are biologically inactive until a large prodomain
is cleaved. Monomers of the mature domain of TGF family members are disulfide linked to form dimers
that strongly resist denaturation.
Participation of at least two cell surface receptors
(type I and type II) with serine/threonine kinase activity is required for biologic effects of TGF-.45 Ligand
binding by the type II receptor (the true ligand-binding receptor) is associated with the formation of complexes of type I and type II receptors. This allows the
type II receptor to phosphorylate and activate the type
I receptor, a transducer molecule that is responsible
for downstream signal transduction. Downstream signal transmission from the membrane-bound receptors
in the TGF- receptor family to the nucleus is primarily mediated by a family of cytoplasmic Smad proteins
that translocate to the nucleus and regulate transcription of target genes.
TGF- has a profound influence on several types of
immune and inflammatory processes. An immunoregulatory role for TGF-1 was identified in part through
analysis of TGF-1 knockout mice that develop a wasting disease at 20 days of age associated with a mixed
inflammatory cell infiltrate involving many internal
organs. This phenotype is now appreciated to be a
result in part of the compromised development of
regulatory T cells when TGF-1 is not available. Development of cells in the dendritic cell lineage is also perturbed in the TGF-1-deficient mice, as evidenced by
an absence of epidermal Langerhans cells and specific
subpopulations of lymph node dendritic cells. TGF-treated fibroblasts display enhanced production of
collagen and other extracellular matrix molecules. In
addition, TGF- inhibits the production of metalloproteinases by fibroblasts and stimulates the production
of inhibitors of the same metalloproteinases (tissue
inhibitors of metalloproteinase, or TIMPs). TGF- may
contribute to the immunopathology of scleroderma
through its profibrogenic effects.46
CHEMOKINES: SECONDARY
CYTOKINES CENTRAL TO
LEUKOCYTE MOBILIZATION
Chemokines are a large superfamily of small cytokines
that have two major functions. First, they guide leukocytes via chemotactic gradients in tissue. Typically,
this is to bring an effector cell to where its activities
are required. Second, a subset of chemokines has the
capacity to increase the binding of leukocytes via their
integrins to ligands at the endothelial cell surface,
which facilitates firm adhesion and extravasation of
leukocytes in tissue. The activities of this important
class of cytokines are sufficiently complex that they are
the subject of a separate chapter (Chapter 12).
CYTOKINE NETWORK
THERAPEUTIC IMPLICATIONS
AND APPLICATIONS
KEY REFERENCES
::
Cytokines
1. Oppenheim JJ: Cytokines: Past, present, and future. Int J

Hematol 74:3, 2001
3. Luger TA et al: Epidermal cell (keratinocyte)-derived
thymocyte-activating factor (ETAF). J Immunol 127:1493,
1981
4. Kupper TS: The activated keratinocyte: A model for inducible cytokine production by non-bone marrow-derived
cells in cutaneous inflammatory and immune responses.
J Invest Dermatol 94:146S, 1990
5. Albanesi C, Pastore S: Pathobiology of chronic inflammatory skin diseases: Interplay between keratinocytes and
immune cells as a target for anti-inflammatory drugs.
Curr Drug Metab 11:210, 2010
6. Kupper TS: Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations. J Clin Invest
86:1783, 1990
7. Beutler B: Microbe sensing, positive feedback loops, and
the pathogenesis of inflammatory diseases. Immunol Rev
227:248, 2009
9. OQuinn DB et al: Emergence of the Th17 pathway and its
role in host defense. Adv Immunol 99:115, 2008
10. Josefowicz SZ, Rudensky A: Control of regulatory T cell
lineage commitment and maintenance. Immunity 30:616,
2009
15. Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors.
Nat Immunol 11:373, 2010
16. OShea JJ, Murray PJ: Cytokine signaling modules in inflammatory responses. Immunity 28:477, 2008
17. Martinon F, Mayor A, Tschopp J: The inflammasomes:
Guardians of the body. Annu Rev Immunol 27:229, 2009
27. Ziegler SF, Artis D: Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 11:289, 2010
35. Griffiths CE et al: Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med
362:118, 2010
43. Eyerich S et al: Th22 cells represent a distinct human T cell
subset involved in epidermal immunity and remodeling. J
Clin Invest 119:3573, 2009
44. Fujita H et al: Human Langerhans cells induce distinct IL22-producing CD4+ T cells lacking IL-17 production. Proc
Natl Acad Sci U S A 106:21795, 2009
Chapter 11
This chapter has attempted to bring some degree of

order and logic to the analysis of a field of human biology that continues to grow at a rapid rate. Although
many things may change in the world of cytokines,
certain key concepts have stood the test of time. Principal among them is the idea that cytokines are emergency molecules, designed to be released locally and
transiently in tissue microenvironments. When cytokines are released persistently, the result is typically
chronic disease. One potential way to treat such diseases is with cytokine antagonists or other drugs that
target cytokines or cytokine-mediated pathways.
Cytokines and cytokine antagonists are being used
therapeutically by clinicians, and development of additional agents continues. With certain notable exceptions, systemic cytokine therapy has been disappointing and is often accompanied by substantial morbidity.
In contrast, local and transient administration of cytokines may yield more promising results. An example
of this approach is the transduction of tumor cells to
express GM-CSF to create the therapeutic cancer vaccines that are capable of boosting antitumor immune
responses.30 Conversely, multiple biologics that specifically block cytokine activity have been developed
and approved for clinical use. Antibodies and TNF
receptorFc fusion proteins are FDA-approved antagonists of TNF- activity that are highly effective at
inducing durable remissions in psoriasis (see Chapters
18 and 234). Antibodies against the p40 subunit shared
by IL-12 and IL-23 are also active in treating psoriasis. An IL-1 receptor-Fc fusion protein, an antibody to
IL-1, and recombinant IL-1Ra are all effective therapy
for patients with the cryopyrin-associated periodic
syndromes. IL-1Ra is FDA-approved for treatment of
adult rheumatoid arthritis. A class of pharmacologic
agents that inhibits the production of multiple T cellderived cytokines is the calcineurin inhibitors. Tacrolimus and pimecrolimus both bind to the immunophilin
FK-506 binding protein-12 (FKBP-12), producing complexes that bind to calcineurin, a calcium-dependent
phosphatase that acts on proteins in the nuclear factor of activated T-cells (NFAT) family to promote their
nuclear translocation and activation of cytokine genes
(including IL-2, IL-4, and IFN-)47 (see Chapters 221 and
233). Finally, fusion toxins linked to cytokines, such as
the IL-2 fusion protein denileukin diftitox, exploit the
cellular specificity of certain cytokinereceptor interactions to kill target cells (see Chapter 234). Denileukin
diftitox is FDA approved for the treatment of cutaneous T-cell lymphoma and has also shown therapeutic
activity in other types of lymphoid malignancies.48
Each of the aforementioned approaches is still relatively new and open to considerable future development. An understanding of cytokines by clinicians of
the future is likely to be central to effective patient care.
141
Chapter 12 :: Chemokines

:: Anke S. Lonsdorf & Sam T. Hwang
CHEMOKINES AT A GLANCE
Chemokines and their receptors are vital
mediators of cellular trafficking.
Most chemokines are small proteins with
molecular weights in the 8- to 10-kDa range.
Section 4
::
142
Chemokines are synthesized constitutively

in some cells and can be induced in many
cell types.
Chemokines play roles in inflammation,
angiogenesis, neural development, cancer
metastasis, hematopoiesis, and infectious
disease.
In skin, chemokines play important roles
in atopic dermatitis, psoriasis, melanoma,
melanoma metastasis, and some viral
(including retroviral) infections.
Promising therapeutic applications of
chemokines include the prevention of
T-cell arrest on activated endothelium or
blocking infection of T cells by human
immunodeficiency virus 1 using CC
chemokine receptor 5 analogs.
INTRODUCTION
The skin is an organ in which the migration, influx,
and egress of leukocytes occur in both homeostatic
and inflammatory processes. Chemokines and their
receptors are accepted as vital mediators of cellular
trafficking. Since the discovery of the first chemoattractant cytokine or chemokine in 1977, 50 additional
new chemokines and 17 chemokine receptors have
been discovered. Most chemokines are small proteins
with molecular weights in the 810 kDa range and
are synthesized constitutively in some cells and can
be induced in many cell types by cytokines. Initially
associated only with recruitment of leukocyte subsets
to inflammatory sites,1 it has become clear that chemokines play roles in angiogenesis, neural development,
cancer metastasis, hematopoiesis, and infectious diseases. This chapter will focus primarily on the function
of chemokines in inflammatory conditions, but will
also touch upon the role of these molecules in other
settings as well.
An overview of the structure of chemokines and chemokine receptors will be provided that will detail the
molecular signaling pathways initiated by the binding
of a chemokine to its cognate receptor. Expression pat-
terns of chemokine receptors will be detailed because

of the many types of immune cells that potentially can
be recruited to skin under inflammatory conditions.
Individual chemokine receptors will be highlighted
in regard to biologic function, including facilitation of
migration of effector T cells into the skin and the egress
of antigen-presenting cells out of the skin. Finally, the
roles of chemokines and their receptors in several cutaneous diseasesatopic dermatitis, psoriasis, cancer,
and infectious diseaseprovide a better idea of the
diversity of chemokine function in skin.
STRUCTURE OF CHEMOKINES
Chemokines are grouped into four subfamilies
based on the spacing of amino acids between the
first two cysteines. The CXC chemokines (also called
-chemokines) show a CXC motif with one nonconserved amino acid between the two cysteines. The
other major subfamily of chemokines lacks the additional amino acid and is termed the CC subfamily (or
-chemokines). The two remaining subfamilies contain
only one member each: the C subfamily is represented
by lymphotactin, and fractalkine is the only member of
the CXXXC (or CX3C) subfamily. Chemokines can also
be assigned to one of two broad and, perhaps, overlapping functional groups. One group (e.g., RANTES,
MIP-1/ LARC, etc.) mediates the attraction and
recruitment of immune cells to sites of active inflammation while other (e.g., SLC and SDF-1) appear to
play a role in constitutive or homeostatic migration
pathways.2
The complexity and redundancy in the nomenclature of chemokines has led to the proposal for a
systematic nomenclature for chemokines based on
the type of chemokine (C, CXC, CX3C, or CC) and a
number based on the order of discovery as proposed
by Zlotnik and Yoshie.2 For example, stromal-derived
factor-1 (SDF-1), a CXC chemokine, has the systematic
name CXCL12. Because both nomenclatures are still
in wide use, the original names (abbreviated in most
cases) as well as systematic names will be used interchangeably throughout the chapter. Table 12-1 provides a list of chemokine receptors of interest in skin
that are discussed in this chapter as well as the major
chemokine ligands that bind to them.
Chemokines are highly conserved and have similar
secondary and tertiary structure. Based on crystallography studies, a disordered amino terminus followed
by three conserved antiparallel -pleated sheets is a
common structural feature of chemokines. Fractalkine
is unique in that the chemokine domain sits atop a
mucin-like stalk tethered to the plasma membrane via
a transmembrane domain and short cytoplasmic tail.30
Although CXC and CC chemokines form multimeric
structures under conditions required for structural
studies, these associations may be relevant only when
TABLE 12-1
Chemokine Receptors in Skin Biology

Chemokine
Receptor
Chemokine Ligand
Expression
Pattern
Comments
References
T, Mo, DC, NK, B
Migration of DC and monocytes; strongly

upregulated in T cells by IL-2
12
CCR2
MCP-1 (CCL2),-3,-4
(CCL13)
T, Mo
Migration of T cells to inflamed sites;

replenish LC precursors in epidermis;
involved in skin fibrosis via MCP-1
35
CCR3
Eotaxin (CCL11) >RANTES,

MCP-2 (CCL8),3,4
Eo, Ba, Th2, K
Migration of Th2 T cells and allergic

immune cells
6,7
CCR4
TARC (CCL17), MDC

(CCL22)
T (benign and
malignant)
Expression in Th2 > Th1 cells; highly

expressed on CLA+ memory T cells; TARC
expression by keratinocytes may be
important in atopic dermatitis; may guide
trafficking of malignant as well as benign
inflammatory T cells
812
CCR5
RANTES, MIP-1,
(CCL3,4)
T, Mo, DC
Marker for Th1 cells; migration to

acutely inflamed sites; may be involved
in transmigration of T cells through
endothelium; major HIV-1 fusion coreceptor
3,13
CCR6
LARC (CCL20)
T, DC, B
Expressed by memory, not naive, T cells;

possibly involved in arrest of memory T cells
to activated endothelium and recruitment
of T cells to epidermis in psoriasis
76,77,82
CCR7
SLC (CCL21), ELC (CCL19)
T, DC, B,
melanoma cells
Critical for migration of naive T cells and

central memory T cells to secondary
lymphoid organs; required for mature DC
to enter lymphatics and localize to lymph
nodes; facilitates nodal metastasis
1418
CCR9
Thymus-expressed
chemokine (CCL25)
T, melanoma
cells
Associated with melanoma small bowel

metastases
19
CCR10
CTACK (CCL27)
T (benign and
malignant),
melanoma cells
Preferential response of CLA+ T cells to

CTACK in vitro; may be involved in T cell
(benign as well as malignant) homing to
epidermis, where CTACK is expressed;
survival of melanoma is skin
2023
CXCR1,2
IL-8 (CXCL8), MGSA/

GRO (CXCL1), ENA-78
(CXCL5)
N, NK, En,
melanoma cells
Recruitment of neutrophils (e.g.,

epidermis in psoriasis); may be involved in
angiogenesis; melanoma growth factor
2426
CXCR3
IP-10 (CXCL10), Mig

(CXCL9), I-TAC (CXCL11)
Marker for Th1 Cells and may be involved

in T cell recruitment to epidermis in CTCL;
induces arrest of activated T cells on
stimulated endothelium
27,28
CXCR4
SDF-1, (CXCL12)
T, DC, En,
melanoma cells
Major HIV-1 fusion coreceptor; involved in

vascular formation; involved in melanoma
metastasis to lungs
3,29
CX3CR1
Fractalkine (CX3CL1)
T, Mo, MC, NK
May be involved in adhesion on activated T

cells, Mo, NK cells to activated endothelium
30,31
::
MIP-1 (CCL3), RANTES

(CCL5), MCP-3 (CCL7)
Chapter 12
CCR1
Chemokines
GRO = growth regulated oncogene; MGSA = melanoma growth stimulatory activity; Mig = monokine-induced by IFN-; I-TaC = interferoninducible T-cell alpha chemoattractant; SDF = stromal-derived factor; MCP = monocyte chemattractant protein; MIP = macrophage inflammatory protein; RANTES = regulated upon activation, normal T cell expressed and secreted; IL-8 = interleukin-8; TARC = thymus and activationregulated chemokine; LARC = liver and activation-regulated chemokine (also known as MIP-3); SLC = secondary lymphoid-tissue chemokine;
MDC = macrophage-derived chemokine; CTACK = cutaneous T cell attracting chemokine; T = T cells; Mo = monocytes; DC = dendritic cells; Eo =
eosinophils; Ba = basophils; B = B cells; En = endothelial cells; Th1,2 = T helper 1,2 cell; N = neutrophils; MC = mast cells; NK = natural killer cells;
CLA = cutaneous lymphocyte-associated antigen; HIV = human immunodeficiency virus.
143
Chemokine receptor-mediated signaling pathways
CK
Plasma membrane
s
GDP
RAMP
RGS
Section 4
GRK
GTP
ER
Pl3K
Rho, Rac
PKC
Ca2+ flux
PTK
MaPK
::
144
PLC
PTK
Cytoskeletal
changes and
gene transcription
Chemotaxis, adhesion,
polarization, and cell
proliferation
Degradation
Figure 12-1 Chemokine receptor-mediated signaling pathways. RAMP = receptor-activity-modifying protein; RGS = regulator of G-protein signaling; GRK = G-protein coupled receptor kinase; DG = 1,2-diacylglycerol; PLC = phospholipase C;
PIP2 = phosphatidylinositol-4,5-bisphosphate; IP3 = inositol-1,4,5-triphosphate; PKC = protein kinase C; CK = chemokine;
PTX = pertussis toxin; ER = endoplasmic reticulum; PTK = protein tyrosine kinase(s); MAPK = Mitogen activated protein
kinase.
chemokines associate with cell-surface components

such as glycosaminoglycans (GAGs) or proteoglycans.
Since most chemokines have a net positive charge,
these proteins tend to bind to negatively charged
carbohydrates present on GAGs. Indeed the ability
of positively charged chemokines to bind to GAGs is
thought to enable chemokines to preferentially associate with the lumenal surface of blood vessels despite
the presence of shear forces from the blood that would
otherwise wash the chemokines away.
CHEMOKINE RECEPTORS AND

SIGNAL TRANSDUCTION
Chemokine receptors are seven transmembrane spanning membrane proteins that couple to intracellular heterotrimeric G-proteins containing , , and
subunits.2 They represent a part of a large family of
G-protein coupled receptors (GPCR), including rhodopsin, that have critical biologic functions. Leukocytes express several G protein subtypes: s, i, and q,
while the and subunits each have 5 and 11 known
subtypes, respectively. This complexity in the formation of the heterotrimeric G-protein may account for
specificity in the action of certain chemokine receptors.
Normally G-proteins are inactive when GDP is bound,
but they are activated when the GDP is exchanged for
GTP (Fig. 12-1). After binding to a ligand, chemokine

receptors rapidly associate with G-proteins, which in
turn increases the exchange of GTP for GDP. Pertussis
toxin is a commonly used inhibitor of GPCR that irreversibly ADP-ribosylates G subunits of the i class
and subsequently prevents most chemokine receptormediated signaling.
Activation of G-proteins leads to the dissociation
of the G and G subunits (Fig. 12-1). The G subunit
has been observed to activate protein tyrosine kinases
and mitogen-activated protein kinase, leading to cytoskeletal changes and gene transcription. The G subunit retains GTP, which is slowly hydrolyzed by the
GTPase activity of this subunit. This GTPase activity
is both positively and negatively regulated by GTPaseactivating proteins [also known as regulator of G-protein signaling (RGS) proteins]. The G dimer initiates
critical signaling events in regard to chemotaxis and
cell adhesion. It activates phospholipase C (PLC)32
leading to formation of diacylglycerol (DAG) and inositol triphosphate [Ins(1,4,5)P3]. Ins(1,4,5)P3 stimulates
Ca2+ entry into the cytosol, which along with DAG,
activates protein kinase C isoforms. While the G subunits have been shown to be critical for chemotaxis, the
G subunit has no known role in chemotactic migration. There is also evidence that binding of chemokine
receptors results in the activation of other intracellular
effectors including Ras and Rho, phosphatidylinositol3-kinase [PI(3)K].33
THE MULTISTEP MODEL OF

LEUKOCYTE RECRUITMENT
In order for leukocytes to adhere and migrate to peripheral tissues, they must overcome the pushing force of
the vascular blood stream as they bind to activated
Chemokines
Generally speaking, chemokines are thought to play

at least three different roles in the recruitment of host
defense cells, predominantly leukocytes, to sites of
inflammation.34 First, they provide the signal or signals required to cause leukocytes to come to a complete stop (i.e., arrest) in blood vessels at inflamed sites
such as skin. Second, chemokines have been shown to
have a role in the transmigration of leukocytes from
the lumenal side of the blood vessel to the ablumenal
side. Third, chemokines attract leukocytes to sites of
inflammation in the dermis or epidermis following
transmigration. Keratinocytes and endothelial cells
are a rich source of chemokines when stimulated by
appropriate cytokines. In addition, chemokines and
their receptors are known to play critical roles in the
emigration of resident skin dendritic cells (i.e., Langerhans cells and dermal dendritic cells) from the skin
to draining lymph nodes (LN) via afferent lymphatic
vessels, a process that is essential for the development
of acquired immune responses.
This section will be divided into three subsections.
The first will introduce basic concepts of how all leukocytes arrest in inflamed blood vessels prior to transmigration by introducing the multistep model of leukocyte recruitment. The second will detail mechanisms
of T cell migration, while the final subsection will
focus on the mechanisms by which chemokines mediate the physiological migration of DC from the skin to
regional LN.
::
CHEMOKINES AND CUTANEOUS

LEUKOCYTE TRAFFICKING
endothelial cells at local sites of inflammation. According to the multistep or cascade model of leukocyte
recruitment (Fig. 12-2), one set of homologous adhesion molecules termed selectins mediates the transient
attachment of leukocytes to endothelial cells while
another set of adhesion molecules termed integrins
and their receptors (immunoglobulin superfamily members) mediates stronger binding (i.e., arrest) and transmigration.35 The selectins (E-, L-, and P-selectins) are
members of a larger family of carbohydrate-binding
proteins termed lectins. The selectins bind their respective carbohydrate ligands located on protein scaffolds
and thus mediate the transient binding or rolling of
leukocytes on endothelial cells.
The skin-associated vascular selectin known as
E-selectin is upregulated on endothelial cells by
inflammatory cytokines such as tumor necrosis factor (TNF)- and binds to sialyl Lewis x-based carbohydrates. E-selectin ligands form distinct epitopes
known as the cutaneous lymphocyte-associated antigen (CLA). CLA is expressed by 10%40% of memory
T cells and has been suggested as a marker for skinhoming T cells.36 At least two chemokine receptors
(CCR10 and CCR4) show preferential expression in
CLA+ memory T cells.8,20 While E-selectin is likely to
be an important component of skin-selective homing, there is also evidence to suggest that L-selectin is
involved in T cell migration to skin.37,38
In the second phase of this model, leukocyte integrins such as those of the 2 family must be turned on
or activated from their resting state in order to bind to
their counter receptors such as intercellular adhesion
molecule-1 (ICAM-1) that are expressed by endothelial
cells. A vast array of data suggest that the binding of
chemokines to leukocyte chemokine receptors plays a
critical role in activating both 1 and 2 integrins.33,39
Activation of chemokine receptors leads to a complex
signaling cascade (Fig. 12-1) that causes a conformational change in individual integrins that leads to
increases in the affinity and avidity of individual leukocyte integrins for their ligands. Furthermore, later
steps of migration (i.e., transmigration or diapedesis)
have been shown to be dependent on chemokines as
well in selective cases.13 In the case of neutrophils, their
ability to roll on inflamed blood vessels likely depends
on their expression of L-selectin and E-selectin ligands
while their arrest on activated endothelia likely
depends on their expression of CXCR1 and CXCR2
as described below for wound healing. Integrin activation via chemokine-mediated signals appears to be
more complex in T cells, which appear to use multiple
chemokine receptors, and is described in more detail
below.
Chapter 12
RhoA and protein kinase C appear to play a role in

integrin affinity changes, while PI(3)K may be critical
for changes in the avidity state of LFA-1. Other proteins
have been found that regulate the synthesis, expression, or degradation of G-protein coupled receptors.
For example, receptor-activity-modifying proteins
(RAMPS) act as chaperones of seven transmembrane
spanning receptors and regulate surface expression as
well as the ligand specificity of chemokine receptors
(Fig. 12-1). Importantly, after chemokine receptors are
exposed to appropriate ligands, they are frequently
internalized, leading to an inability of the chemokine
receptor to mediate further signaling. This downregulation of chemokine function, which has been termed
desensitization, occurs because of phosphorylation
of Ser/Thr residues in the C-terminal tail by proteins
termed GPCR kinases (GRK) and subsequent internalization of the receptor (Fig. 12-1). Desensitization may
be an important mechanism for regulating the function
of chemokine receptors by inhibiting cell migration as
leukocytes arrive at the primary site of inflammation.
CHEMOKINE-MEDIATED MIGRATION
OF T CELLS
Antigen-inexperienced T cells are termed naive and
can be identified by expressing three cell surface
proteins: CD45RA (an isoform of the pan-leukocyte
marker), L-selectin, and the chemokine receptor CCR7.
These T cells migrate efficiently to secondary LN,
145
Multistep model of leukocyte recruitment

1
Rolling
selectins
Integrin activation
integrins, chemokines
3
Other
E-selectin
ligands
PSGL1/CLA
L-selectin
Section 4
P-
E-
Integrins
PSGL1/CLA
Chemokine
receptor
Chemokine
L-selectin
ligands
Proteoglycan
::
146
Firm adhesion
integrins, Ig superfamily
ICAMs
VCAM
Tissue
Figure 12-2 Multistep model of leukocyte recruitment. Leukocytes, pushed by the blood stream, first transiently bind or
roll on the surface of activated endothelial cells via rapid interactions with P-, E-, or L-selectin. Chemokines are secreted
by endothelial cells and bind to proteoglycans that present the chemokine molecules to chemokine receptors on the
surface of the leukocyte. After chemokine receptor ligation, intracellular signaling events lead to a change in the conformation of integrins and changes in their distribution on the plasma membrane resulting in Integrin Activation. These
changes result in high affinity/avidity binding of integrins to endothelial cell intercellular adhesion molecules (ICAMs) and
vascular cell adhesion molecule-(VCAM)-1 in a step termed Firm Adhesion, which is then followed by transmigration of
the leukocyte between endothelial cells and into tissue.
where they may make contact with antigen-bearing

dendritic cells from the periphery. Once activated by
dendritic cells presenting antigen, T cells then express
CD45RO, are termed memory T cells, and appear
to express a variety of adhesion molecules and chemokine receptors, which facilitate their extravasation
from blood vessels to inflamed peripheral tissue. A
specific subset of CCR7, L-selectin memory T cells has
been proposed to represent an effector memory T cell
subset that is ready for rapid deployment at peripheral
sites in terms of their cytotoxic activity and ability to
mobilize cytokines.14
Although chemokines are both secreted and soluble,
the net positive charge on most chemokines allows
them to bind to negatively charged proteoglycans such
as heparin sulfate that are present on the lumenal surface of endothelial cells, thus allowing them to be presented to T cells as they roll along the lumenal surface
(Fig. 12-2). After ligand binding, chemokine receptors
send intracellular signals that lead to increases in the
affinity and avidity of T-cell integrins such as LFA-1
and VLA-4 for their endothelial receptors ICAM-1 and
VCAM-1, respectively.40 Only a few chemokine receptors (CXCR4, CCR7, CCR4, and CCR6) are expressed at
sufficient levels on resting peripheral blood T cells to
mediate this transition. With activation and IL-2 stimulation, increased numbers of chemokine receptors
(e.g., CXCR3) are expressed on activated T cells, mak-
ing them more likely to respond to other chemokines.

In several different systems, inhibition of specific chemokines produced by endothelial cells or chemokine
receptors found on T cells dramatically influences T
cell arrest in vivo and in vitro.41
CXCR3 serves as a receptor for chemokine ligands
Mig, IP-10, and I-Tac. All three of these chemokines
are distinguished from other chemokines by being
highly upregulated by interferon-. Resting T cells do
not express functional levels of CXCR3, but upregulate this receptor with activation and cytokines such
as IL-2. Once expressed on T cells, CXCR3 is capable
of mediating arrest of memory T cells on activated
endothelial cells.27 The expression of its chemokine ligands is strongly influenced by the cytokine
interferon-, which synergistically works with proinflammatory cytokines such as TNF- to increase
expression of these ligands by activated endothelial
cells27 and epithelial cells.
In general, activation of T cells by cytokines such
as IL-2 is associated with the enhanced expression of
CCR1, CCR2, CCR5, and CXCR3. Just as Th1 and Th2
(T cell) subsets have different functional roles, it might
have been predicted that these two subsets of T cells
would express different chemokine receptors. Indeed,
CCR49,42,43 and CCR36 are associated with Th2 cells in
vitro while Th1 cells are associated with CCR5 and
CXCR3.44
and function of skin-homing T cells in inflammatory

disease models.51,52
CHEMOKINES IN THE TRAFFICKING

OF DENDRITIC CELLS FROM SKIN TO
REGIONAL LYMPH NODES
::
Chemokines
Antigen-presenting cells, including dendritic cells

(DC) of the skin, are critical initiators of immune
responses and their trafficking patterns are thought
to influence immunological outcomes. Their mission
includes taking up antigen at sites of infection or injury
and bringing these antigens to regional LN where they
both present antigen and regulate the responses of T
and B cells. Skin-resident DCs are initially derived
from hematopoietic bone marrow progenitors53 and
migrate to skin during the late prenatal and newborn
periods of life. Under resting (steady state) conditions, homeostatic production by keratinocytes of
CXCL14 (receptor unknown) may be involved in
attracting CD14+ DC precursors to the basal layer of the
epidermis.54 Similarly, Langerhans cells (LC) as well as
CD1c+ LC precursors are strongly chemoattracted to
keratinocyte-derived CCL20.55 Under inflammatory
conditions, when skin-resident DC and LC leave the
skin in large numbers, keratinocytes release a variety
of chemokines, including CCL2 and CCL7 (via CCR2)4
and CCL20 (via CCR6),56 which may attract monocytelike DC precursors to the epidermis in order to replenish the LC population.
When activated by inflammatory cytokines (e.g.,
TNF- and IL-1), lipopolysaccharide, or injury, skin
DC, including LC, leave the epidermis, enter afferent
lymphatic vessels, and migrate to draining regional
LN where they encounter both naive and memory T
cells. Chemokines guide the DC on this journey. Activated DC specifically upregulate expression of CCR7,
which binds to secondary lymphoid tissue chemokine
(SLC/CCL21), a chemokine expressed constitutively
by lymphatic endothelial cells15,57 (eFig. 12-2.1 in online
edition). SLC guides DC into dermal lymphatic vessels
and helps retain them in SLC-rich regional draining LN
(Fig. 12-3).58
Interestingly, naive T cells also strongly express
CCR7 and use this receptor to arrest on high endothelial venules.59 The importance of the CCR7 pathway is
demonstrated by LC from CCR7 knockout mouse that
demonstrate poor migration from the skin to regional
LN16 and by the observation that antibodies to SLC
block migration of DC from the periphery to LN.15
Thus, CCR7 and its ligands facilitate the recruitment
of at least two different kinds of cellsnaive T cells
and DCto the LN through two different routes under
both inflammatory16 and resting conditions.58
After DC reach the LN, they must interact with T
cells to form a so-called immunological synapse that
is critical for T cell activation. Activated DC secrete
a number of chemokines, including macrophagederived chemokine (MDC),60 which attracts T cells to
the vicinity of DC and promotes adhesion between the
two cell types.61,62 CCR5 (via CCL3/4) has also been
identified as mediating recruitment of naive CD8+ T
Chapter 12
In some instances, chemokine receptors may be

regarded as functional markers that characterize distinct T helper cell subsets while also promoting their
recruitment to inflammatory sites characterized by
allergic or cell-mediated immune responses,
respectively. When T cells are activated in vitro in the
presence of Th1-promoting cytokines, CXCR3 and
CCR5 appear to be highly expressed, while in the
presence of Th2-promoting cytokines, CCR4, CCR8,
and CCR3 expression predominates. In rheumatoid
arthritis, a Th1-predominant disease, many infiltrating T cells express CCR5 and CXCR345 whereas,
in atopic disease, CCR4 expressing T cells may be
more frequent.9 CCR6 has recently been described
as a marker for a newly characterized T-helper subset, expressing the hallmark effector cytokines IL-17
and IL-22.46 These so-called Th17 cells play a central role in the pathogenesis of psoriasis and other
chronic inflammatory autoimmune diseases.47 However, in normal skin, the majority of skin resident
T cells also coexpress CCR6, suggesting that CCR6
and CCL20 interactions regulate T cell infiltration in
the skin under inflammatory as well as homeostatic
conditions.48
While certain chemokine receptors characterize
distinct T-cell subsets, flexible regulation of their
expression may increase the migratory potential of
circulating T cells to diverse tissues. For example,
under some conditions, both Th1 and Th2 type T
cells can express CCR4.43 Similarly, T regulatory
cells (Treg) and Th17 cells share chemokines receptors with other T cell lineages but may alter their
chemokine receptor expression profiles, depending
on the microenvironment in which they are activated.49
The epidermis is a particularly rich source of
chemokines, including RANTES, MIP-3a (CCL20),
MCP-1, IP-10, IL-8, LARC, and TARC, which likely
contribute to epidermal T cell migration. Keratinocytes from patients with distinctive skin diseases
appear to express unique chemokine expression
profiles. For instance, keratinocytes derived from
patients with atopic dermatitis synthesized mRNA
for RANTES at considerably earlier time points in
response to IL-4 and TNF- in comparison to healthy
individuals and psoriatic patients.50 Keratinocytes
derived from psoriatic patients synthesized higher
levels of IP-10 with cytokine stimulation as well
as higher constitutive levels of IL-8,50 a chemokine
known to recruit neutrophils. IL-8 may contribute to
the large numbers of neutrophils that localize to the
suprabasal and cornified layers of the epidermis in
psoriasis. IP-10 may serve to recruit activated T cells
of the Th1 helper phenotype to the epidermis and
has been postulated to have a role in the recruitment
of malignant T cells to the skin in cutaneous T cell
lymphomas.28
CTACK/CCL27 is selectively and constitutively
expressed in the epidermis, and its expression is only
marginally increased under inflammatory conditions.21
Interestingly, CTACK has been reported to preferentially attract CLA+ memory T cells in vitro21 and has
been demonstrated to play a role in the recruitment
147
Trafficking of epidermal Langerhans cells
Activation
(injury, infection, cytokines)
Section 4
CCR7
E-cadherin
::
Recruitment
CCR2, CCL7
CXCL14
BCZ
TCZ
SLC
ELC
SLC
Lymph node
Lymphatic vessel
Figure 12-3 Trafficking of epidermal Langerhans cells

to regional lymph nodes. Langerhans cells are activated
by a variety of stimuli including injury, infectious agents,
and cytokines such as IL-1 and TNF-. Having sampled
antigens, the activated LC downregulate E-cadherin and
strongly upregulate CCR7. Sensing the CCR7-ligand,
SLC (), produced by lymphatic endothelial cells, the LC
migrate into lymphatic vessels, passively flow to the lymph
nodes, and stop in the T-cell zones (TCZ) that are rich in
two CCR7 ligands, SLC and ELC. Note that chemokines also
contribute to the recruitment of LC under both resting and
inflammatory conditions. BCZ, B-cell zones.
cells to aggregates of antigen-specific CD4+ T cells and

DC.63 Therefore, chemokines orchestrate a complex
series of migration patterns bringing both DC and T
cells to the confines of the LN, where expression of
chemokines by DC themselves appears to be a direct
signal for binding of the T cell (Fig. 12-3).
CHEMOKINES IN DISEASE
ATOPIC DERMATITIS
148
Atopic dermatitis is a prototypical Th2-mediated,

allergic skin disease with multifactorial genetic and
environmental factors involved in its pathogenesis.
Although multiple chemokines have been associated
with the atopic phenotype, the roles of CCR4 and CCR10
in AD have been particularly well documented.64 Clinical data from humans as well as experimental data
in the NC/Nga mouse model of atopic dermatitis

suggest that the Th2-associated chemokine receptor,
CCR4, in conjunction with its ligand, TARC/CCL17,
may play a role in recruiting T cells to atopic skin. In
patients with atopic dermatitis, CLA+CCR4+CCR10+
lymphocytes were found to be increased in the peripheral blood and in lesional skin compared to controls.9
Moreover, serum levels of TARC/CCL17 and CTACK/
CCL27 in atopic dermatitis patients were significantly
higher than concentrations found in healthy or psoriatic controls and correlated with disease severity.10
CCL18, whose receptor is currently unknown, has
been reported to be expressed at higher levels in the
skin of patients with atopic disease compared to psoriasis.65 CCL18 is produced by antigen-presenting
cells and attracts CLA+ memory T cells to the skin.66
Elevated levels of CCL18 can be found in the skin
and sera of patients with AD but show a significant
decrease after therapy.67 Of note, CCL18 and another
chemokine, CCL1 (produced by mast cells and endothelial cells), are elicited in volunteer skin after topical
challenge with dust mite allergen and Staphylococcal
superantigen.65,68
The recruitment of eosinophils to skin is a frequently
observed finding in allergic skin diseases, including
atopic dermatitis and cutaneous drug reactions, and
likely is mediated by chemokines. Eotaxin/CCL11
was initially isolated from the bronchoalveolar fluid of
guinea pigs after experimental allergic inflammation
and binds primarily to CCR3, a receptor expressed by
eosinophils,69 basophils, and Th2 cells.6 Injection of
eotaxin into the skin promotes the recruitment of eosinophils while anti-eotaxin antibodies delay the dermal
recruitment of eosinophils in the late-phase allergic
reaction in mouse skin.70 Immunoreactivity and mRNA
expression of eotaxin and CCR3 are both increased in
lesional skin and serum of patients with atopic dermatitis, but not in nonatopic controls.71,72 Eotaxin has
also been shown to increase proliferation of CCR3expressing keratinocytes in vitro.73 Finally, expression
of eotaxin (and RANTES) by dermal endothelial cells
has been correlated with the appearance of eosinophils in the dermis in patients with onchocerciasis that
experience allergic reactions following treatment with
ivermectin.74 The observations above suggest that production of eotaxin and CCR3 may contribute to the
recruitment of eosinophils and Th2 lymphocytes in
addition to stimulating keratinocyte proliferation.
PSORIASIS
Psoriasis is characterized by hyperplasia of the epidermis (acanthosis) and a prominent dermal and epidermal inflammatory infiltrate, typically resulting in
thickened, hyperkeratotic plaques. The inflammatory
infiltrate of psoriatic skin is predominantly composed
of Th1- and Th17-polarized memory T cells, as well as
neutrophils, macrophages, and increased numbers of
dendritic cells.75 As shown in eFig. 12-3.1 in online edition and reviewed by others,64 there is a growing body
of evidence supporting a central role for chemokines
in regulating the complex events leading to psoriatic
Chemokines
Chemokines may play a role in tumor formation and

immunity in several distinct ways, including the
control of angiogenesis and the induction of tumor
immune responses.85 CXC chemokines that express a
three-amino-acid motif consisting of glu-leu-arg (ELR)
immediately preceding the CXC signature are angiogenic while most non-ELR CXC chemokines, except
SDF-1, are angiostatic. Interestingly, it is not clear that
ELR chemokines actually bind to chemokine receptors in order to reduce angiogenesis. It has been proposed that they act by displacing growth factors from
::
CANCER
proteoglycans. In any event, the balance between ELR+

versus ELR chemokines is thought to contribute to
the complex regulation of angiogenesis at tumor sites.
IL-8, a prototypical ELR+ chemokine, can be secreted
by melanoma cells and has been detected in conjunction with metastatic dissemination of this cancer,86
which may be related to its ability to attract circulating tumor cells to primary tumors and to influence leukocyte and endothelial cell recruitment.87,88
IL-8 may also act as an autocrine growth factor for
melanoma24 as well as several other types of cancer.
Although CXCR1 and CXCR2 bind IL-8 in common,
several other ELR+ CXC chemokines also bind to and
activate CXCR2.
Tumors, including melanoma, have long been
known to secrete chemokines that can attract a variety of leukocytes. The question arises as to why this
is not deleterious to the tumor itself. Breast cancers,
for instance, are known to secrete macrophage chemotactic protein-1 (MCP-1), a chemokine that attracts
macrophages through CCR2. Higher tissue levels of
MCP-1 correlate with increasing number of macrophages within the tissue. While chemokines secreted
by tumor cells do lead to recruitment of immune cells,
this does not necessarily lead to increased clearance of
the tumor.89
Inflammatory cells such as macrophages may actually play a critical role in cancer invasion and metastasis. Firstly, MCP-1 may increase expression of macrophage IL-4 through an autocrine feedback loop and
possibly skew the immune response from Th1 to Th2.
Interestingly, MCP-1-deficient mice show markedly
reduced dermal fibrosis following dermal challenge
with bleomycin, a finding of possible relevance to
the pathogenesis of conditions such as scleroderma.5
Secondly, macrophages may promote tumor invasion and metastasis.90 The antitumor effects of specific
chemokines may occur by a variety of mechanisms.
ELR CXCR3 ligands such as IP-10 are potently antiangiogenic and may act as downstream effectors of
IL-12-induced, NK cell-dependent angiostasis.91 Of
note, some cancer cells can synthesize LARC, attracting immature DC that express CCR6.92 Experimentally,
LARC has been transduced into murine tumors, where
it attracts DC in mice and suppresses tumor growth in
experimental systems.93 Lastly, chemokines produced
by tumor cells may attract CD4+CD25+ T regulatory
cells (Tregs) that suppress host antitumor cytolytic T
cells.94
Tumor metastasis is the most common cause of mortality and morbidity in cancer. With skin cancers such
as melanoma, there is a propensity for specific sites
such as brain, lung, and liver, as well as distant skin
sites. Cancers may also metastasize via afferent lymphatics and eventually reach regional draining LN.
The discovery of nodal metastasis often portends a
poor prognosis for the patient. In fact, the presence of
nodal metastases is one of the most powerful negative
predictors of survival in melanoma.95
Chemokines may play an important role in the sitespecific metastases of cancers of the breast and of melanoma96 (Fig. 12-4). Human breast cancer as well as melanoma lines express the chemokine receptors CXCR4
Chapter 12
skin inflammation. Chemokines, including CCL2076

and CCL178 mediate the arrest of effector memory T
cells on endothelial cells that synthesize these chemokines.77 In addition, both CCL17 and CCL20 can be
synthesized by keratinocytes, possibly contributing to
T cell migration to the epidermis.
While psoriasis has traditionally been considered
a classical Th1-associated disease, accumulating evidence points to an important pathogenetic contribution of Th17 cells, which strongly express CCR6.79 Th17
cells, their signature effector cytokines IL-17 and IL-22,
as well as high levels of IL-23, a major growth and
differentiation factor for Th17 cells, are abundant in
psoriatic skin lesions.80 Recent research suggests that
CCR6 and its ligand, CCL20, are important mediators
of psoriasis since both CCL20 as well as CLA+CCR6+
skin-homing Th17 cells are found in abundance in
lesional psoriatic skin.80,81 Moreover, CCR6-deficient
mice failed to develop psoriasis-like inflammation82
in response to intradermal IL-23 injections, a murine
model for human psoriasis83 (eFig. 12-3.2 in online edition). Interestingly, CCR6 was required for both T cell
dependent as well as T cell independent skin inflammation in this model.82
Neutrophils found in the epidermis of psoriatic skin
are probably attracted there by high levels of IL-8,
which would act via CXCR1 and CXCR2. In addition
to attracting neutrophils, IL-8 is an ELR+ CXC chemokine that is known to be angiogenic, and it may also
attract endothelial cells. This may lead to the formation of the long tortuous capillary blood vessels in the
papillary dermis that are characteristic of psoriasis.
Moreover, keratinocytes also express CXCR2 and thus
may be autoregulated by the expression of CXCR2
ligands in the skin. Of note, an IL-8/CXCL8-producing population of memory T cells that express CCR6
has been isolated from patients with acute generalized exanthematous pustulosis (AGEP), a condition
induced most commonly by drugs (e.g., aminopenicillins) and characterized by small intraepidermal or
subcorneal sterile pustules.84 Similar T cells have been
isolated from patients with Behets disease and pustular psoriasis.78 It is possible that this subpopulation
of T cells contributes to neutrophil accumulation in
the stratum corneum (Munros abscesses) in psoriasis
and other inflammatory skin disorders characterized
by neutrophil-rich infiltrates in the absence of frank
infection.
149
Chemokine receptors in melanoma progression and metastasis
Tumor cells
Lungs
CXCR4
Lymph node
CCR7/CCR10
Section 4
Primary metastatic
lesion
CCR10
::
150
Small intestine
CCR9
Lymphatic vessel
Figure 12-4 Chemokine receptors in melanoma progression and metastasis. Chemokine receptors play distinct roles in
melanoma metastasis.96 CCR10 may enhance survival of primary melanoma tumors and skin metastases. CCR7, CCR10,
and, possibly, CXCR4 may contribute to lymph node metastasis. CXCR4 appears to be involved in primary tumor development and metastasis at distant organ sites such as the lungs. CCR9 has been implicated in melanoma small bowel metastasis in patients.
and CCR7, whereas normal breast epithelial cells and

melanocytes do not appear to express these receptors.97 CXCR4 is expressed in over 23 different solid and
hematopoietic cancers. Broad expression of this receptor may be due to its regulation by hypoxia, a condition
common to growing tumors, via the hypoxia inducible factor-1 transcription factor.98 Notably stromal
fibroblasts within human cancers express the CXCR4
ligand, CXCL12, which stimulates tumor growth as
well as angiogenesis.99 In several different animals of
breast cancer97 and melanoma metastasis,29 inhibition of
CXCR4 with antibodies or peptides resulted in dramatically reduced metastases to distant organs. Expression
of CCR7 by cancer cells, including gastric carcinoma and
melanoma, appears to be critical for invasion of afferent
lymphatics and LN metastasis. CCR7-transfected B16
murine melanoma cells were found to metastasize with
much higher efficiency to regional LN compared to control B16 cells after inoculation into the footpad of mice,17
but CCR7 also directly stimulates primary B16 tumor
development as well.100 CCR9 may also play a role in
melanoma metastasis to the small bowel, which shows
high expression of the CCR9 ligand, CCL25.19
CCR10 is highly expressed by melanoma primary
tumors22 and is correlated with nodal metastasis in melanoma patients101 and in experimental animal models
(eFig. 12-4.1 in online edition).22 Engagement of CCR10
by CTACK results in activation (via phosphorylation) of
the phosphatidylinositol 3-kinase (PI3K) and Akt signaling pathways, leading to antiapoptotic effects in melanoma cells.22 Because CTACK is constitutively produced
by keratinocytes, it may act as a survival factor for both
primary as well as secondary (metastatic) melanoma
tumors that express CCR10. In fact, CCR10-activated
melanoma cells become resistant to killing by melanoma
antigen-specific T cells (eFig. 12-4.1 in online edition).22
Interestingly, CCR4,11 CXCR4,102 and CCR1023,103 have
been implicated in the trafficking and/or survival of
malignant T (lymphoma) cells to skin. Thus, a limited
number of specific chemokine receptors appear to play
distinct, nonredundant roles in facilitating cancer progression and metastasis (summarized in Fig. 12-4).
INFECTIOUS DISEASES
Although chemokines and chemokine receptors may
have evolved as a host response to infectious agents,
recent data suggest infectious organisms may have
coopted chemokine- or chemokine receptor-like molecules to their own advantage in selected instances. A
variety of microorganisms express chemokine receptors, including US28 by cytomegalovirus and Kaposis sarcoma herpes virus (or human herpes virus-8)
G-protein coupled receptor (GPCR). In the case of
KSHV GPCR, this receptor is able to promiscuously
neutropenia and abnormal neutrophil morphology.

The nearly universal presence of HPV infections associated with this syndrome can involve multiple common,
as well as genital, wart subtypes (eFig. 12-4.2 in online
edition) and suggest a critical role for normal CXCR4
function in immunological defense against this common human pathogen.
SUMMARY
::
Chemokines
The skin is rich in cells (keratinocytes, fibroblasts,

endothelial cells, and immune cells) that are able to
produce chemokines. Chemokines not only orchestrate
the migration of inflammatory cells but also play roles
in angiogenesis, cancer metastasis, and cellular proliferation. Other unanticipated biologic roles may ultimately be discovered. Just two of the promising therapeutic applications of chemokines (or molecules that
mimic chemokines) may be in (1) preventing undesirable migration into the skin by preventing arrest of T
cells or other inflammatory cells on activated endothelium, and (2) blocking the infection of dendritic cells
and T cells by HIV-1 virus using CCR5 analogs. Signaling pathways are just beginning to be understood,
and further work needs to be done to understand the
regulation of these receptors, the specificity of intracellular activities, and the mechanism by which chemokine receptors work in the face of multiple chemokines
present in many inflammatory sites.
Chapter 12
bind several chemokines. More importantly, it is constitutively active and may work as a growth promoter
in Kaposis sarcoma.104
The human immunodeficiency virus (HIV)-1, the
causative agent of the acquired immunodeficiency syndrome (AIDS), is an enveloped retrovirus that enters
cells via receptor-dependent membrane fusion (see
Chapter 198). CD4 is the primary fusion receptor for all
strains of HIV-1 and binds to HIV-1 proteins, gp120 and
gp41. However, different strains of HIV-1 have emerged
that preferentially use CXCR4 (T-tropic) or CCR5
(M-tropic) or either chemokine receptor as a coreceptor
for entry. While other chemokine coreceptors can potentially serve as coreceptors, most clinical HIV-1 strains
are primarily dual-tropic for either CCR5 or CXCR4.3
The discovery of a 32-base pair deletion (D32)
in CCR5 in some individuals that leads to low levels of CCR5 expression in T cells and dendritic cells
and correlates with a dramatic resistance to HIV-1
infection demonstrated a clear role for CCR5 in the
pathogenesis of HIV-1 infection.105 Interestingly, the
frequency of D32 mutations in humans is surprisingly
high, and the complete absence of CCR5 in homozygotes has only been associated with a more clinically
severe form of sarcoidosis. Otherwise, these individuals are healthy. In fact, there is an association of less
severe autoimmune diseases in patients with these
mutations.106
LC reside in large numbers in the genital mucosa
and may be one of the first initial targets of HIV-1 infection.107 Since infected (activated) LC likely enter dermal
lymphatic vessels and then localize to regional LN as
described earlier, the physiologic migratory pathway
of LC may also coincidentally lead to the transmission of HIV-1 to T cells within secondary lymphoid
organs. CCR5 is expressed by immature or resting LC
in the epidermis and is the target of CCR5 analogs of
RANTES that block HIV infection.108 Already, an FDAapproved small molecule inhibitor of CCR5, maraviroc,
is available for use in treatment of HIV disease and may
show fewer adverse effects than certain reverse transcriptase inhibitors.109 CXCR4 antagonists may also
be of clinical utility with T- or dual-tropic viruses.110
A newly described autosomal dominant genetic syndrome comprised of warts (human papilloma virus
(HPV)-associated), hypogammaglobulinemia, infections, and myelokathexis (WHIM) is the result of an
activating mutation (deletion) in the cytoplasmic tail of
the CXCR4 receptor or in yet unidentified downstream
regulators of CXCR4 function.111,112 Bacterial infections
are common because myelokathexis is associated with
KEY REFERENCES
1. Charo IF, Ransohoff RM: The many roles of chemokines
and chemokine receptors in inflammation. N Engl J Med
354(6):610-621, 2006
2. Zlotnik A, Yoshie O: Chemokines: A new classification
system and their role in immunity. Immunity 12(2):121127, 2000
29. Murakami T et al: Expression of CXC chemokine receptor (CXCR)-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res 62:73287334, 2002
34. Homey B: Chemokines and inflammatory skin diseases.
Adv Dermatol 21:251-277, 2005
58. Ohl L et al: CCR7 governs skin dendritic cell migration
under inflammatory and steady-state conditions. Immunity 21(2):279-288, 2004
82. Hedrick MN et al: CCR6 is required for IL-23-induced
psoriasis-like inflammation in mice. J Clin Invest 119(8):
2317-2329, 2009
151
Chapter 13 :: Allergic Contact Dermatitis

:: Mari Paz Castanedo-Tardan &
Kathryn A. Zug
ALLERGIC CONTACT DERMATITIS
AT A GLANCE
Section 4
::
152
Allergic contact dermatitis (ACD) is a

cell-mediated (type IV), delayed type,
hypersensitivity reaction caused by skin
contact with an environmental allergen.
Prior sensitization to a chemical is required
for allergy to develop.
The clinical manifestation of ACD is an
eczematous dermatitis. The acute phase
is characterized by pruritus, erythema,
edema, and vesicles usually confined to the
area of direct exposure. Recurrent contact
to the allergen in a sensitized individual
will result in chronic disease, characterized
by lichenified erythematous plaques with
variable hyperkeratosis and fissuring that
may spread beyond the areas of direct
exposure.
Itch and swelling are key components of the
history and can be a clue to allergy.
The hands, feet, and face (including the
eyelids) are some of the common sites for
ACD.
Patch testing is fundamental for the
identification of causal allergens and is
indicated for patients with persistent or
recurrent dermatitis in whom ACD is
suspected.
Avoidance is the mainstay of treatment for

ACD. Educating patients about avoidance
of the allergen and its potentially related
substances, and providing suitable
alternatives are crucial to a good outcome.
As the largest organ in the human body, the skin is a

complex and dynamic organ that serves among many
other purposes, the function of maintaining a physical
and immunologic barrier to the environment. Therefore,
the skin is the first line of defense after exposure to a
variety of chemicals. Allergic contact dermatitis (ACD)
accounts for at least 20% or more of the new incident
cases in the subgroup of contact dermatitides (irritant contact dermatitis accounts for the remaining 80%).1 ACD,
as the name implies, is an adverse cutaneous inflam-
matory reaction caused by contact with a specific exogenous allergen to which a person has developed allergic sensitization. More than 3,700 chemicals have been
implicated as causal agents of ACD in humans.2 Following contact with an allergen, the skin reacts immunologically, giving the clinical expression of eczematous
inflammation. In ACD the severity of the eczematous
dermatitis can range from a mild, short-lived condition to a severe, persistent, chronic disease. Appropriate allergen identification through proper epicutaneous
patch testing has been demonstrated to improve quality
of life as measured by standard tools,3 as it allows for
appropriate avoidance of the inciting allergen and possibly sustained remission of this potentially debilitating condition. Recognition of the presenting signs and
symptoms, and appropriate patch testing are crucial in
the evaluation of a patient with suspected ACD.
EPIDEMIOLOGY
A small but substantial number of studies have investigated the prevalence of contact allergy in the general
population and in unselected subgroups of the general population. In 2007, Thyssen and colleagues4 performed a retrospective study that reviewed the main
findings from previously published epidemiological
studies on contact allergy in unselected populations
including all age groups and most publishing countries (mainly North America and Western Europe).
Based on these heterogeneous published data collected between 1966 and 2007, the median prevalence
of contact allergy to at least one allergen in the general
population was 21.2%. Additionally, the study found
that the most prevalent contact allergens in the general
population were nickel, thimerosal, and fragrance mix.
Importantly, the prevalence of contact allergy to specific allergens differs between various countries5,6 and
the prevalence to a specific allergen is not necessarily
static, as it is influenced by changes and developments
in the regional environment, exposure patterns, regulatory standards, and societal customs and values.
On a final note about epidemiology, contact allergy
caused by ingredients found in personal care products
(cosmetics, toiletries) is a well-known problem, with
approximately 6% of the general population estimated
to have a cosmetic-related contact allergy.19,20 Contact
allergy to ingredients in personal care products will be
further discussed in this chapter.
AGE
Over the past decade, multiple studies have recognized contact dermatitis as an important cause of
childhood dermatitis, and a common diagnosis among
children; being equally as likely in childhood as in

adulthood,21,22 although the most common allergens
identified differ between the age groups. On the other
hand, although fragrance mix allergy is an important
sensitizer in all ages, certain studies, such as the 2001
Augsburg study, which was based on adults aged
2875 years, have shown a significant increase in fragrance mix allergy with increasing age.23 Similarly,
Magnusson et al24 demonstrated a high prevalence rate
(4.7%) of Myroxylon pereirae (balsam of Perua marker
for fragrance allergy) sensitization among 65-year-old
Swedish patients. Similarly, a recent Danish study
demonstrated the prevalence allergy to preservatives
being higher among those aged 4160 years.25
Allergic contact dermatitis represents a classic cellmediated, delayed (type IV) hypersensitivity reac-
Allergic Contact Dermatitis
ETIOLOGY AND PATHOGENESIS
tion. Such immunological reaction, results from exposure and subsequent sensitization of a genetically
susceptible host, to an environmental allergen, which
on reexposure triggers a complex inflammatory reaction. The resulting clinical picture is that of erythema,
edema, and papulo-vesiculation, usually in the distribution of contact with the instigating allergen,
and with pruritus as a major symptom Fig. 13-1.35 To
mount such reaction, the individual must have sufficient contact with a sensitizing chemical, and then
have repeated contact with that substance later. This
is an important distinction to irritant contact dermatitis (ICD) in which no sensitization reaction takes
place, and the intensity of the irritant inflammatory
reaction is proportional to the doseconcentration
and amount of the irritant. In ACD, only minute
quantities of an allergen are necessary to elicit overt
allergic reactions. There are two distinct phases in the
development of ACD: the sensitization phase and the
elicitation phase.36
::
Because very few studies have looked at the induction

of allergic contact sensitization in men and women
under controlled circumstances, gender differences in
the development of ACD are largely unknown. When
the human repeat-insult patch testing method was
used to assess induction rates for ten common allergens, women were more often sensitized to seven of
the ten allergens studied.26 With regard to frequency,
Thyssen and colleagues found that the median prevalence of contact allergy among the general population
was 21.8% in women versus 12% in men. When looking specifically at nickel sensitivity, the same study
showed that the prevalence was much higher among
women than men (17.1% in woman vs. 3% in men).
This might be due to the fact that numerous studies
have demonstrated that pierced ears are a significant
risk factor for development of nickel allergy.2731 Thus,
the higher prevalence of nickel allergy in women may
be explained by the higher median prevalence of
pierced ears in women in comparison with men (81.5%
in women vs. 12% in men) of the population studied.
The role of race, if any, in the development of ACD to
some potent allergens such as para-phenylenediamine
(PPD), remains controversial.32,33 Limited studies have
suggested lower sensitizations rates to nickel and neomycin in African Americans compared to Caucasians.
With regard to the patch-test protocol, the evaluation
of positive reactions may be slightly more difficult in
darker skin types (Fitzpatrick types V and VI), as erythema may not be as obvious, posing the risk of overlooking a mild positive allergic reaction. However, the
edema and papules/vesicles are usually obvious and
palpable; therefore palpation of the patch-test site can
help to detect allergic reactions in patients with darker
skin types. Finally, the darker the skin, the more difficult it is to mark the patch-test site after removal. For
very dark skin, a florescent marking ink is probably
best, the markings being located by a Woods light in a
darkened room.34
Figure 13-1 Erythematous papules and vesicles are characteristics of contact allergy in the acute stage.
Chapter 13
GENDER AND RACE
SENSITIZATION PHASE
Most environmental allergens are small, lipophilic
molecules with a low molecular weight (<500 Daltons).
The unprocessed allergen is more correctly referred to
as a hapten. Once the hapten penetrates the skin, it
binds with epidermal carrier proteins to form a haptenprotein complex, which produces a complete antigen. Next, the antigen presenting cells (APC) of the skin
(Langerhans cells and/or dermal dendritic cells), take
up the haptenprotein complex and express it on its
surface as an HLA-DR molecule. The antigen-presenting cell then migrates via the lymphatics to regional
lymph nodes where it presents the HLA-DRantigen
complex to naive antigen-specific T cells that express
both a CD4 molecule that recognizes the HLA-DR and
more specifically a T-cell receptor CD3 complex that
recognizes the processed antigen. The antigen can also
be presented in the context of the MHC class I molecules, in which case it would be recognized by CD8
cells. Subsequently, the naive T cells are primed and
differentiate into memory (also referred to as effector T cells) which undergo clonal expansion, acquire
skin-specific homing antigens, and emigrate out of the
153
Section 4
::
154
Box 13-1 New Developments in Contact Dermatitis

Emerging evidence suggests that innate immune cells such as Natural Killer (NK) cells play a significant role in
ACD.
NK T cells (a hybrid between an NK cell and a conventional T cell) have been found to be necessary for the initiation of
ACD and are also present in the elicitation phase of ACD.
Recent studies suggest that Langerhans cells (LC) that have been credited with an indispensable role in ACD may not
be essential for the development of contact hypersensitivity. New studies of mice that lack LHCs suggest that they may
even play a regulatory role in ACD.
Dermal dendritic cells may be the antigen presenting cells (APC) that complement epidermal LCs.
T-regulatory (T-reg) cells may be critical in the control of ACD (resolution of T-cell inflammation). Loss of T-reg cell
activity may play a role in chronic inflammation.
Mast cells appear to be pivotal in determining the magnitude of the inflammatory reaction.
Keratinocytes play a role in all phases of ACD; from the initiation phase when their production of TNF- after antigen
exposure modulates APC migration and T-cell trafficking; through the peak of the inflammatory phase when they
interact directly with epidermotrophic T cells; to the resolution of ACD through tolerogenic antigen presentation and
the production of anti-inflammatory cytokines such as IL-10 and IL-16, which recruit T-regs.
From Gober MD, Gaspari AA: Allergic contact dermatitis. Curr Dir Autoimmun 10:1, 2008.
lymph node into the circulation.37,38 These clones of

CD4+ Th1 and CD8+ type 1 cytotoxic T cells are then
able to act as effectors on target cells presenting the
antigen in the future.39 The sensitization phase generally lasts 1015 days and is often asymptomatic.40 Subsequent exposure to the antigen, or rechallenge, leads
to an elicitation phase. Such rechallenge can occur via
multiple routes, including transepidermal, subcutaneous, intravenous, intramuscular, inhalation, and oral
ingestion.41
ELICITATION PHASE
During this phase, both the APCs and the keratinocytes can present antigen and lead to subsequent
recruitment of hapten-specific T cells. In response, the
T cells release cytokines, including IFN- and TNF-,
which, in turn, recruit other inflammatory cells while
stimulating macrophages and keratinocytes to release
more cytokines.42,43 An inflammatory response occurs
as monocytes migrate into the affected area, mature
into macrophages, and thereby attract more T cells.
This localized proinflammatory state results in the
classical clinical picture of spongiotic inflammation
(redness, edema, papules and vesicles, and warmth).
Recent advances in the knowledge of the pathophysiology of ACD have demonstrated the important role
of the skin innate immunity in the sensitization process; have revisited the dogma that Langerhans cells
are mandatory for ACD; and have addressed the
nature, mode, and site of action of the regulatory T
cells that control the skin inflammation (Box 13-1)
(see also Chapter 10).44,45 This new understanding
may facilitate the development of strategies for tolerance induction, as well as the identification of novel
targets for pharmacological agents for the treatment
of ACD.
CLINICAL APPROACH
An algorithmic approach to the patient is described in
the following sections.
CONSIDERATION OF THE DIAGNOSIS

The character and distribution of the dermatitis
should raise the index of suspicion for ACD. Therefore, any patient who presents with an eczematous
dermatitis should be regarded as possibly having
ACD (Fig. 13-2). Additionally, one must also consider
contact allergy in patients with other types of dermatitis (e.g., atopic) that is persistent and recalcitrant
despite appropriate standard therapies, as well as in
patients with erythroderma, or scattered generalized
dermatitis.46 Furthermore, it is important to note that
patients with stasis dermatitis are at increased risk
of developing ACD from topical medications and
lotions which are often applied under occlusion over
chronically inflamed and broken skin (Fig. 13-3). For
that reason, ACD should always be in the differential of eczematous lesions surrounding leg ulcers.
Finally, it is important to avoid some commonly held
misconceptions about ACD that can alter a physicians ability to recognize contact dermatitis. These
were described by Marks and DeLeo and include the
following:

ACD is not always bilateral even when the antigen

exposure is bilateral (i.e., shoe or glove allergy).
Even when exposure to an allergen is uniform (e.g.,
contact allergy to an ingredient of a cream that is
applied on all of the face), eczematous manifestations are very often patchy.
ACD can and does affect the palms and the soles.
Figure 13-2 Typical appearance of eczematous dermatitis compatible with ACD. A. Note the erythematous scaly plaques
with some fissuring on the hands. B. Erythematous papules, scattered on the extensor forearms. This is a typical picture of
contact allergy to a skin care product ingredient.
Chapter 13
::
The first step in the diagnosis of ACD is a careful

medical and environmental exposure history. History taking should begin with a discussion of the
present illness focusing on the site of onset of the
problem and the topical agents used to treat the problem (including over the counter and prescription
medications). A past history of skin disease, atopy,
and general health should be routinely investigated.
This is followed by a detailed history of the usage of
personal care products (soap, shampoo, conditioner,
deodorant, lotions, creams, medications, hair styling
products, etc.), and investigation of the patients avocations or hobbies. The occupation should be ascertained as well, and if it appears contributory, or there
are potential allergenic exposures, then a thorough
occupational history should be taken. Occupations
Figure 13-3 Stasis dermatitis is a risk factor for the development of contact allergy. This is likely because of more
frequent application of products that contain contact
allergens to this area. Products without high frequency
positive allergens are preferred in this area.
requiring frequent hand washing, glove use, or frequent chemical exposure should be prime suspects,
among others.
CLINICAL MANIFESTATIONS
CUTANEOUS FINDINGS
The classic presentation of ACD is a pruritic, eczematous dermatitis initially localized to the primary site
of allergen exposure. Geometric or linear patterns or
involvement of focal skin areas, may also be suggestive
of an exogenous etiology (Fig. 12-4B). A linear or streaky
array on the extremities, for example, often represents
ACD from poison ivy, poison oak, or poison sumac.
Occasionally, the actual sensitizing substance in these
plants, an oleoresin named urushiol may be aerolized
when the plants are burned, leading to a more generalized and severe eruption on exposed areas such as the
face and arms. Transfer of the resin from sources other
than directly from the plant (such as clothes, pets, or
hands) may result in rashes on unexpected sites (i.e.,
genital involvement in a patient with poison ivy). Thus,
relevant historic data gathered from thoughtful questioning may prove as useful as the distribution of the
lesions.
It is important to note that lesions of ACD will vary
morphologically depending on the stage of the disease. For example, during the acute phase, lesions are
marked by edema, erythema, and vesicle formation.
As the vesicles rupture, oozing ensues and papules
and plaques appear. Stronger allergens often result
in vesicle formation, whereas weaker allergens often
lead to papular lesion morphology, with surrounding erythema and edema. Subacute ACD on the other
hand, will present with erythema, scaly juicy papules
and weeping; whereas chronic ACD can present with
scaling, fissuring, and lichenification. A key symptom
for allergy is pruritus, which seems to occur more
typically with allergy, than a complaint of burning.47
HISTORY TAKING
155
Section 4
::
Figure 13-4 ACD to para-phenylenediamine. A. Notice the eczema on the distribution of the hairline and behind the ears.
B. Dermatitis on the forehead where the bangs came in contact with the skin of the same patient. C. para-Phenylenediamine, the most frequent relevant allergen in hair dye, is a strong sensitizer. It will darken the patch-test site. There is a
strong edematous and vesicular reaction that is spreading, a 3+ reaction to this patch test.
Moreover, there are some noneczematous clinical variants of ACD that are infrequently observed.48 These
include among others:

156
Purpuric ACD is mainly observed on the lower legs

and/or feet and has been reported with a wide
variety of allergens including textile dyes.
Lichenoid ACD is considered a rare variant. Clinical
features mimic lichen planus and has been associated with metallic dyes in tattoos. Oral lichenoid
ACD from dental amalgams can resemble typical
oral lichen planus.
Pigmented ACD has been mainly described in populations from Asian ethnicity.
Lymphomatoid ACD is based only on histopathological criteria (presence of significant dermal
infiltrate displaying features of pseudolymphoma). Clinical signs which are nonspecific
include erythematous plaques, sometimes very
infiltrated, at the site of application of the contact
allergen. Some examples include allergy to metal,
allergy to hair dye, and to dimethylfumarate,
a mold inhibitor found in sachets within some
furniture implicated in causing a severe epidemic
of ACD.
TOPOGRAPHIC APPROACH
Dermatitis distribution is usually the single most
important clue to the diagnosis of ACD. Typically, the
area of greatest eczematous dermatitis is the area of
greatest contact with the offending allergen(s). Location, in fact, can be one of the most valuable clues as
to which chemical might be the culprit of a patients
ACD. For instance, an eczematous dermatitis in the
peri/infraumbilical area suggests contact allergy to
metal snaps in jeans and belt buckles, whereas eczema
distributed around the hairline and behind the ears
suggests contact allergy to an ingredient(s) in hair
products (hair dyes, shampoo, conditioners, styling
products) (Fig. 13-4). Using the same rationale, eczema
on the dorsum of the feet suggests contact allergy to
products used to make shoe uppers like leather, rubber,
or dyes, while eczematous dermatitis on the weightbearing surfaces of the feet suggests contact allergy to
products used to make insoles/soles like rubber and
adhesive materials. Notably, facial, eyelid, lip, and
neck patterns of dermatitis should always raise suspicion of a cosmetic-related contact allergy. However, for
all of these presentations, correct identification of the
EYELIDS. The eyelids are one of the most sensitive skin areas, and are highly susceptible to irritants
and allergens perhaps due to the thinness of the eyelid skin, as compared with the rest of the skin, and
perhaps because they can accumulate the offending
chemical in the skin folds. Transfer of small amounts
SCALP. Allergens applied to the scalp most often

produce patterns of dermatitis on the forehead and
lateral aspect of the face, eyelids, ears, neck, and
hands; whereas the scalp remains uninvolved, suggesting that the scalp is particularly resistant to
contact dermatitis. Nevertheless, patients exquisitely
sensitive to certain ingredients in hair products such
as PPD or glyceryl monothioglycolate may show a
marked scalp reaction with edema and crusting. PPD
is one of the most potent sensitizers known and is
widely used as an ingredient in hair dyes. In general,
PPD sensitization manifests on the face and scalp of
female adult patients who had contact with a hair
dye.5154 Glyceryl thioglycolate (GMT), on the other
hand, is a chemical substance used in permanent
wave solutions. Allergic sensitivity to GMT can manifest as intense scalp reactions with scaling, edema,
and crusting.55
::
FACE. The face is a common site for ACD. Among

patients with facial dermatitis, women are more commonly affected than men, particularly by cosmeticassociated allergens such as fragrances, PPD, preservatives, and lanolin alcohols (eFig. 13-4.1 in online
edition).49 Allergens can be applied to the face directly
but can also be indirectly transferred from airborne
or hand-to-face exposure. In addition to allergens
found as ingredients in cosmetics, products used to
apply themsuch as cosmetic sponges, have also
been reported to produce facial dermatitis in rubbersensitive patients.50 A similar situation is seen with
nickel-plated objects used on the hair, such as bobby
pins and curlers that may produce scalp and facial dermatitis in nickel-sensitive patients.
of allergens used on the scalp, face, or hands can be

enough to cause an eczematous reaction of the eyelids, while the primary sites of contact remain unaltered (eFig. 13-4.2 in online edition). Similarly, volatile agents may affect the eyelids first and exclusively,
causing airborne eyelid contact dermatitis. Sources
of contact dermatitis of the eyelids include cosmetics
such as mascara, eyeliners and eye shadows, adhesive
in fake eyelashes, and nickel and rubber in eyelash
curlers. Furthermore, marked edema of the eyelids is
often a feature of hair-dye dermatitis.56 As mentioned
earlier in this chapter, eyelids are also known for being
a typical site for ectopic contact dermatitis caused by
ingredients found in nail lacquer, such as tosylamide
formaldehyde resin (TSFR), the chemical added to
nail varnish to facilitate adhesion of the varnish to the
nail and epoxy resin, also added to some nail polishes.
Topical antibiotics (like bacitracin and neomycin) and
certain metals such as gold57 can also cause eyelid contact dermatitis. In fact, in the 2007 NACDG analysis of
contact allergens associated with eyelid dermatitis,58
gold was the most common allergen accounting for
pure eyelid dermatitis. Notably, it has been observed
that upon contact with hard particles such as titanium
dioxide (used to opacify facial cosmetics, and in sunscreens as a physical blocker of ultraviolet light), gold
found in jewelry may abrade, resulting in the release
of gold particles that can then make contact with facial
and eyelid skin, causing dermatitis.59 Aside from gold,
fragrances and preservatives have been found to be
the main cosmetic allergens to cause dermatitis limited to the eyelids.60
Chapter 13
culprit chemical(s) will still require patch testing, since

even the most astute and experienced clinician is, for
the most part, unable to properly surmise the positive
allergen(s) prior to testing. The pattern of dermatitis
should be mainly used in determining whether or not
to patch test, and which allergens and screening series
to test.
Occasionally, the topographic approach does not
hold, and the distribution can actually be misleading.
This mainly refers to cases of ectopic ACD or airborne
ACD. Ectopic ACD can follow two circumstances:
Auto transfer, in which the allergen is inconspicuously
transferred to other body sites by the fingersthe classical example being nail lacquer dermatitis located on
the eyelids or lateral aspects of the neck; and heterotransfer, in which the offending allergen is transferred
to the patient by someone else (spouse, parent, etc.);
this is described in the literature as connubial or consort ACD.
A discussion of allergens in the context of common
patterns of presentation is briefly detailed below.
LIPS. According to an NACDG study, approximately

one-third of patients with cheilitiswithout other
areas of dermatitisare typically found to have an
allergen as a contributing factor.61,62 Allergic contact
cheilitis (ACC) has been reported to result from the
use of a wide array of products including cosmetics
such as lip balms, lipsticks, lip glosses, moisturizers,
sunscreens, nail products, and oral hygiene products
(mouthwashes, toothpastes, dental floss) (Fig. 13-5).6365
Figure 13-5 Allergic Contact Cheilitis. Fragrances and

flavorings are top among the most common causes of
contact allergy in patch-tested patients with cheilitis.
157
Section 4
::
158
ACC has a marked female predominance, with

most studies reporting a range of 70.7%90% female
patients.66 This is likely explained by the assumption
that women wear more cosmetics and lip products
than men. Most studies have reported fragrance allergens [such as fragrance mix and Myroxylon pereirae
(Balsam of Peru)] as the most common cause of contact allergy in patch-tested patients with cheilitis.67 Of
note, some uncommonly reported allergens, namely,
benzophenone-3 and gallates, may be relevant to a dermatitis localized to the lips. Benzophenone-3, a major
constituent of many sunscreens, is also a common
ingredient in many lip products and is increasingly
reported as a culprit for ACC.68,69 Gallates are antioxidants used in waxy or oily products such as lip balms,
lipsticks, and lip glosses.70
NECK. The neck is also a highly reactive site for

ACD. Cosmetics applied to the face, scalp, or hair
often initially affect the neck. Nail-polish ingredients
(tosylamide formaldehyde resin and epoxy resin) are
common culprits in this region.71 Furthermore, as a
cultural practice, perfumes are sprayed on the neck.
In a fragrance-sensitized individual, the practice of
repeated application of fragrances to the anterior neck
may result in the appearance of a dermatitic plaque on
the neck, which has been coined the atomizer sign.72
Also, in this topographic area, metal allergy can manifest as chronic eczematous dermatitis from exposure to
necklaces and jewelry clasps that contain nickel and/
or cobalt.
TORSO. The torso can encounter fragrances, preservatives, surfactants, and other chemicals from the
use of personal care products; yet it is also susceptible to allergens found in textiles. Textile-associated
allergens include disperse dyes (azoanilines) and
formaldehyde-releasers used as durable press chemical finishes (DPCF). In the past, finishes used to contain large amounts of free formaldehyde, which led to
many cases of allergic contact dermatitis to clothing
in the 1950s and 1960s. However, currently most finishes are based on modified dimethylol dihydroxyethyleneurea, which releases less formaldehyde. Importantly, recent studies have shown that the amount of
free formaldehyde in most garments will likely be
below the threshold for the elicitation of dermatitis
for all but the most sensitive patients, and that the
amount of free cyclized urea in clothes is unlikely to
be high enough to cause sensitization.73
AXILLAE. Heat, humidity, and friction of the axillary
fold may contribute to the leaching of textile resins and
dyes and dermatitis accentuation in these areas.74 The
axillary region is also uniquely exposed to deodorants and antiperspirants. These products contain most
notably the contact allergens fragrances and preservatives (formaldehyde releasers, parabens, etc.). A commonly observed effect with the use of these products is
the sparing of the axillary vault, mainly secondary to
perspiration diluting the allergens. Aerosolized exposure of the allergens through antiperspirant/deodorants in spray, may lead to scattering of the allergen and
the resulting picture may be that of scattered satellite

papules.
HANDS AND FEET. Hand dermatitis has a particularly high incidence secondary to the fact that
the hands are the main means of interaction with the
environment, with increased possibility for numerous allergen exposures. Hand dermatitis accounts for
as much as 80% of the occupationally related skin diseases, especially in certain wet work occupations
such as health care workers, food handlers, etc.75
Thus, careful consideration should be given to occupation-specific exposures in the evaluation of patients
with hand dermatitis. As an example, a hairdresser
may be sensitized to ingredients in hair-care products
such as PPD, glyceryl monothioglycolate, or cocamidopropyl betaine (a surfactant-detergent, commonly
found in shampoos), whereas a construction worker
may become allergic to chromium through exposure
to wet cement. Clinical clues that should raise a higher
index of suspicion of ACD include the involvement of
the finger web spaces and the dorsal hands, as well
as the predominance of pruritus as a symptom. Still
the multifactorial etiology of hand dermatitis (irritant exposure, atopy, pompholyx or chronic vesicular hand eczema, psoriasis, dermatophyte infection,
among others) adds to the complexity of both diagnosing and treating these patients. Chronic hand
dermatitis is an indication for patch testing, as causal
or contributing allergy can result in improvement or
resolution of the problem. Similarly, the evaluation of
foot dermatitis should include patch testing with the
allergens most commonly associated with this condition. These include, rubber-related chemicals (such
as mercaptobenzothiazole, carba mix, thiuram mix,
mercapto mix, black rubber mix, and mixed dialkyl
thioureas) potentially present as components of shoes
and insoles; glues and adhesives used in shoe manufacturing like 4-tert-butylphenol formaldehyde resin;
and potassium dichromate found in tanned leathermade shoes. Testing materials should also include
topical antibiotics, corticosteroids, or antifungal
medications (both over-the-counter and prescription)
that may have been used by the patient to treat the
affected area.
Other topographic areas affected by ACD include
the oral mucosa, which may present with contact
stomatitis from dental metals and the perianal area,
which may react to sensitizing chemicals in proctologic
preparations such as benzocaine.
SCATTERED GENERALIZED
DERMATITIS
Patients with scattered generalized dermatitis (SGD)
usually present a difficult diagnostic and therapeutic
challenge. Patch testing can be a strategy for evaluating ACD as a potential relevant factor. In 2008, Zug
and NACDG colleagues 76 examined the yield of patch
testing as well as the relevant allergens in patients
with SGD referred for patch testing. Of 10,061 patients
studied during a period of 4 years, 14.9% had SGD.
Men and patients with a history of atopic eczema were

more likely to have dermatitis in this distribution. Of
the total of patients presenting with SGD, 49% had at
least one relevant positive patch-test reaction. Preservatives, fragrances, propylene glycol, cocamidopropyl
betaine, ethyleneurea melamine formaldehyde, and
corticosteroids were among the more frequently relevant positive allergens.
TABLE 13-2
Systemic Drugs that Can Cause Systemic

Reactivation of ACD
Contact Allergena
SYSTEMIC CONTACT DERMATITIS
Stage 1
The skin symptoms are limited to

the site (s) of application of contact
allergen(s).
Stage 2
There is a regional dissemination of

symptoms (via lymphatic vessels),
extending from the site of application of
allergen(s).
Stage 3
Can be further subdivided in

Stage 3A: Corresponds to
hematogenous dissemination of ACD at
a distance.
Stage 3B: Corresponds to systemic
reactivation of ACD (nontopical trigger)
Data from Lachapelle JM: Dermato-allergolie de contact. Nouv Dermatol (Strasbourg) 20:450, 2001 and Lachapelle JM, Maibach HI: Patch
Testing and Prick Testing: A Practical Guide. Berlin, Germany, SpringerVerlag, 2003.
Aminophylline
Piperazine antihistamines:
hydroxyzine, cetirizine,
levocetirizine and meclizine
Thiuram (rubber
antioxidant)
Tetraethyl thiuram disulfide

(generic name: disulfiram)
Thimerosal (mercuryderived preservative)
Piroxicam
To which a patient had previously become sensitized by direct, topical application of the contact allergen to the skin.
contact dermatitis, there is no occurrence of topical

skin contact to the allergen. Clinically, systemic contact dermatitis has a wide spectrum of presentation,
from a recall reaction (dermatitis at the site of prior
topical sensitization), to widespread dermatitis and
erythroderma. Other patterns that have been associated with systemic contact dermatitis include axillary
vaults, upper inner thighs, and buttockssometimes
described as baboon syndrome,79 which has been
associated with some internally ingested allergens,
i.e., cashew nut shell oil causing a cross-reaction to
the allergen urushiol. Dyshidrotic hand eczema/pompholyx are conditions in which oral challenges with
nickel, and Myroxylon pereirae have demonstrated
flaring of this type of hand eczema in some studies
(eFig. 13-5.1 in online edition).80 Of particular notoriety is the allergen Myroxylon pereirae also known as
balsam of Peru, a substance derived from Myroxolon
balsamum, a tree that is native to the country of El Salvador. Because the main components of Myroxylon
pereirae (cinnamic acid, cinnamyl cinnamate, benzyl
benzoate, benzoic acid, benzyl alcohol, and esterified
polymers of coniferyl alcohol) are naturally derived,
they have a significant number of natural cross-reactors. Certain foods, such as tomatoes and tomato-containing products, citrus fruit peel/zest, chocolate, ice
cream, wine, beer, vermouth, dark colored sodas, and
spices such as cinnamon, cloves, curry, and vanilla,
have chemical ingredients related to balsam of Peru.81
Consumption of these foods may result in a systemic
reactivation of ACD in some patients allergic to balsam of Peru. Salam and Fowler drew attention to this
ability of orally ingested balsam-related substances
to induce systemic contact dermatitis, and reported
that, in their study, remarkably almost half of the
subjects with a positive patch test to Myroxylon
pereirae who followed a balsam of Peru-reduction
diet, had a significant to complete improvement of
their dermatitis. Finally, some oral or IV medications
may cause systemic reactivation of ACD in patients
Stages of the Allergic Contact Dermatitis

Syndrome
Ethylenediamine
dihydrochloride
(stabilizer infrequently
found in skin care
products)
::
TABLE 13-1
Related Drug with

Potential to Cause Systemic
Reactivation of ACD
Chapter 13
In 2001, members of the International Contact Dermatitis Research Group (ICDRG) developed the
concept of the allergic contact dermatitis syndrome
(ACDS).77 This concept considers the various facets
of contact allergy, including morphological aspects
and staging by symptomatology. ACDS has three
stages that can be defined (Table 13-1) and with
many causes (Table 13-2).
Systemic contact dermatitis describes a systemic
reactivation of allergic contact dermatitis; in other
words, a cutaneous eruption in response to systemic
(nontopical) exposure to an allergen.78 In considering
the chains of events resulting in the development of
systemic reactivation of ACD, the ICDRG has suggested that the occurrence of some successive steps is
necessary. Initially, direct skin contact with an allergen results in sensitization. Second, in some relatively
uncommon cases, weeks or even years after that first
episode of ACD, the patient is systemically exposed to
exactly the same allergen, or to a related substance that
is chemically closely related to it (cross-sensitization),
elicitating a systemic reactivation of ACD. There are
multiple routes of exposure for the elicitation of systemic contact dermatitissubcutaneous, intravenous,
intramuscular, inhalation, and oral ingestion. It is
important then to note, that by definition, in systemic
159
previously sensitized to related allergens by direct

skin contact8285 (Table 13-2).
FREQUENCY APPROACH
Section 4
::
160
Because frequent is frequent, the approach to a

patient with suspected ACD can also be done taking
into account the most likely culprits based on frequency data of a given region, and the patients occupation or other individual exposures. This approach
should not replace by any means actual patch testing;
nevertheless, a working knowledge of the most common allergens can prove to be useful when evaluating
a patient with suspected ACD. Next is a brief description of the most frequently patch-test positive allergens in North America.
NICKEL. Nickel is a ubiquitous metal used in a

wide range of products including those that have a
prolonged contact with the skin (costume jewelry,
suspenders, zippers, button snaps, belt buckles, eyeglasses frames, cell phones, nickel-containing coins,
keys, among many others). There is a well-documented
rising incidence of nickel allergy in the United States
and elsewhere, with high nickel sensitization rates
documented in children.86 Ear piercing at an early age,
in addition to the trend of a greater number of other
body piercings, are consistently linked to the rise in
nickel sensitization in the recent decade.87,88 Currently,
nickel allergy is the most common cause of contact
dermatitis in the industrial world, particularly affecting females.89 Several studies have examined the striking discrepancy of sensitization incidence to nickel in
females versus males and have associated this with
ear piercing.90,91 Classically, nickel contact dermatitis
presents as an eruption on the earlobes, the neckline,
the wristband, or the periumbilical area since those are
common areas for exposure to nickel-containing jewelry or button snaps, zippers, and belt buckles. Facial
dermatitis caused by nickel has also been reported to
musical instruments and more recently to cell phones.92
Furthermore, the presence of nickel in implantable
medical devices and potential complications derived
from nickel allergy is a rising subject of discussion.
The relevance of nickel allergy in the failure of metal
orthopedic implants and cardiac devices is not clear.
Documented cases of joint replacement failure associated with nickel or other metal sensitivity are clearly
rare, and arthroplasty prostheses rarely cause a problem in the nickel sensitive individual. Existing publications are largely retrospective and thus can only
suggest a possible association of nickel allergy with
implant failure rather than determine causation.93
Similarly, eczematous reactions temporally related to
joint replacement or implantation of other orthopedic devices (i.e., metallic plates and screws) although
reported, are infrequent (eFig. 13-5.2 in online edition).
More studies are needed in this area.
In an attempt to prevent the development of nickel
sensitivity, Denmark in 1990, and the rest of the European Union in 1994, have regulated the amount on
nickel that may be released from objects with direct

and prolonged skin contact (0.5 g nickel/cm2/week;
revision for 2004: 0.2 g nickel/cm2/week for items
inserted into pierced parts of the body). Recent evidence indicates that the prevalence of nickel allergy is
decreasing among young Danish females from 27.6%
in 1985 to 16.8% in 2007.94 The American Academy of
Dermatology and the American Contact Dermatitis
Society favor enacting similar legislation in the United
States.
FRAGRANCES. Fragrances are aromatic compounds that impart a smell or odor. They can be natural (from botanical or animal products) or synthetic in
origin. It has been estimated that between 1% and 4%
of the general population is allergic to fragrances.95,96
Fragrance allergy is one of the two top causes of contact allergy to personal care products; the typical sites
of involvement include the face and hands, as well
as behind the ears, neck, and axillae, in addition to a
scattered generalized distribution of eczematous dermatitis.97,98 Two of the main substances used by most
patch-test groups for screening are among the top ten
allergens in North America. The first is fragrance mix
I, which is a mixture of eight fragrance allergens, and
the second is Myroxylon pereirae (MP) also known as
balsam of Peru (BOP), whose main components are
fragrance ingredients.99 MP is considered to be a good
marker for fragrance allergy, able to identify approximately 50% of fragrance allergic individuals.100 MPrelated substances can be found in products such as
cosmetics, perfumes, pharmaceutical preparations,
toothpastes and mouthwashes, as well as in scents
and flavorings for foods and drinks. Similarly, certain
foods, such as the ones mentioned earlier in the chapter, contain chemical ingredients related to MP. Surgical adhesives used postprocedure to secure dressings
also may cross-react and produce dermatitis in individuals sensitive to MP.
NEOMYCIN. Neomycin belongs to the aminoglycoside family of antibiotics commonly used in topical formulations for the prevention and treatment of
superficial skin, ear, and eye infections. The frequency
of neomycin sensitization in the general population is
1.1%,101 while reported sensitization rates in selected
patient populations referred for patch testing vary from
as low as 1.1102 to as high as 10%, the latter reported
by the NACDG.103 This high rate of sensitization in
North America may be due to the availability of this
antibiotic in numerous over-the-counter preparations,
especially triple antibiotic creams and ointments.104
Subgroups at higher risk include patients with stasis dermatitis and leg ulcers, anogenital dermatitis,
and otitis externa. Because antibiotic preparations are
applied to already damaged skin, ACD from neomycin is not always easily recognized. It often presents
as persistence or worsening of a preexisting dermatitis.105 Additionally, it may mimic cellulitis; the clue for
contact allergy is itching rather than pain. An intensification of itch and the progression of lesions beyond
the initial site of involvement may offer clues to the
COBALT. Cobalt
is a colorless gas with preservative and disinfectant

properties. Although there is a wide range of uses
for formaldehyde-like cleansing products, glues, biocides, and photographic developers, currently it is
rarely used as-is in personal care because it has demonstrated to be a frequent sensitizer.107 Therefore, many
manufacturers have replaced the use of formaldehyde
with formaldehyde-releasing preservatives (FRPs) to
preserve personal care products.108 FRPs include quaternium-15, imidazolidinyl urea (Germall), diazolidinyl urea (Germall II), DMDM hydantoin (Glydant),
2-bromo-2-nitropropane-1, 3-diol (Bronopol), and tris
nitromethane (Tris Nitro).109 Of these, Quaternium-15
is the most common cosmetic preservative allergen
(Figs. 13-6 and 13-7).110112
FORMALDEHYDE AND FORMALDEHYDERELEASING PRESERVATIVES. Formaldehyde
BACITRACIN. Bacitracin is a topical antibiotic

frequently used for postoperative and general wound
care by both the medical profession and the general
public since it is readily available in over-the-counter
preparations. Bacitracin is known to be a common
sensitizer and can cause not only allergic contact
dermatitis but also urticarial reactions and even, rarely,
anaphylaxis.115 It is important to note that despite
its high prevalence, bacitracin is not included as a
screening allergen in the currently available T.R.U.E.
Test series, which will be further discussed briefly
in this chapter. Interestingly, patients often show
simultaneous sensitivity to bacitracin and neomycin,
although the two substances are not chemically
related, meaning there is coreactivity but not crossreactivity between both substances. Independent
sensitization probably occurs to both antibiotics, which
are often used simultaneously in over-the-counter
combinations.116
::
c orrect diagnosis. Occupational dermatitis involving

the hands can occur in nurses, physicians, pharmacists, dentists, and veterinarians.106
Chapter 13
Figure 13-6 This eczematous dermatitis was caused by

the most frequent preservative allergen, quaternium-15,
which was present in the patients moisturizer.
is a metal which is often added

to other metals to increase overall strength. Cobalt
is commonly a contaminant present in nickel ores
and is frequently a minor element in nickel compounds.113 As with nickel, a majority of sensitization
exposures result from contact with jewelry, clothing
snaps, buckles, coins, keys, and other metal objects.
Furthermore, it can also be found in prosthetic joint
replacements, dental alloys, ceramics, paints, tattoo
dyes, cement (mostly in Europe), and multivitamins
containing vitamin B12 (cobalt is a main component
of vitamin B12, Cyanocobalamine).114 Concomitant
allergy to nickel and cobalt is often observed among
patients with dermatitis, probably as a result of
cosensitization. In general, the best way of avoiding
contact with metallic cobalt is by avoiding contact
with nickel-plated objects that come in direct contact
with the skin.
M E T HYL D I B R O M O G LU TA R O N I T R I L E/
PHENOXYETHANOL. Methyldibromogluta-
ronitrile/Phenoxyethanol (MDGN/PE) is a preservative combination also known as Euxyl K400. It

has become an increasingly important sensitizing
agent,117 resulting in a ban on use in Europe, first
from stay-on cosmetics in 2005, and later from rinseoff cosmetics in 2007, in an attempt to decrease the
rates of contact allergy.118 The use of MDGN/PE is
not banned in cosmetics produced outside the European Union, and therefore toiletries sold elsewhere
may contain MDGN/PE, albeit at a lesser concentration than had been allowed European formulations.
Most allergic reactions to MDGN/PE are due to the
use of personal care products containing the allergen, especially creams, lotions, wet wipes, and liquid
soaps.
Figure 13-7 An example of a weak, 1+ reaction to quaternium-15.
para-PHENYLENEDIAMINE. PPD is an oxidizing agent used as a permanent hair dye. Both consumers and hairdressers alike are at risk for sensitization.
As mentioned earlier in this chapter, contact allergy
to PPD often presents as facial dermatitis near the
161
Section 4
::
162
hairline, but it may also involve the eyelids and the

neck, while the scalp may or may not be spared.119
Once oxidized, PPD is no longer allergenic, thus, dyed
hair itself does not pose further risk of allergic stimulation. This is in contrast to permed hair, in which the
allergen, glyceryl monothioglycolate, retains ability to
further stimulate dermatitis in the allergic individual
(i.e., an allergic hairdresser cutting the hair of a client
who has had GMT permanent waving applied to the
hair weeks ago). PPD has the potential to cross-react
with other para-amino group chemicals such as paraaminobenzoic acid (PABA), sulfonylureas, hydrochlorothiazide, benzocaine, procainamide, and certain azo
and aniline dyes.120,121 Additionally, PPD has gained
notoriety for its use in adulterating natural henna to
make black henna, a substance increasingly used to
make temporary tattoos.122,123
PATCH TESTING
ALLERGEN SELECTION
T.R.U.E. TEST. The commercially available patch-test
screening tool with US Food and Drug Administration
(FDA) approval is the Thin-layer Rapid Use Epicutaneous
(T.R.U.E.) Test (Mekos Laboratories AS, Hillerod,
Denmark). As of March 2010, there were 28 (plus 1
negative control) T.R.U.E. Test allergens organized into
three panels (panels 1.1, 2.1, and 3.1). Of the top 30 most
frequently positive NACDG screening allergens for the
20052006 period, Zug and NACDG colleagues found
that 10 important allergens were not currently available
for testing and identification with the T.R.U.E. Test panels:
bacitracin,
methyldibromoglutaronitrile,
bronopol,
cinnamic aldehyde, propylene glycol, DMDM hydantoin,
iodopropynyl butylcarbamate, ethyleneurea/melamine
formaldehyde, disperse blue 106, and amidoamine. Of
these, bacitracin is likely the most important. Named
Allergen of the Year in 2003 by the American Contact
Dermatitis Society, bacitracin is now the seventh most
Figure 13-8 This patient had multiple relevant positive

patch tests. Bacitracin, chloroxylenol, and 2-hydroxyethyl
methacrylate are relevant to this patients severe dermatitis but are not allergens on the currently available commercial screening series.
frequently positive allergen according to prevalence data

from this study group (Fig. 13-8).
RESULT INTERPRETATION
Reading reactions elicited by the patch test is a crucial step in the patch-test procedure. Patches should
be applied to healthy skin on the patients back and
left under occlusion for 48 hours (eFig. 13-8.2 in online
edition). Traditionally, patch-test reading is carried out
in most patch-test clinics twice: the day of patch-test
removal 48 hours after application (day 2 = D2), and
96 hours after epicutaneous exposure (day 4 = D4), or
day 7. It is important to note that certain allergens are
acknowledged for being late-reactors. For example,
if neomycin or PPD allergies are suspected, additional
readings at 57 days may be needed.125 Likewise, some
researchers have also found that readings for metals
and corticosteroids should sometimes be delayed to
7 days.126 The reason for this is that all these allergens
are characterized as being late-bloomers. On the
other hand, a study by Geier and colleagues showed
that by delaying readings to 7 days, some reactions
to certain fragrances and preservative allergens may
dissipate.127 Therefore, the optimal protocol is probably to read the test at day 2 and day 4, the conventional way, and then on day 7 if allergies to metals,
topical antibiotics (neomycin), and PPD are strongly
suspected, or if the patient notes a newly developed
reaction after day 4. Patients are instructed to report
back to their physician should any additional positive
reactions appear at day 5 or beyond to detect any late reactors or active sensitization that may have occurred. At
each test reading, it is traditional to note the results
as negative or positive, and grade the positive results
on a quantitative scale. The ICDRG has recommended
to score patch-test reactions according to the scoring
system recommended by Wilkinson and colleagues128
which is on a + to +++ scoring system; where + represents a weak nonvesicular reaction but with palpable erythema; ++ represents a strong (edematous
or vesicular) reaction; and +++ represents an extreme
(bullous or ulcerative) reaction (Figs. 12-6C and
13-7). Very weak or questionable reactions where
there is only faint or macular (nonpalpable) erythema
are recorded by a question mark (?+), and irritant
reactions are recorded as IR. Irritant patch-test reactions have varied clinical signs which are related to
the nature and the concentration of the irritant129 and
are classically described as (1) erythematous reactions
limited to the site of application of the chemical, with
sharp, well-delineated margins; discretely scaly (may
look chapped) and usually not edematous. Among
the patch-test allergens, fragrance mix, cocamidopropyl betaine, iodopropynyl butylcarbamate, glutaraldhehyde, and thiuram mix are identified as the most
common allergens to produce such marginal irritant
reactions. (2) Purpuric reactions with petechial hemorrhage, which are seen in about 5% of patients tested to
cobalt chloride. This is sometimes referred as punctate
purpura of cobalt and should always be interpreted as
an irritant reaction. Another top allergen that has been
ASSIGNING CLINICAL RELEVANCE
The differential diagnosis of ACD includes a wide

range of inflammatory skin disorders (Box 13-2).135,136
DIFFERENTIAL DIAGNOSIS
::
The diagnosis of contact allergy is mainly determined

by the outcome of patch testing. However, a positive
test reaction is not necessarily an indicator of clinical disease, i.e., ACD, as the patch test only measures
whether the individual is sensitized or not. Sensitization does not necessarily equate with clinical allergic
disease. A good example of this point is the case of
thimerosal. This mercuric preservative is unique in
the sense that it commonly causes positive patch-test
reactions but very seldom nowadays does thimerosal
allergy account for the patients dermatitis. Most allergic patients have presumably been sensitized to this
preservative through vaccination but have no clinical
disease associated with this sensitization.130 Establishing the relevance of a positive patch-test result is critical. However, it should be noted that lack of relevance
does not mean a patient is not allergic to the chemical
in question, but more specifically that this chemical is
not the causal agent for the dermatitis currently being
evaluated. Therefore determination of current clinical
relevance is essential in declaring ACD.
Chapter 13
observed to cause purpuric reactions during patch

testing is PPD. (3) Pustular reactions: there can be a
unique large pustule at the site of application (more
characteristic of caustic, strong irritant reactions), or
more commonly, small follicular pustules over an erythematous background. This type of reaction mainly
occurs with metallic salts such as potassium dichromate, cobalt, nickel, gold, and copper, and mainly in
atopic patients. Other patch-test reactions that should
be interpreted with caution given their mild irritant
potential include the preservatives formaldehyde,
benzalkonium chloride, and iodopropynyl butylcarbamate (IPBC); the rubber allergen carba mix, fragrance chemicals such as fragrance mix I and propolis
(bee glue); the foaming agent cocamidopropyl betaine; and the emulsifiers: oleamidopropyl dimethylamine and triethanolamine. It is important to mention
that even paying close attention to the aforementioned
morphological features, irritant reactions are still difficult to interpret, and the morphology of the patch-test
response can still be a confusing guide to whether the
response is allergic or irritant. When morphology is
not enough, it is advisable to keep in mind that in general when the patch-test reaction is sufficiently strong,
an irritant reaction will be early appearing (during the
first reading), and promptly healing (often times the
reaction is not as strong or sometimes not even present during the second reading). In contrast, a strong
allergic reaction usually spreads, is more slowly disappearing, and is more clearly eczematous.
Box 13-2 Differential Diagnosis of ACD

Diagnosis
Irritant contact dermatitis (ICD)
Atopic dermatitis
Nummular dermatitis (ND)
Asteatotic eczema
Stasis dermatitis
Pompholyx and/or dyshidrotic eczema
Psoriasis
Mycosis fungoides (patch/plaque stage

cutaneous T-cell lymphoma)
Diagnostic Clues
Physical findings can be indistinguishable clinically; in general there is an
absence of vesiculation (only very strong irritants produce vesicles) and
burning exceeds itching. Does not spread beyond the area of contact with
continued exposure.
Distribution of skin findings can be helpful; atopic patients can and do
develop contact allergies. Worsening disease can indicate new contact
allergy development.
Widespread ACD can assume this pattern in certain patients; nonetheless,
the classical morphology of coin-shaped, well-demarcated plaques on the
legs, dorsal hands, and extensor surfaces favors ND.
Greasy and scaly papulosquamous plaques usually located in the hairbearing regions, glabella, and nasolabial folds.
Parchment-like patches with no edema or vesiculation on the lower legs.
Papulosquamous plaques with dyschromia located on the shins and medial surfaces of the lower legs, with presence of concomitant varicosities.
Deep-seated vesicles on palms, soles, sides of the fingers, and volar edges.
When it presents in its classic form, diagnosis can be straightforward,
however, when the lesions are few and limited to the hands and/or feet
differentiation can be more difficult. Classical location and predominance
in areas of trauma (Koebnerization) can be helpful as well as the presence
(if any) of concomitant arthritis.
The well demarcated, atrophic, poikilodermatous, scaly patches and
plaques of MF are usually found in nonsun-exposed areas of the skin, such
as the trunk, breasts, hips, and buttocks (bathing suit distribution).
163
Histologically, the presence of eosinophilic spongiosis

and multinucleate dermal dendritic fibrohystiocytic
cells is especially suggestive of ACD, when encountered in the presence of a lymphocytic infiltrate, dermal eosinophils, and hyperkeratosis.137
COMPLICATIONS
COMPLICATIONS OF PATCH TESTING
Section 4
::
164
Patch testing is considered a safe diagnostic procedure

and unwanted effects are seldom encountered. The
most common side effect is itching at the site of a positive test reaction, and irritation and pruritus from tape
application. Less commonly, postinflammatory hypoor hyperpigmentation can occur. Hyperpigmentation
is more likely in darkly pigmented persons; it fades
progressively with time and the use of topical corticosteroids. It is important to note that exposure to sunlight or artificial UV immediately following removal of
patch tests especially to fragrance materials, can lead
to hyperpigmentation of the patch-test site in relation
with photosensitivity. Persistence of a positive reaction
is another adverse reaction that may occur. A patchtest reaction that may persist for more than 1 month is
that due to gold in a gold sensitive patient. Induction
of a dermatitis flare-up at the original site of an existing or preexisting dermatitis (that was caused by the
positive patch-test allergen) can also occur. This can
be minimized by testing patients free of any current
active dermatitis. Also, a positive patch-test reaction
in a patient who has active psoriasis or lichen planus
may reproduce these dermatoses at the patch-test sites
(as a Koebner phenomenon), during the weeks following
patch testing.138 These lesions can be cleared with the
use of topical corticosteroids. Finally, the possibility
of becoming sensitized (active sensitization) to one of
the tested allergens exists; however, it has proven to
be low.139 Serious adverse effects during patch testing
such as anaphylactoid reactions from allergens known
to cause a type I (immediate) hypersensitivity reaction
such as bacitracin and neomycin are exceptionally rare.
COMPLICATIONS DERIVED FROM

FAILURE TO PATCH TEST
The greatest hazard is omission to patch-test appropriate patients with dermatitis. Such omission potentially
dooms the patient to repeated episodes of avoidable
contact dermatitis. In 2004, the American Academy
of Dermatology and the Society of Investigative Dermatology studied the burden of skin disease and estimated that 72 million people in the United States suffer from ACD.140 It is the third most common reason
for patients to seek consultation with a dermatologist,
accounting for 9.2 million visits in 2004 alone. Likewise,
in that same year, primary care physicians received 5
million visits for unexplained dermatitis or eczema.141
Whereas many of these patients will respond readily
to standard treatments, there will be others that demonstrate recalcitrant eczema. It has been estimated
that approximately 16% of all chronic eczema patients

would benefit from patch testing.142 Clinical experience
suggests this number is much larger. Based on those
figures, it could be estimated that approximately 2.2
million patients each year in the United States would
benefit from patch testing.
PROGNOSIS/CLINICAL COURSE
It is difficult to assess the actual prognosis of ACD
because there is no standardized instrument for such
evaluation. The disruption of work, ability to return
to work, and improvement of dermatitis with time are
among outcome measures that have been studied in
patients with ACD. Recent study designs have aimed
to capture the increasingly important outcome measure
of health-related quality of life (QoL).143 When different
QoL assessment tools have been applied to populations
of patients with ACD it has been demonstrated that ACD
negatively impacts QoL significantly. Holness and colleagues144 found that pain, itching, embarrassment, work
interference, and sleep difficulties were the most significant effects in QoL of their patch-test population. Kadyk
et al145 found the greatest impact on emotions, followed
by symptoms, functioning, and occupational impact.
Similarly, Woo and colleagues146 reported that patients
with the final diagnosis of ACD had a mean baseline QoL
equal to that of patients experiencing hair loss and psoriasis. Zug et al147 found that patients referred for patch testing were severely affected by frustration, reported feeling
annoyed, and had a great concern about the persistence
of their skin problem. Notably a factor that is strongly
predictive of a negative impact on QoL is hand involvement of ACD. Similarly, the extent of the disease148 and
the duration of symptoms before diagnosis are both correlated with a poor prognosis and recalcitrant disease.149
On the other hand, increased patient knowledge has
been associated with improved prognosis in some studies.150,151 Much of this information is extrapolated from
data regarding occupational contact dermatitis.
TREATMENT
Because allergen identification can be achieved
through proper patch testing, there is a good potential for a sustained remission. Therefore, identification
and removal of the inciting agent(s), and they are often
multiple, should always be the goal in the diagnosis
and treatment of ACD.152
KEY REFERENCES
22. Zug KA et al: Contact allergy in children referred for
patch testing: North American contact dermatitis group
data, 20012004. Arch Dermatol 144:1329, 2008
44. Gober MD, Gaspari AA: Allergic contact dermatitis. Curr
Dir Autoimmun 10:1, 2008
48. Lachapelle JM, Maibach HI: Patch Testing and Prick Testing: A Practical Guide. Berlin, Germany, Springer-Verlag,
2003
86. Kornik R, Zug KA: Nickel. Dermatitis 19:3, 2008
93. Schram SE, Warshaw EM, Laumann A: Nickel hypersensitivity: A clinical review and call to action. Int J Dermatol
49:115, 2010
103. Zug KA et al: Patch-test results of the North American
contact dermatitis group, 20052006. Dermatitis 20:149,
2009
108. Scheman A et al: Contact allergy: Alternatives for
the 2007 North American contact dermatitis group
(NACDG) standard screening tray. Dis Mon 54:7, 2008
140. Bickers DR et al: The burden of skin diseases: 2004 a joint

project of the American Academy of Dermatology association and the society for Investigative dermatology.
J Am Acad Dermatol 55:490, 2006
143. Skoet R, Zacharie R, Agner T: Contact dermatitis and
quality of life: A structured review of the literature. Br J
Dermatol 149:79, 2003
160. Jacob SE, Steele T: Corticosteroid classes: A quick reference guide including patch test substances and cross reactivity. J Am Acad Dermatol 54:723, 2006
A chronic or chronically relapsing disorder

with major features of:
Pruritus;
Eczematous dermatitis (acute, subacute, or
chronic) with typical morphology and agespecific patterns;
Facial and extensor involvement in
infancy; and
Flexural eczema/lichenification in children
and adults.
INTRODUCTION
Atopic dermatitis (AD) is a chronically relapsing skin
disease that occurs most commonly during early
infancy and childhood. It is frequently associated with
abnormalities in skin barrier function, allergen sensitization, and recurrent skin infections. There is no single
distinguishing feature of AD or a diagnostic laboratory
test. Thus, the diagnosis is based on the constellation of
clinical findings listed in Table 14-1.1
EPIDEMIOLOGY
Since the 1960s, there has been a more than
threefold increase in the prevalence of AD.2 AD is
Commonly associated with the following:

Personal or family history of atopy (allergic
rhinitis, asthma, atopic dermatitis).
Xerosis/skin barrier dysfunction.
Immunoglobulin E reactivity.
Atopic Dermatitis (Atopic Eczema)
Prevalence peak of 1520% in early

childhood in industrialized countries.
::
ATOPIC DERMATITIS AT A GLANCE
Chapter 14
Chapter 14 :: Atopic Dermatitis (Atopic Eczema)

:: D
onald Y.M. Leung, Lawrence F. Eichenfield,
& Mark Boguniewicz
Genetic basis influenced by environmental

factors with alterations in immunologic
responses in T cells, antigen processing,
inflammatory cytokines, host defense
proteins, allergen sensitivity, and
infection.
a major public health problem worldwide, with a

prevalence in children of 1020% in the United States,
Northern and Western Europe, urban Africa, Japan,
Australia, and other industrialized countries.3 The
prevalence of AD in adults is approximately 13%.
Interestingly, the prevalence of AD is much lower in
agricultural regions of countries such as China and
in Eastern Europe, rural Africa, and Central Asia.
However, the most recent data from the International
Study of Asthma and Allergies in Childhood (ISAAC)
Phase Three study confirms that AD is a disease with
high prevalence, affecting patients in both developed
and developing countries.4 There is also a female preponderance for AD, with an overall female/male ratio
of 1.3:1.0.
The basis for this increased prevalence of AD is not
well understood. However, wide variations in preva-
165
TABLE 14-1
Features of Atopic Dermatitis

Major Features
Pruritus
Rash on face and/or extensors in infants and young
children
Lichenification in flexural areas in older children
Tendency toward chronic or chronically relapsing dermatitis
Personal or family history of atopic disease: asthma, allergic
rhinitis, atopic dermatitis
Section 4
::
Other Common Findings

Dryness
DennieMorgan folds (accentuated lines or grooves below
the margin of the lower eyelid)
Allergic shiners (darkening beneath the eyes)
Facial pallor
Pityriasis alba
Keratosis pilaris
Ichthyosis vulgaris
Hyperlinearity of palms and soles
White dermatographism (white line appears on skin within
1 minute of being stroked with blunt instrument)
Conjunctivitis
Keratoconus
Anterior subcapsular cataracts
Elevated serum immunoglobulin E
Immediate skin test reactivity
lence have been observed within countries inhabited

by similar ethnic groups, suggesting that environmental factors are critical in determining disease expression. Some of the potential risk factors that may be
associated with the rise in atopic disease include small
family size, increased income and education both in
whites and blacks, migration from rural to urban environments, and increased use of antibiotics, that is, the
so-called Western lifestyle.5,6 This has resulted in the
hygiene hypothesis that allergic diseases might be
prevented by infection in early childhood transmitted by unhygienic contact with older siblings.7 Given
the increase in autoimmune diseases such as diabetes, abnormalities in T regulatory cells have also been
implicated.

AD is a highly pruritic inflammatory skin disease that
results from complex interactions between genetic susceptibility genes resulting in a defective skin barrier,
defects in the innate immune system, and heightened
immunologic responses to allergens and microbial
antigens.8
DECREASED SKIN BARRIER FUNCTION

166
AD is associated with a marked decrease in skin barrier

function due to the downregulation of cornified envelope genes (filaggrin and loricrin), reduced ceramide
levels, increased levels of endogenous proteolytic

enzymes, and enhanced transepidermal water loss.9,10
Addition of soap and detergents to the skin raises its
pH, thereby increasing activity of endogenous proteases, leading to further breakdown of epidermal barrier function. The epidermal barrier may also be damaged by exposure to exogenous proteases from house
dust mites and Staphylococcus aureus (S. aureus). This
is worsened by the lack of certain endogenous protease inhibitors in atopic skin. These epidermal changes
likely contribute to increased allergen absorption into
the skin and microbial colonization. Because epicutaneous, as compared to systemic or airway, sensitization to allergen results in higher level allergic immune
responses, decreased skin barrier function could act as
a site for allergen sensitization and predispose such
children to the development of food allergy and respiratory allergy.11
IMMUNOPATHOLOGY OF ATOPIC
DERMATITIS
Clinically unaffected skin of AD patients manifests
mild epidermal hyperplasia and a sparse perivascular
T cell infiltrate.12 Acute eczematous skin lesions are
characterized by marked intercellular edema (spongiosis) of the epidermis. Dendritic antigen-presenting
cells [e.g., Langerhans cells (LCs), macrophages] in
lesional and, to a lesser extent, in nonlesional skin of
AD exhibit surface-bound immunoglobulin E (IgE)
molecules. A sparse epidermal infiltrate consisting primarily of T lymphocytes is also frequently observed.
In the dermis of the acute lesion, there is an influx
of T cells with occasional monocyte-macrophages. The
lymphocytic infiltrate consists predominantly of activated memory T cells bearing CD3, CD4, and CD45
RO (suggesting previous encounter with antigen).
Eosinophils are rarely present in acute AD. Mast cells
are found in normal numbers in different stages of
degranulation.
Chronic lichenified lesions are characterized by
a hyperplastic epidermis with elongation of the rete
ridges, prominent hyperkeratosis, and minimal spongiosis. There is an increased number of IgE-bearing
LCs in the epidermis, and macrophages dominate
the dermal mononuclear cell infiltrate. Mast cells are
increased in number but are generally fully granulated. Neutrophils are absent in AD skin lesions
even in the setting of increased S. aureus colonization
and infection. Increased numbers of eosinophils are
observed in chronic AD skin lesions. These eosinophils undergo cytolysis with release of granule protein contents into the upper dermis of lesional skin.
Eosinophil-derived extracellular major basic protein
can be detected in a fibrillar pattern associated with
the distribution of elastic fibers throughout the upper
dermis. Eosinophils are thought to contribute to allergic inflammation by the secretion of cytokines and
mediators that augment allergic inflammation and
induce tissue injury in AD through the production
of reactive oxygen intermediates and release of toxic
granule proteins.
CYTOKINES AND CHEMOKINES
KEY CELL TYPES IN ATOPIC

DERMATITIS SKIN
T CELLS. Skin homing memory T cells play an

important role in the pathogenesis of AD, particularly during the acute phase of illness. This concept
is supported by the observation that primary T-cell
immunodeficiency disorders are frequently associated
with eczematous skin lesions that clear after successful bone marrow transplantation.21 Furthermore, in
animal models of AD, the eczematous rash does not
occur in the absence of T cells. In addition, treatment
with topical calcineurin inhibitors (TCIs), which target
activated T cells, significantly reduces the clinical skin
rash of AD.22
::
ANTIGEN-PRESENTING CELLS. DCs play an

important role in detecting environmental allergens
or pathogens via pattern recognition receptors such as
toll-like receptors (TLR). AD skin contains two types
of high-affinity, IgE receptor-bearing (FcR) myeloid
DCs: (1) LCs and (2) inflammatory dendritic epidermal cells (IDECs). IgE-bearing LCs appear to play an
important role in cutaneous allergen presentation to
IL-4-producing Th2 cells.18 In this regard, IgE-bearing LCs from AD skin lesions, but not LCs that lack
surface IgE, are capable of presenting allergens to T
cells. These results suggest that cell-bound IgE on LCs
facilitates capture and internalization of allergens into
LCs before their processing and antigen presentation
to T cells. IgE-bearing LCs that have captured allergen
likely activate memory Th2 cells in atopic skin, but
they may also migrate to the lymph nodes to stimulate nave T cells there to further expand the pool of
systemic Th2 cells. Stimulation of FcRI on the surface
of LCs by allergens induces the release of chemotactic signals and recruitment of precursor cells of IDECs
and T cells in vitro. Stimulation of FcRI on IDECs
leads to the release of proinflammatory signals, which
contribute to amplification of the allergic immune
response.
In contrast to other inflammatory skin diseases, such
as allergic contact dermatitis or psoriasis vulgaris, very
low numbers of plasmacytoid DCs (pDCs), which play
an important role in host defense against viral infections, can be detected within the AD skin lesion.19
pDCs in the peripheral blood of patients with AD have
been shown to bear the trimeric variant of FcRI on
their cell surface, which is occupied by IgE molecules.
The modified immune function of pDCs of patients
with AD after FcRI-mediated allergen stimulation
might contribute to a local deficiency of type I IFNs,
thereby contributing to increased susceptibility of AD
patients toward viral skin infections such as eczema
herpeticum.20
Chapter 14
Atopic skin inflammation is orchestrated by the local

expression of proinflammatory cytokines and chemokines.12 Cytokines such as tumor necrosis factor-
(TNF-) and interleukin 1 (IL-1) from resident cells
[keratinocytes, mast cells, dendritic cells (DCs)] bind
to receptors on the vascular endothelium, activating
cellular signaling pathways, which leads to the induction of vascular endothelial cell adhesion molecules.
These events initiate the process of tethering, activation, and adhesion to vascular endothelium followed
by extravasation of inflammatory cells into the skin.
Once inflammatory cells have infiltrated into the skin,
they respond to chemotactic gradients established by
chemokines that emanate from sites of injury or infection.
Acute AD is associated with the production of
T helper 2 type (Th2) cytokines, notably IL-4 and
IL-13,13 which mediate immunoglobulin isotype
switching to IgE synthesis and upregulate expression of adhesion molecules on endothelial cells. The
important role that Th2 cytokines play in the skins
inflammatory response is supported by the observation that transgenic mice genetically engineered to
overexpress IL-4 in their skin develop inflammatory
pruritic skin lesions similar to AD, suggesting that
local skin expression of Th2 cytokines plays a critical
role in AD. There has also been considerable interest
in IL-31, which is a novel Th2 cytokine that induces
severe pruritus and dermatitis in experimental animals. IL-31 has also been found to be increased in AD
skin and serum levels of IL-31 correlate with severity
of skin disease.14
In chronic AD, there is an increase in the production
of IL-5, which is involved in eosinophil development
and survival. Increased production of granulocyte
macrophage colony-stimulating factor in AD inhibits
apoptosis of monocytes, thereby contributing to the
persistence of AD.15 The maintenance of chronic AD
also involves production of the Th1-like cytokines IL-12
and IL-18, as well as several remodeling-associated
cytokines, including IL-11 and transforming growth
factor-1.16
The skin-specific chemokine, cutaneous T cellattracting chemokine [CTACK; CC chemokine ligand
27 (CCL27)], is highly upregulated in AD and preferentially attracts skin homing cutaneous lymphoid
antigen (CLA)+ CC chemokine receptor 10+ (CCR10+)
T cells into the skin.17 CCR4 expressed on skin homing CLA+ T cells can also bind to CCL17 on the vascular endothelium of cutaneous venules. Selective
recruitment of CCR4-expressing Th2 cells is mediated by macrophage-derived chemokine and thymus
and activation-regulated cytokine, both of which are
increased in AD. Severity of AD has been linked to
the magnitude of thymus and activation-regulated
cytokine levels. In addition, chemokines such as fractalkine, interferon (IFN)--inducible protein 10, and
monokine induced by IFN- are strongly upregulated in keratinocytes and result in Th1-cell migration toward epidermis, particularly in chronic AD.
Increased expression of the CC chemokines, macrophage chemoattractant protein-4, eotaxin, and RANTES (regulated on activation, normal T cell expressed
and secreted) contribute to infiltration of macrophages, eosinophils, and T cells into both acute and
chronic AD skin lesions.
167
Section 4
::
168
Several studies have demonstrated the presence of

Th2-like T cells in acute AD that produce cytokines
that enhance allergic skin inflammation. During the
chronic phase of AD, there is a switch to Th1-like cells
that primarily produce IFN-. These Th1-like cells
induce the activation and apoptosis of keratinocytes.23
Recently, T regulatory (Treg) cells have been described
as a further subtype of T cells that have immunosuppressive function and cytokine profiles distinct from
both Th1 and Th2 cells.24 Treg cells are able to inhibit
the development of both Th1 and Th2 responses.
Mutations in a nuclear factor expressed in Treg cells,
FoxP3, result in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome
characterized by elevated serum IgE, food allergy, and
dermatitis that may be eczematous or psoriasiform. A
deficiency of resident Treg cells has also been reported
in AD skin.25 Interestingly, staphylococcal superantigens subvert Treg cell function and may thereby augment skin inflammation.26
There has also been considerable interest in the role
of Th17 cells in the immunopathogenesis of AD.27
These cells produce inflammatory cytokines such as
IL-17 and are thought to play a role in host defense by
inducing keratinocytes to produce antimicrobial peptides as well as promote neutrophil chemotaxis. Th17
cells are increased in the skin lesions of autoimmune
diseases, such as psoriasis, where they may promote
inflammatory responses, including neutrophil infiltration but also reduce skin infection.28 Compared to psoriasis, AD skin lesions have significantly fewer T cells
expressing IL-17, but increased numbers of IL-4+ cells.29
Furthermore, it has been found that the Th2 cytokines,
IL-4 and IL-13, inhibit IL-17 induced generation of
antimicrobial peptides.30 Interestingly, an independent
increase of IL-22 expressing cells, originally thought to
be produced by Th17 cells, can be found in AD skin
and it has been suggested that these may contribute to
epidermal hyperplasia.31
KERATINOCYTES. Keratinocytes play a critical

role in the augmentation of atopic skin inflammation.
AD keratinocytes secrete a unique profile of chemokines and cytokines after exposure to proinflammatory cytokines. This includes high levels of RANTES
after stimulation with TNF- and IFN-.32 They are
also an important source of thymic stromal lymphopoietin (TSLP), which activates DCs to prime nave
T cells to produce IL-4 and IL-13 (i.e., promotes Th2
cell differentiation).33 The importance of TSLP in AD
pathogenesis is supported by the observation that
mice genetically manipulated to overexpress TSLP
in the skin develop AD-like skin inflammation. Skinderived TSLP is also thought to trigger the development of asthma.34,35
Keratinocytes are critical to the skins innate immune
responses, expressing Toll-like receptors, producing
proinflammatory cytokines and antimicrobial peptides (such as human defensins and cathelicidins) in
response to tissue injury or invading microbes.36 Several studies have now demonstrated that AD keratinocytes produce reduced amounts of antimicrobial peptides and this may predispose such individuals to skin
colonization and infection with S. aureus, viruses, and

fungi. However, this defect appears to be acquired as
the result of Th2-cytokine (IL-4, IL-10, and IL-13) mediated inhibition of TNF- and IFN--induced antimicrobial peptide generation.
GENETICS
AD is a complex disease that is familially transmitted with a strong maternal influence.37 Genome-wide
linkage studies of families with AD have implicated
chromosomal regions that overlap with other inflammatory skin diseases such as psoriasis. Together with
candidate gene studies, these have provided interesting insights into the pathogenesis of AD. Although
many genes are likely to be involved in the development of AD, there has been particular interest in
the potential role of skin barrier/epidermal differentiation genes and immune response/host defense
genes.
Loss-of-function mutations in FLG, which encodes
the epidermal barrier protein, filaggrin, have been
demonstrated to be a major predisposing factor for
AD,38 as well as ichthyosis vulgaris, a common keratinizing disorder associated with AD (Figs. 14-1 and
14-2). Patients with filaggrin null mutations often
have early onset, severe eczema, high level allergen
sensitization, and develop asthma later in childhood.
Of note, the filaggrin gene is found on chromosome
1q21 that contains genes (including loricrin and S100
calcium-binding proteins) in the epidermal differentiation complex, known to be expressed during terminal differentiation of the epidermis. DNA microarray
analyses have demonstrated upregulation of S100 calcium-binding proteins and downregulation of loricrin
and filaggrin in AD. Candidate gene approaches have
also implicated variants in the SPINK5 gene, which is
expressed in the uppermost epidermis where its product, LEKT1, inhibits two serine proteases involved in
desquamation and inflammation (stratum corneum
tryptic enzyme and stratum corneum chymotryptic
Figure 14-1 Ichthyosis vulgaris commonly accompanies

atopic dermatitis and is thought to be responsible for the
barrier defect in a subset of patients. Note the larger scales
on the lower extremities.
interferon and IL-18 genes support the role of CD4+ T

cells and dysregulation of Th1 genes in the pathophysiology of AD. As well, reports of AD association with
polymorphisms of the NOD1 gene, which encodes
cytosolic pathogen recognition receptor and toll-like
receptors, suggest an important role for host defense
genes in the pathogenesis of AD. The reader is referred
to Chapter 10 and reference 35 for a detailed discussion
of the genetics of AD.
BASIS OF PRURITUS IN ATOPIC

DERMATITIS
::
enzyme). Stratum corneum tryptic enzyme and stratum corneum tryptic enzyme expression is increased
in AD, suggesting that an imbalance of protease versus protease inhibitor activity may contribute to atopic
skin inflammation.9
These observations establish a key role for impaired
skin barrier function in the pathogenesis of AD, as
impaired skin barrier formation allows increased
transepidermal water loss and, importantly, increased
entry of allergens, antigens, and chemicals from
the environment resulting in skin inflammatory
responses. It is important to note that these filaggrin
mutations, and likely other mutations affecting the
skin barrier, can occur in clinically normal individuals, and in patients with ichthyosis vulgaris without
clinical evidence of skin inflammation. The majority of patients with AD outgrow their inflammatory
skin disease by adolescence. Thus, AD is a complex
trait that involves interactions between multiple gene
products requiring environmental factors and the
immune response to result in the final clinical phenotype. Chromosome 5q31-33 contains a clustered
family of functionally related cytokine genesIL-3,
IL-4, IL-5, IL-13, and granulocyte macrophage colonystimulating factorwhich are expressed by Th2 cells.
A case control comparison has suggested a genotypic
association between the T allele of the 590C/T polymorphism of the IL-4 gene promoter region with AD.
Because the T allele is associated with increased IL-4
gene promoter activity when compared to the C allele,
this suggests that genetic differences in transcriptional
activity of the IL-4 gene influence AD predisposition.
In addition, an association of AD with a gain-of-function mutation in the subunit of the IL-4 receptor
has been reported, providing further support of the
concept that IL-4 gene expression plays a role in AD.
Functional mutations in the promoter region of the CC
chemokines, RANTES, and eotaxin, as well as variants
in IL-13, the subunit of the high affinity cell surface
receptor for IgE (FcR1) found on basophils and mast
cells suggest an overlapping of genetic basis with
other atopic diseases.
Recent studies demonstrating a significant association between TSLP gene polymorphisms and AD provide further support for the importance of Th2 polarization in this disease.37 The involvement of T cell
Pruritus is a prominent feature of AD, manifested as

cutaneous hyperreactivity and scratching following
exposure to allergens, changes in humidity, excessive sweating, and low concentrations of irritants.
Control of pruritus is important because mechanical injury from scratching can induce proinflammatory cytokine and chemokine release, leading to a
vicious scratchitch cycle perpetuating the AD skin
rash. The mechanisms of pruritus in AD are poorly
understood. Allergen-induced release of histamine
from skin mast cells is not an exclusive cause of pruritus in AD, because H1 antihistamines are not effective
in controlling the itch of AD.39 However, recent studies demonstrating a potential role for H4 receptors in
skin pathobiology suggests that histamine may play
a contributory role.40 However, the observation that
treatment with topical corticosteroids and calcineurin
inhibitors is effective at reducing pruritus suggests
that the inflammatory cells play an important role
in pruritus.41,42 Molecules that have been implicated
in pruritus include T-cell-derived cytokines such as
IL-31, stress-induced neuropeptides, and proteases
which can act on protease-activated receptors, eicosanoids, and eosinophil-derived proteins.43,44 The
reader is referred to Chapter 103 for a detailed discussion of the pathophysiology of pruritus.
Chapter 14
Figure 14-2 Hyperlinear palms.
CLINICAL FINDINGS
The diagnosis of AD is based on the constellation of
clinical features summarized in Table 14-1. AD typically begins during infancy. Approximately 50% of
patients develop this illness by the first year of life
and an additional 30% between the ages of 15 years.
Between 5080% of patients with AD develop allergic
rhinitis or asthma later in childhood. Many of these
patients outgrow their AD as they are developing respiratory allergy.
CUTANEOUS LESIONS
Intense pruritus and cutaneous reactivity are cardinal features of AD. Pruritus may be intermittent
throughout the day but is usually worse in the early
evening and night. Its consequences are scratching,
prurigo papules (Fig. 14-3), lichenification (Fig. 14-4),
and eczematous skin lesions. Acute skin lesions are
169
Section 4
Figure 14-4 Lichenification and excoriations on the

dorsal aspect of the hand in a child with atopic dermatitis.
::
Figure 14-3 Prurigo papules in a patient with atopic dermatitis.

characterized by intensely pruritic, erythematous papules associated with excoriation, vesicles over erythematous skin, and serous exudate (Fig. 14-5). Subacute
dermatitis is characterized by erythematous, excoriated, scaling papules (Fig. 14-6). Chronic AD is characterized by (1) thickened plaques of skin, (2) accentuated skin markings (lichenification), and (3) fibrotic
papules (prurigo nodularis; Fig. 14-7). In chronic AD,
all three stages of skin reactions frequently coexist in
the same individual. At all stages of AD, patients usually have dry, lackluster skin.
The distribution and skin reaction pattern vary
according to the patients age and disease activity.
During infancy, the AD is generally more acute and
170
primarily involves the face (Fig. 14-8), scalp, and the

extensor surfaces of the extremities (Fig. 14-9). The
diaper area is usually spared. In older children, and in
those who have long-standing skin disease, the patient
develops the chronic form of AD with lichenification
and localization of the rash to the flexural folds of
the extremities (Fig. 14-10). AD often subsides as the
patient grows older, leaving an adult with skin that is
prone to itching and inflammation when exposed to
exogenous irritants. Chronic hand eczema may be the
primary manifestation of many adults with AD (Fig.
14-11). Other associated features of AD are listed in
Table 14-1.
LABORATORY TESTS
Laboratory testing is not needed in the routine evaluation and treatment of uncomplicated AD. Serum
Figure 14-5 A. Pronounced weeping and crusting of eczematous lesions in childhood atopic dermatitis. B. Excoriated
papules and crusting (with secondary infection) in an acute flare of atopic dermatitis.
Chapter 14
::
IgE levels are elevated in approximately 7080% of

AD patients. This is associated with sensitization
against inhalant and food allergens and/or concomitant allergic rhinitis and asthma.8 In contrast, 2030%
of AD patients have normal serum IgE levels. This
subtype of AD has a lack of IgE sensitization against
inhalant or food allergens. However, some of these
patients may possess IgE sensitization against microbial antigens such as S. aureus toxins, and Candida
albicans or Malassezia sympodialis can be detected. As
well, some of these patients show positive reactions
using the atopy patch test despite negative immediate skin tests.
The majority of patients with AD also have peripheral
blood eosinophilia. Patients with AD have increased
spontaneous histamine release from basophils. These
findings likely reflect a systemic Th2 immune response
in AD especially those patients who have elevated
serum IgE levels. Importantly, the peripheral blood
skin homing CLA+ T cells in AD expressing either CD4
or CD8 spontaneously secrete IL-5 and IL-13, which
functionally prolong eosinophil survival and induce
IgE synthesis.
DIAGNOSIS AND DIFFERENTIAL

DIAGNOSIS
Table 14-1 lists the clinical features of AD. Of the major
features, pruritus and chronic or remitting eczematous
Figure 14-7 Severe lichenification and hyperpigmented

prurigo papules seen in a patient with chronic atopic dermatitis.
Figure 14-6 Confluent erythematous papules on the

cheeks of an infant with subacute atopic dermatitis.
Chronic exposure to saliva and moist food at this location
has been thought to contribute to the distribution.
dermatitis with typical morphology and distribution

are essential for diagnosis. Other features, including
allergy or elevated IgE, are variable, and some of the
associated features in the table may not be useful
discriminators of individuals with AD from the unaffected general population. Various diagnostic criteria
have been proposed to assist with clinical diagnosis,
Figure 14-8 Edematous, erythematous eyelids with lichenification and hyperpigmentation in an adolescent
with atopic dermatitis. Note the infraocular (Dennie
Morgan) folds.
171
Section 4
Figure 14-11 Typical papules, vesicles, and erosions seen

in atopic hand dermatitis.
::
172
Figure 14-9 Itching infant with atopic dermatitis. (Used

with permission from Oholm Larsen, MD.)
definition of patients for clinical studies, and epidemiologic population studies.45 A refined list of diagnostic criteria suitable for epidemiologic studies has
been derived and validated by workers in the United
Kingdom.46
Figure 14-10 Childhood atopic dermatitis with lichenification of antecubital fossae and generalized severely pruritic eczematous plaques.
Box 14-1 lists a number of inflammatory skin

diseases, immunodeficiencies, skin malignancies,
genetic disorders, infectious diseases, and infestations that share symptoms and signs with AD. These
should be considered and ruled out before a diagnosis of AD is made. Infants presenting in the first year
of life with failure to thrive, diarrhea, a generalized
scaling erythematous rash, and recurrent cutaneous and/or systemic infections should be evaluated
for severe combined immunodeficiency syndrome.
WiskottAldrich syndrome is an X-linked recessive
disorder characterized by cutaneous findings almost
indistinguishable from AD (see Chapter 143). It is
associated with thrombocytopenia, variable abnormalities in humoral and cellular immunity, and recurrent severe bacterial infections. The hyper-IgE syndrome is characterized by elevated serum IgE levels,
defective T-cell function, recurrent deep-seated bacterial infections, including cutaneous abscesses due to
S. aureus and/or pruritic skin disease due to S. aureus
pustulosis, or by recalcitrant dermatophytosis. A
papulopustular eruption of the face and scalp may be
seen in early life. Although S. aureus is an important
pathogen in this disorder, infection with other bacteria, viruses, and fungi may occur, particularly when
patients are on chronic antistaphylococcal antibiotic
prophylaxis. Hyper-IgE is most commonly an autosomal dominant disorder due to mutations in STAT3,
which also features pneumonia with pneumatocele
formation, dental anomalies with retained primary
teeth, bone fractures, and osteopenia. Autosomal
recessive forms of hyper-IgE syndrome show severe
eosinophilia, recurrent viral and bacterial infections,
an increased risk of autoimmune disease, and serious
neurologic manifestations, but not the pneumatoceles
and dental or skeletal defects. To date, deficiencies of
Tyk2 and dedicator of cytokinesis 8 protein (DOCK8)
deficiency have been found, leading to a global defect
in T-cell activation.47
It is important to recognize that an adult who presents with an eczematous dermatitis with no history of
childhood eczema, respiratory allergy, or atopic family
history may have allergic contact dermatitis. A contact
Box 14-1 Differential Diagnosis of Atopic Dermatitis

MOST LIKELY
Contact dermatitis (allergic and irritant)
Scabies
Psoriasis
Ichthyosis vulgaris
Keratosis pilaris
Dermatophytosis
CONSIDER
allergen should be considered in any patient whose

AD does not respond to appropriate therapy. Of note,
contact allergy to topical glucocorticoids and TCIs has
been reported in patients with chronic dermatitis. In
addition, cutaneous T-cell lymphoma must be ruled
out in any adult presenting with chronic dermatitis
poorly responsive to topical glucocorticoid therapy.
Ideally, biopsies should be obtained from three separate sites, because the histology may show spongiosis
and cellular infiltrate similar to AD. Eczematous dermatitis has been also reported with human immunodeficiency virus as well as with a variety of infestations
such as scabies. Other conditions that can be confused
with AD include psoriasis, ichthyoses, and seborrheic
dermatitis.
Primary Immunodeficiency Disorders

Severe combined immunodeficiency disorder
DiGeorge syndrome
Hypogammaglobulinemia
Agammaglobulinemia
WiskottAldrich syndrome
Ataxia-telangiectasia
Immune dysregulation, polyendocrinopathy,
enteropathy, X-linked (IPEX) syndrome
Hyperimmunoglobulin E syndrome (autosomal
dominant and recessive forms)
Chronic mucocutaneous candidiasis
Omenn syndrome
Other Genetic Syndromes
Netherton syndrome
Cutaneous T-cell lymphoma (mycosis fungoides

or Szary syndrome)
Human immunodeficiency virus-associated
dermatoses
Lupus erythematosus
Dermatomyositis
Graft-versus-host disease
Pemphigus foliaceus
Photosensitivity disorders (hydroa vacciniforme,
polymorphous light eruption, porphyrias)
Metabolic/Nutritional
Phenylketonuria
Prolidase deficiency
Multiple carboxylase deficiency
Zinc deficiency (acrodermatitis enteropathica;
prematurity; deficient breast milk zinc; cystic
fibrosis)
Others: biotin, essential fatty acids, organic
acidurias
::
LESS COMMON/RARE DISORDERS PREDOMINANT

IN ADOLESCENTS AND ADULTS
LESS COMMON/RARE DISORDERS PREDOMINANT

IN INFANTS/CHILDREN
Chapter 14
Asteatotic eczema
Lichen simplex chronicus
Nummular dermatitis
Juvenile palmarplantar dermatosis
Impetigo
Drug eruptions
Perioral dermatitis
Pityriasis alba
Photosensitivity disorders (hydroa vacciniforme;
polymorphous light eruption, porphyrias)
Molluscum dermatitis
Inflammatory, Autoimmune Disorders

Eosinophilic gastroenteritis
Gluten-sensitive enteropathy
Neonatal lupus erythematosus
Proliferative Disorders
Langerhans cell histiocytosis
COMPLICATIONS
OCULAR PROBLEMS
Eye complications associated with severe AD can lead
to significant morbidity. Eyelid dermatitis and chronic
blepharitis are commonly associated with AD and
may result in visual impairment from corneal scarring. Atopic keratoconjunctivitis is usually bilateral
and can have disabling symptoms that include itching, burning, tearing, and copious mucoid discharge.
Vernal conjunctivitis is a severe bilateral recurrent
chronic inflammatory process associated with papillary hypertrophy, or cobblestoning of the upper eyelid
173
Section 4
conjunctiva. It usually occurs in younger patients and

has a marked seasonal incidence, often in the spring.
The associated intense pruritus is exacerbated by
exposure to irritants, light, or sweating. Keratoconus
is a conical deformity of the cornea believed to result
from chronic rubbing of the eyes in patients with
AD and allergic rhinoconjunctivitis. Cataracts were
reported in the early literature to occur in up to 21%
of patients with severe AD. However, it is unclear
whether this was a primary manifestation of AD or
the result of the extensive use of systemic and topical
glucocorticoids, particularly around the eyes. Indeed,
more recent studies suggest that routine screening for
cataracts in patients with AD may not be productive
unless there is concern about potential side effects
from steroid therapy.
INFECTIONS
::
AD can be complicated by recurrent viral skin infections that may reflect local defects in T-cell function.48
The most serious viral infection is herpes simplex (see
Chapter 193), which can affect patients of all ages,
resulting in Kaposi varicelliform eruption or eczema
herpeticum. After an incubation period of 512 days,
multiple, itchy, vesiculopustular lesions erupt in a
disseminated pattern; vesicular lesions are umbilicated, tend to crop, and often become hemorrhagic and
crusted (Fig. 14-12). Punched out and extremely painful erosions result. These lesions may coalesce to large,
denuded, and bleeding areas that can extend over the
entire body.
Although smallpox infections have been eradicated
worldwide since the late 1970s, threats of bioterrorism
(with smallpox and other infectious agents) have made
nations reconsider their policies toward initiating vaccination programs. In AD patients, smallpox vaccination (or even exposure to vaccinated individuals) (see
Chapter 195) may cause a severe widespread eruption
(called eczema vaccinatum) that appears very similar to
eczema herpeticum. Thus, in patients with AD, vaccination is contraindicated unless there is a clear risk of
smallpox. In addition, decisions regarding vaccination
of family members should take into consideration the
potential of eczema vaccinatum in household contacts.
Superficial fungal infections are also more common

in atopic individuals and may contribute to the exacerbation of AD. Patients with AD have an increased
prevalence of Trichophyton rubrum infections compared
to nonatopic controls. There has been particular interest in the role of M. sympodialis (Pityrosporum ovale or
P. orbiculare) in AD. M. sympodialis is a lipophilic yeast
(see Chapters 188 and 189) commonly present in the
seborrheic areas of the skin. IgE antibodies against M.
furfur are commonly found in AD patients and most
frequently in patients with head and neck dermatitis.
In contrast, IgE sensitization to M. sympodialis is rarely
observed in normal controls or asthmatics. Positive
allergen patch-test reactions to this yeast have also
been demonstrated. The potential importance of M.
sympodialis as well as other dermatophyte infections is
further supported by the reduction of AD skin severity
in such patients after treatment with antifungal agents.
S. aureus is found in more than 90% of AD skin
lesions. Honey-colored crusting, folliculitis, and pyoderma are indicators of secondary bacterial skin infection, usually due to S. aureus, that requires antibiotic
therapy. Regional lymphadenopathy is common in
such patients. The importance of S. aureus in AD is
supported by the observation that patients with severe
AD, even those without overt infection, can show
clinical response to combined treatment with antistaphylococcal antibiotics and topical glucocorticoids.
Although recurrent staphylococcal pustulosis can be a
significant problem in AD, deep-seated S. aureus infections occur rarely and should raise the possibility of
an immunodeficiency syndrome such as hyper-IgE
syndrome. Methicillin-resistant S. aureus has become
an increasingly important pathogen in patients with
AD.49
HAND DERMATITIS
Patients with AD often develop nonspecific, irritant hand dermatitis. It is frequently aggravated by
repeated wetting and by washing of the hands with
harsh soaps, detergents, and disinfectants. Atopic
individuals with occupations involving wet work are
prone to develop an intractable hand dermatitis in the
occupational setting. This is a common cause of occupational disability.
EXFOLIATIVE DERMATITIS
174
Figure 14-12 Eczema herpeticum. Typical vesicles and

crusting in a patient with disseminated disease.
Patients with extensive skin involvement may develop

exfoliative dermatitis (see Chapter 23). This is associated with generalized redness, scaling, weeping, crusting, systemic toxicity, lymphadenopathy, and fever.
Although this complication is rare, it is potentially
life threatening. It is usually due to superinfection,
for example, with toxin-producing S. aureus or herpes
simplex infection, continued irritation of the skin, or
inappropriate therapy. In some cases, the withdrawal
of systemic glucocorticoids used to control severe AD
may be a precipitating factor for exfoliative erythroderma.
PROGNOSIS AND CLINICAL

COURSE
TOPICAL THERAPY
CUTANEOUS HYDRATION. Patients with AD
have abnormal skin barrier function with increased
transepidermal water loss and decreased water content and dry skin (xerosis) contributing to disease
morbidity by the development of microfissures and
Successful treatment of AD requires a systematic, multipronged approach that incorporates education about
the disease state, skin hydration, pharmacologic therapy, and the identification and elimination of flare factors such as irritants, allergens, infectious agents, and
emotional stressors (Fig. 14-13).51,52 Many factors lead
to the symptom complex characterizing AD. Thus,
treatment plans should be individualized to address
each patients skin disease reaction pattern, including the acuity of the rash, and the trigger factors that
are unique to the particular patient. In patients refractory to conventional forms of therapy, alternative antiinflammatory and immunomodulatory agents may be
necessary.53
::
TREATMENT
Chapter 14
The natural history of AD is not completely known

because studies have been flawed in terms of inadequate sample size, an unclear definition of remission,
inadequate length of follow-up, selection bias in the
initial cohort, and excessive loss of patients to followup. Nevertheless, although the outcome of AD may
be difficult to predict in any given individual, the disease generally tends to be more severe and persistent
in young children. Periods of remission appear more
frequently as the patient grows older. Spontaneous
resolution of AD has been reported to occur after age
5 years in 4060% of patients affected during infancy,
particularly if their disease is mild. Although earlier
studies suggested that approximately 84% of children
outgrow their AD by adolescence, more recent studies have reported that AD disappears in approximately
20% of children followed from infancy until adolescence, but becomes less severe in 65%. In addition, more
than one-half of adolescents treated for mild dermatitis
may experience a relapse of disease as adults. Filaggrin mutations have been associated with higher rates
of persistent atopic dermatitis into later childhood and
adulthood.50 Importantly, for occupational counseling,
adults whose childhood AD has been in remission for
a number of years may present with hand dermatitis,
especially if daily activities require repeated hand wetting. The following predictive factors correlate with a
poor prognosis for AD: widespread AD in childhood,
associated allergic rhinitis and asthma, family history
of AD in parents or siblings, early age at onset of AD,
being an only child, and very high serum IgE levels.
cracks in the skin, which serve as portals of entry for

skin pathogens, irritants, and allergens. FLG gene
mutations have also been shown to result in decreased
epidermal levels of natural moisturizing factor.54 This
problem can become aggravated during the dry winter months and in certain work environments. Warm
soaking baths for approximately 10 minutes followed
by the application of an occlusive emollient or topical
medication to retain moisture can give such patients
excellent symptomatic relief. Bathing without emollient use may result in drier skin.55 Use of an effective
emollient combined with hydration therapy helps
to restore and preserve the stratum corneum barrier,
and may decrease the need for topical glucocorticoids. Moisturizers are available in the form of lotions,
creams, or ointments. Some lotions and creams may be
irritating due to added preservatives, solubilizers, and
fragrances. Lotions containing water may be drying
due to an evaporative effect.
Hydrophilic ointments can be obtained in varying
degrees of viscosity according to the patients preference. Occlusive ointments are sometimes not well tolerated because of interference with the function of the
eccrine sweat ducts and the induction of folliculitis. In
these patients, less occlusive agents should be used.
Topical therapy to replace abnormal epidermal lipids, improve skin hydration, and decrease skin barrier dysfunction may be useful therapeutically. Studies have shown benefits of topical preparations with
distinct compositions of lipids and ceramides, as well
as a nonsteroidal cream containing palmitamide MEA,
an essential fatty acid, and a hydrolipidic cream with
glycyrrhetinic acid (MAS063ADP).56,57 Further clinical studies to define the benefits relative to traditional
moisturizers and topical anti-inflammatory agents will
be helpful.
Hydration, by baths or wet dressings, promotes
transepidermal penetration of topical glucocorticoids.
Dressings may also serve as an effective barrier against
persistent scratching, allowing more rapid healing of
excoriated lesions.58 Wet dressings, or wet wraps are
recommended for use on severely affected or chronically involved areas of dermatitis refractory to therapy.59
However, overuse of wet dressings may result in maceration of the skin complicated by secondary infection.
Wet dressings or baths also have the potential to promote drying and fissuring of the skin if not followed
by topical emollient use. Thus, wet dressing therapy
is reserved for poorly controlled AD and should be
closely monitored by a physician.
TOPICAL ANTI-INFLAMMATORY
THERAPY
A recent study looked at TEWL, as well as several
other parameters of epidermal barrier including stratum corneum hydration and dye penetration.60 The
authors found improvement in all parameters when
AD patients were treated with both a topical steroid
(betamethasone valerate 0.1% cream) and a topical calcineurin inhibitor (pimecrolimus 1% cream) applied
to paired lesions of the upper extremities. Electron
175
Approach to patient with atopic dermatitis (AD)
Patient presents with history of pruritic dermatitis
Patient meets Hanifin and Rajka criteria for diagnosis of ADa
General skin care measures:
Section 4
::
education
appropriate skin hydration and use of emollients/skin barrier repair measures
avoidance of irritants
identification and avoidance of proven allergens
anti-inflammatory therapy (topical steroids, topical calcineurin inhibitorsb)
antipruritic interventions (sedating antihistamines, behavioral modification)
identification and treatment of complicated bacterial, viral, or fungal infections
treatment of psychosocial aspects of disease
Evaluate for other

conditions
Successful outcome?
Titration of topical therapy, using emollients/barrier repair measures

topical steroids or topical calcineurin inhibitors as needed intermittently
Re-assess diagnosis of AD
Consider role of unrecognized infectious agents, allergens; etc.
Consider poor understanding or non-adherence with treatment plan
Successful outcome?
Consultation with AD specialist

Consider skin biopsy
Consider hospitalization
Consider cyclosporin A, ultraviolet therapy, etc.
Figure 14-13 Approach to patient with atopic dermatitis (AD). aSee Table 14-1. bSecond-line therapy per black box
warning.
176
microscopic evaluation of barrier structure showed

prevalently ordered stratum corneum lipid layers
and regular lamellar body extrusion in the calcineurin inhibitor-treated skin but inconsistent extracellular
lipid bilayers and only partially filled lamellar bodies
in the steroid-treated skin. Both treatments normalized epidermal differentiation and reduced epidermal
hyperproliferation. Both anti-inflammatory therapies
increased expression of filaggrin and involucrin in the
skin. Betamethasone valerate was superior in reducing clinical symptoms and epidermal proliferation,
but twice daily use over the 3-week period of the study
led to epidermal thinning. The authors concluded that
since pimecrolimus improved the epidermal barrier
and did not cause cutaneous atrophy, it might be more
suitable for long-term treatment of AD. However,
the finding that the topical steroid was more effective in reducing clinical symptoms and inflammation
supports the use of topical steroids for acute intervention of AD flares.
::
TOPICAL CALCINEURIN INHIBITORS. Topical

tacrolimus and pimecrolimus have been developed
as nonsteroidal immunomodulators.68 Tacrolimus
ointment 0.03% has been approved for intermittent
treatment of moderate to severe AD in children aged
2 years and older, with tacrolimus ointment 0.1%
approved for use in adults; pimecrolimus cream 1%
is approved for treatment of patients aged 2 years
and older with mildmoderate AD. Both drugs have
proven to be effective with a good safety profile for
treatment up to 4 years with tacrolimus ointment69 and
up to 2 years with pimecrolimus cream.70 A frequently
observed side effect with TCIs is a transient burning
sensation of the skin. Importantly, treatment with TCIs
is not associated with skin atrophy,71 thus they are
particularly useful for the treatment of areas such as
the face and intertriginous regions. Ongoing surveillance and recent reports have not shown a trend for
increased frequency of viral superinfections, especially
eczema herpeticum.72 The long-term safety of TCIs
has not been established. Rare cases of skin malignancy and lymphoma have been reported with topical
tacrolimus, though the level of data quality and applicability of these reports was judged low in the report
of a scientific consensus conference.73 Importantly, a
case-control study of a large database that identified a
cohort of 293,253 patients with AD found no increased
risk of lymphoma with the use of TCIs.74 Twice to three
times weekly maintenance therapy using tacrolimus
ointment has also been reported in both adults and
children with AD.75,76
Chapter 14
TOPICAL GLUCOCORTICOID THERAPY. Topical glucocorticoids are the cornerstone of treatment for
anti-inflammatory eczematous skin lesions. Because
of potential side effects, most physicians use topical
glucocorticoids only to control acute exacerbations of
AD. However, recent studies suggest that once control
of AD is achieved with a daily regimen of topical glucocorticoid, long-term control can be maintained in a
subset of patients with twice weekly applications of
topical fluticasone to areas that have healed but are
prone to developing eczema.61
Patients should be carefully instructed in the use of
topical glucocorticoids to avoid potential side effects.
The potent fluorinated glucocorticoids should be
avoided on the face, the genitalia, and the intertriginous areas. A low-potency glucocorticoid preparation
is generally recommended for these areas. Patients
should be instructed to apply topical glucocorticoids
to their skin lesions and to use emollients over uninvolved skin. Failure of a patient to respond to topical
glucocorticoids is sometimes due in part to an inadequate supply. It is important to remember that it takes
approximately 30 g of cream or ointment to cover the
entire skin surface of an adult once. To treat the entire
body twice daily for 2 weeks requires approximately
840 g (2 lb) of topical glucocorticoids.
There are seven classes of topical glucocorticoids,
ranked according to their potency based on vasoconstrictor assays. Because of their potential side effects,
the ultrahigh-potency glucocorticoids should be used
only for very short periods of time and in areas that are
lichenified but not on the face or intertriginous areas.
The goal is to use emollients to enhance skin hydration and low-potency glucocorticoids for maintenance
therapy. Midpotency glucocorticoids can be used for
longer periods of time to treat chronic AD involving
the trunk and extremities. Newer formulations of topical steroids include gel formulations without alcohol
bases that moisturize skin, and solutions, oils, foams,
and shampoos that may be useful on hair-bearing surfaces.
Factors which influence topical glucocorticoid
potency and side effects include the molecular structure of the compound, the vehicle, the amount of medication applied, the duration of application, occlusion,
as well as host factors, including age, body surface area
and weight, skin inflammation, anatomic location of
treated skin, and individual differences in cutaneous
or systemic metabolism. Side effects from topical glucocorticoids are directly related to the potency ranking
of the compound and the length of use, so it is incumbent on the clinician to balance the need for a more
potent steroid with the potential for side effects. In
addition, ointments have a greater potential to occlude
the epidermis, resulting in enhanced systemic absorption when compared to creams. Side effects from topical glucocorticoids can be divided into local side effects
and systemic side effects resulting from suppression of
the hypothalamicpituitaryadrenal axis. Local side
effects include the development of striae, skin atrophy,
perioral dermatitis, and acne rosacea. The potential for

potent topical glucocorticoid to cause adrenal suppression is greatest in infants and young children. Several
topical steroid formulations have been specifically
tested for safety and received specific US Federal Drug
Administration (FDA) approval for use in younger
children such as desonide hydrogel and nonethanolic foam, fluocinolone acetonide oil, and fluticasone
0.05% cream.6265 Mometasone cream and ointment are
approved for children aged 2 years and older.
Because normal-appearing skin in AD shows evidence of immunologic dysregulation, the use of topical corticosteroids as maintenance therapy has been
reported in several controlled studies.66 Once control
of AD with a once daily regimen was achieved, longterm control could be maintained with twice weekly
application of fluticasone to previously involved areas.
Given recent insights into skin barrier and immunologic abnormalities and colonization of normalappearing skin in AD by S. aureus, it is important to
appreciate that proactive therapy is an attempt to control residual disease, not just application of an active
drug to nonaffected skin.67
IDENTIFICATION AND ELIMINATION

OF TRIGGERING FACTORS
GENERAL CONSIDERATIONS. Patients with
AD are more susceptible to irritants than are unaffected individuals. Thus, it is important to identify and
177
Section 4
::
178
eliminate aggravating factors that trigger the itch

scratch cycle. These include soaps or detergents, contact with chemicals, smoke, abrasive clothing, and
exposure to extremes of temperature and humidity.
Alcohol and astringents found in toiletries are drying.
When soaps are used, they should have minimal defatting activity and a neutral pH. New clothing may be
laundered before wearing to decrease levels of formaldehyde and other added chemicals. Residual laundry
detergent in clothing may be irritating. Using a liquid
rather than powder detergent and adding a second
rinse cycle facilitates removal of the detergent.
Recommendations regarding environmental living
conditions should include temperature and humidity
control to avoid problems related to heat, humidity,
and perspiration. Every attempt should be made to
allow children to be as normally active as possible.
Certain sports, such as swimming, may be better tolerated than other sports involving intense perspiration, physical contact, or heavy clothing and equipment, but chlorine should be rinsed off immediately
after swimming and the skin lubricated. Although
ultraviolet (UV) light may be beneficial to some
patients with AD, sunscreens should be used to avoid
sunburn. However, because sunscreens can be irritants, care should be used to identify a nonirritating
product.
SPECIFIC ALLERGENS. Foods and aeroallergens such as dust mites, animal danders, molds,
and pollens have been demonstrated to exacerbate
AD. Potential allergens can be identified by taking a
careful history and carrying out selective skin-prick
tests or specific serum IgE levels. Negative skin tests
or serum tests for allergen-specific IgE have a high
predictive value for ruling out suspected allergens.
However, a normal total serum IgE level does not
rule out the possibility of allergen-specific IgE being
present. Positive skin or in vitro tests, particularly
to foods, often do not correlate with clinical symptoms and should be confirmed with controlled food
challenges and elimination diets. Avoidance of foods
implicated in controlled challenges results in clinical
improvement. Extensive elimination diets, which in
some cases can be nutritionally deficient, are rarely,
if ever, required, because even with multiple positive skin tests, the majority of patients react to three
or fewer foods on controlled challenge. In dust miteallergic patients with AD, prolonged avoidance of
dust mites has been found to result in improvement
of their skin disease. Avoidance measures include
use of dust mite-proof encasings on pillows, mattresses, and box springs; washing bedding in hot
water weekly; removal of bedroom carpeting; and
decreasing indoor humidity levels with air conditioning. Because there are many triggers contributing to the flares of AD, attention should be focused
on identifying and controlling the flare factors that
are important to the individual patient. Infants and
young children are more likely to have food allergies, whereas older children and adults are more
likely to be sensitive to environmental aeroallergens.
Contact allergens have been increasingly recognized

in AD. A recent study found that of children with
relevant positive reactions, 34% had a diagnosis of
AD.77
EMOTIONAL STRESSORS. Although emotional

stress does not cause AD, it often exacerbates the illness. AD patients often respond to frustration, embarrassment, or other stressful events with increased pruritus and scratching. In some instances, scratching is
simply habitual and less commonly associated with
significant secondary gain. Psychological evaluation
or counseling should be considered in patients who
have difficulty with emotional triggers or psychological problems, contributing to difficulty in managing
their disease. It may be especially useful in adolescents
and young adults who consider their skin disease
disfiguring. Relaxation, behavioral modification, or
biofeedback may be helpful in patients with habitual
scratching.58
INFECTIOUS AGENTS. Antistaphylococcal antibiotics are very helpful in the treatment of patients
who are heavily colonized or infected with S. aureus.78
Cephalosporins or penicillinase-resistant penicillins
(dicloxacillin, oxacillin, or cloxacillin) are usually
beneficial for patients who are not colonized with
resistant S. aureus strains. Because erythromycinresistant Staphylococci are common, erythromycin
and newer macrolide antibiotics are usually of limited utility. Topical antimicrobials such as mupirocin, fusidic acid, or more recently retapamulin offers
some utility in the treatment of impetiginized lesions.
A Cochrane Database analysis of interventions for
impetigo found that topical mupirocin and topical
fusidic acid are equal to or more effective than oral
treatment for patients with limited disease and that
fusidic acid and mupirocin are of similar efficacy.79
Patients should be cautioned against using topical
antibiotics in an as-needed manner that can lead to
resistant organisms.80
Use of neomycin topically can result in development of allergic contact dermatitis as neomycin is
among the more common allergens causing contact dermatitis. However, in patients with extensive superinfection, a course of systemic antibiotics
is most practical. Methicillin-resistant Staphylococci
may require culture and sensitivity testing to assist
in appropriate antibiotic selection. Baths with dilute
sodium hypochlorite (bleach) may also benefit AD
patients with superinfected eczema, especially those
with recurrent MRSA, although they can occasionally be irritating. Of note, a controlled study of twice
weekly bleach baths for 3 months showed clinical
benefit, although skin colonization by S. aureus did
not disappear, even when combined with intranasal
mupirocin 5 days each month.81
Herpes simplex can provoke recurrent dermatitis
and may be misdiagnosed as S. aureus infection. The
presence of punched-out erosions, vesicles, and/or
infected skin lesions that do not respond to oral antibiotics should initiate a search for herpes simplex. This
PHOTOTHERAPY
Natural sunlight is frequently beneficial to patients
with AD. However, if the sunlight occurs in the setting
of high heat or humidity, thereby triggering sweating and pruritus, it may be deleterious to patients.
Broadband UVB, broadband UVA, narrowband UVB
(311 nm), UVA-1 (340 to 400 nm), and combined UVAB
phototherapy can be useful adjuncts in the treatment of AD. Investigation of the photoimmunologic
mechanisms responsible for therapeutic effectiveness
indicates that epidermal LCs and eosinophils may be
targets of UVA phototherapy, with and without psoralen, whereas UVB exerts immunosuppressive effects
via blocking of function of antigen-presenting LCs
and altered keratinocyte cytokine production. Photochemotherapy with psoralen and UVA light may
be indicated in patients with severe, widespread AD,
although studies comparing it with other modes of
phototherapy are limited. Short-term adverse effects
with phototherapy may include erythema, skin pain,
pruritus, and pigmentation. Long-term adverse effects
include premature skin aging and cutaneous malignancies (see Chapters 237 and 238 for detailed discussion of phototherapy and photochemotherapy, respectively).
be directed primarily at the underlying causes. Reduction of skin inflammation and dryness with topical glucocorticoids and skin hydration, respectively,
often symptomatically reduce pruritus. Inhaled and
ingested allergens should be eliminated if documented
to cause skin rash in controlled challenges. Systemic
antihistamines act primarily by blocking the H1 receptors in the dermis, thereby ameliorating histamineinduced pruritus. However, histamine is only one of
many mediators that can induce pruritus of the skin.
Therefore, certain patients may derive minimal benefit from antihistaminic therapy. Some antihistamines
are also mild anxiolytics and may offer symptomatic
relief through tranquilizing and sedative effects. Studies of newer, nonsedating antihistamines show variable results in the effectiveness of controlling pruritus
in AD, although they may be useful in the subset of
AD patients with concomitant urticaria or concurrent
allergic rhinitis.
Because pruritus is usually worse at night, the
sedating antihistamines, for example, hydroxyzine or
diphenhydramine, may offer an advantage with their
soporific side effects when used at bedtime. Doxepin
hydrochloride has both tricyclic antidepressant and
H1- and H2-histamine receptor-blocking effects. It can
be used in doses of 1075 mg orally at night or up to
75 mg bid in adult patients. If nocturnal pruritus remains severe, short-term use of a sedative to
allow adequate rest may be appropriate. Treatment
of AD with topical antihistamines is generally not
recommended because of potential cutaneous sensitization. However, short-term (1 week) application
of topical 5% doxepin cream has been reported to
reduce pruritus without sensitization. Of note, sedation is a side effect of widespread application of doxepin cream, and allergic contact dermatitis has been
reported.
Coal tar preparations may have antipruritic and

anti-inflammatory effects on the skin, although usually not as pronounced as those of topical glucocorticoids.82 Tar preparations may be useful in reducing the
potency of topical glucocorticoids required in chronic
maintenance therapy of AD. Newer coal tar products
have been developed that are more acceptable with
respect to odor and staining of clothes than some older
products. Tar shampoos can be beneficial for scalp
dermatitis and are often helpful in reducing the concentration and frequency of topical glucocorticoid
applications. Tar preparations should not be used on
acutely inflamed skin, because this often results in skin
irritation. Side effects associated with tars include folliculitis and photosensitivity. There is a theoretic risk of
tar being a carcinogen based on observational studies
of workers using tar components in their occupations;
however, epidemiologic studies do not confirm similar
outcomes when used topically.83
::
PRURITUS. The treatment of pruritus in AD should
TAR PREPARATIONS
Chapter 14
can be diagnosed by a Giemsa-stained Tzanck smear

of cells scraped from the vesicle base, direct immunofluorescence assay, polymerase chain reaction identification of herpes genetic material, or by viral culture. For infection suspected to be caused by herpes
simplex, topical anti-inflammatory agents might be
discontinued, at least temporarily. Antiviral treatment
for cutaneous herpes simplex infections is of critical
importance in the patient with widespread AD because
life-threatening dissemination has been reported. Acyclovir, 400 mg three times daily for 10 days or 200 mg
four times daily for 10 days by oral administration (or
an equivalent dosage of one of the newer antiherpetic
medications), is useful in adults with herpes simplex
confined to the skin. Intravenous treatment may be
necessary for severe disseminated eczema herpeticum.
The dosage should be adjusted according to weight in
children.
Dermatophyte infections can complicate AD and
may contribute to exacerbation of disease activity.
Patients with dermatophyte infection or IgE antibodies to Malassezia may benefit from a trial of topical or
systemic antifungal therapy.
HOSPITALIZATION
AD patients who appear erythrodermic or who have
widespread severe skin disease resistant to outpatient therapy should be hospitalized before considering systemic alternative therapies (see section Systemic Therapy). In many cases, removing the patient
from environmental allergens or emotional stresses,
intense patient education, and assurance of compliance with therapy results in a sustained improvement
in their AD. Clearing of the patients skin during
179
hospitalization also allows the patient to undergo

allergen skin testing and appropriately controlled
provocative challenges to correctly identify or rule
out potential allergens.
SYSTEMIC THERAPY
Systemic therapies discussed below were reviewed in
a consensus conference.53
Section 4
::
180
SYSTEMIC GLUCOCORTICOIDS. The use of

systemic glucocorticoids, such as oral prednisone, is
rarely indicated in the treatment of chronic AD. Some
patients and physicians prefer the use of systemic glucocorticoids to avoid the time-consuming skin care
involving hydration and topical therapy. However, the
dramatic clinical improvement that may occur with
systemic glucocorticoids is frequently associated with
a severe rebound flare of AD after the discontinuation
of systemic glucocorticoids. Short courses of oral glucocorticoids may be appropriate for an acute exacerbation of AD whereas other treatment measures are being
instituted. If a short course of oral glucocorticoids is
given, it is important to taper the dosage and to begin
intensified skin care, particularly with topical glucocorticoids and frequent bathing followed by application of emollients to prevent rebound flaring of AD.
CYCLOSPORINE. Cyclosporine is a potent immunosuppressive drug that acts primarily on T cells by
suppressing cytokine transcription. The drug binds
to cyclophilin, an intracellular protein, and this complex, in turn, inhibits calcineurin, a molecule required
for initiation of cytokine gene transcription. Multiple
studies demonstrate that both children and adults with
severe AD, refractory to conventional treatment, can
benefit from short-term cyclosporine treatment. Various oral-dosing regimens have been recommended:
5 mg/kg has generally been used with success in shortterm and long-term (1 year) use, whereas some authorities advocate body-weight-independent daily dosing
of adults with 150 mg (low dose) or 300 mg (high dose)
daily of cyclosporine microemulsion. Treatment with
cyclosporine is associated with reduced skin disease
and an improved quality of life (see Chapter 233 for
further discussion). Discontinuation of treatment
may result in rapid relapse of skin disease, although
some patients may have sustained remission. Elevated
serum creatinine or more significant renal impairment
and hypertension are specific side effects of concern
with cyclosporine use.
ANTIMETABOLITES. Mycophenolate mofetil is
a purine biosynthesis inhibitor used as an immunosuppressant in organ transplantation, which has been
used for treatment of refractory inflammatory skin
disorders (see Chapter 233). Open-label studies report
that short-term oral mycophenolate mofetil, 2 g daily,
as monotherapy results in clearing of skin lesions in
adults with AD resistant to other treatment, including
topical and oral steroids and psoralen and UVA light.
The drug has generally been well tolerated with the
exception of one patient developing herpes retinitis

that may have been secondary to this immunosuppressive agent. Dose-related bone marrow suppression has
also been observed. Similar results were previously
reported in another open study of ten patients with a
mean reduction in the SCORAD (SCORing Atopic Dermatitis) index of 68% in all ten patients. Of note, not all
patients benefit from treatment. Therefore, the medication should be discontinued if patients do not respond
within 4 to 8 weeks. Dose finding and well-controlled
studies are needed for this drug.
Methotrexate is an antimetabolite with potent inhibitory effects on inflammatory cytokine synthesis and
cell chemotaxis. Methotrexate has been used for adult
AD patients with recalcitrant disease, although controlled trials are lacking. Dosing more frequently than
the typical weekly dosing for psoriasis has been advocated.84 In open-label studies, initial improvement
was observed after a period ranging from 2 weeks to
3 months (mean 9.95 weeks +/ 3.17).
Azathioprine is a purine analog with anti-
inflammatory and antiproliferative effects. It has been
used for severe AD, and several controlled trials have
been reported in adults and children.85,86 Myelosuppression is a significant adverse effect. Thiopurine
methyl transferase levels may predict individuals at
risk.87
OTHER THERAPIES
INTERFERON-. IFN- is known to suppress IgE
responses and downregulate Th2 cell proliferation and
function. Several studies of patients with AD, including a multicenter, double-blind, placebo-controlled
trial88 and two long-term open trials,89,90 have demonstrated that treatment with recombinant human IFN-
results in clinical improvement. Reduction in clinical
severity of AD correlated with the ability of IFN- to
decrease total circulating eosinophil counts. Influenzalike symptoms are commonly observed side effects
early in the treatment course.
OMALIZUMAB. Treatment of patients with severe
AD and elevated serum IgE levels with monoclonal
anti-IgE has shown lack of efficacy in three adult
patients91 and significant improvement in three
adolescent patients.92 In an open study of 11 adult
patients with high IgE levels treated with anti-IgE,
some patients had very good clinical improvement,
others had none and several had worsening of their
AD based on change in SCORAD.93 To date, specific
markers have not been found to identify potential
responders.
ALLERGEN IMMUNOTHERAPY. Unlike allergic
rhinitis and extrinsic asthma, immunotherapy with
aeroallergens has not proven to be efficacious in the
treatment of AD. There are anecdotal reports of both
disease exacerbation and improvement. A recent study
of specific immunotherapy over 12 months in adults
with AD sensitized to dust mite allergen showed
improvement in SCORAD as well as reduction in
topical steroid use.94 However, well-controlled studies

are still required to determine the role for immunotherapy with this disease. More recently, a controlled
study with sublingual immunotherapy showed benefit in a subset of children with AD sensitized to dust
mite allergen.95 This data need to be reproduced in a
larger pediatric population, given the natural history
of AD.
ORAL VITAMIN D. A pilot randomized, doubleblind placebo-controlled study looked at the benefit of
oral vitamin D supplementation in children with AD
from February to March in Boston.106 Eleven pediatric patients primarily with mild AD were treated with
either vitamin D (1,000 IU ergocalciferol) or placebo
once daily for a month. IGA score improved in four
of six subjects in the vitamin D group (80%), as compared to one of five subjects in the placebo group (p
= 0.04). In addition, there was a greater reduction in
EASI score in the vitamin D, as compared to the placebo group, although the difference was not statistically significant. In addition, in a controlled study, 14
healthy subjects and 14 subjects with AD were supplemented with 4,000 IU per day of oral vitamin D3 (cholecalciferol) for 3 weeks.107 Expression of the AMP cathelicidin was significantly increased in the skin biopsies of AD lesions, as compared to those in healthy
skin or uninvolved AD skin, suggesting a role for oral
vitamin D in improving innate immune responses in
AD patients.108
::
PROBIOTICS. Perinatal administration of the probiotic Lactobacillus rhamnosus strain GG was shown to
reduce the incidence of AD in at-risk children during
the first 2 years of life.97 Mothers were given either placebo or Lactobacillus GG daily for 4 weeks before delivery and then either the mother (if breast-feeding) or the
infant continued with daily therapy for 6 months. In
a follow-up study, the same group assessed the persistence of potential to prevent AD at 4 years.98 The
results suggest that the preventive effect of Lactobacillus GG on AD could extend beyond infancy.
In a second study, children with AD treated with
two Lactobacillus strains for 6 weeks experienced
improvement of their eczema compared to placebotreated patients, although their SCORAD index did
not change significantly.99 The treatment response was
found to be more pronounced in patients with positive skin-prick tests and elevated IgE levels. Another
study of children with moderate to severe AD treated
for 8 weeks with L. fermentum in a placebo-controlled
study showed persistent improvement in SCORAD at
16 weeks.100 These studies suggest that probiotics, or
at least some Lactobacillus strains, may have preventative, lasting effects on the incidence of AD in a subset
of patients. More research into subgroups of responders, optimal therapy [route (i.e., directly to infant or
via mothers milk); length of treatment; strain of Lactobacillus], as well as mechanisms involved is clearly
needed.101
A recent meta-analysis found a modest role for
probiotics in children with moderately severe disease in reducing SCORAD (mean change from baseline, 3.01; 95% confidence interval, 5.36 to 0.66; P
= .01).102 Duration of probiotic administration, age,
and type of probiotic used did not affect outcomes.
Another meta-analysis found that current evidence is
more convincing for probiotics efficacy in prevention,
rather than treatment of AD in children.103 In contrast
to earlier studies, supplementation with Lactobacillus GG during pregnancy and early infancy neither
reduced the incidence of AD nor altered the severity
of AD in affected children, but was associated with
increased rate of recurrent episodes of wheezy bronchitis.104 A Cochrane review concluded that probiotics
are not an effective treatment for eczema in children
CHINESE HERBAL MEDICATIONS. Several

placebo-controlled clinical trials have suggested that
patients with severe AD may benefit from treatment
with traditional Chinese herbal therapy (see Chapter
241). They had significantly reduced skin disease and
decreased pruritus. However, the beneficial response
of Chinese herbal therapy is often temporary, and
effectiveness may wear off despite continued treatment. The possibility of hepatic toxicity, cardiac side
effects, or idiosyncratic reactions remains a concern.
The specific ingredients of the herbs also remain to be
elucidated and some preparations have been found
to be contaminated with corticosteroids. At present,
Chinese herbal therapy for AD is considered investigational.
Chapter 14
EXTRACORPOREAL PHOTOPHERESIS. Extracorporeal photopheresis consists of the passage of

psoralen-treated leukocytes through an extracorporeal
UVA light system. Clinical improvement in skin lesions
associated with reduced IgE levels has been reported
in a few patients with severe, resistant AD who were
treated with extracorporeal photopheresis and topical
glucocorticoids.96
and that probiotic treatment carries a small risk of

adverse events.105
TABLE 14-2
Online Resources for Patients With AD

and Their Families
Coping Strategies and Support Groups
National Eczema Association (www.nationaleczema.org)
Under My Skin: A Kids Guide to Atopic Dermatitis
(www.undermyskin.com)
Specialized AD Care
American Academy of Dermatology EczemaNet
(www.skincarephysicians.com/eczemanet/index.html)
The Eczema Center at Rady Childrens Hospital
(www.eczemacenter.org)
National Jewish Health (www.njc.org)
Northwestern University Eczema Care and Education
Center (www.eczemacarecenter.com)
Information on Allergic Triggers
American Academy of Allergy, Asthma & Immunology
(www.aaaai.org)
Food Allergy & Anaphylaxis Network (www.foodallergy.org)
181
EDUCATION AS INTERVENTION
Education may be considered as a therapeutic intervention for the management of atopic dermatitis.51,52 Intensive disease education has been shown in randomized,
controlled trials to improve subjective quality-of-life
and objective eczema severity scores.109 Intensive education may include comprehensive center-based
patient/family teaching, written handouts, and care
plans, patient/family support groups, and Internetaccessed media. Several resources available online are
listed in Table 14-2.
Section 4
KEY REFERENCES
::
1. Cork MJ et al: Epidermal barrier dysfunction in atopic

dermatitis. J Invest Dermatol 129:1892, 2009
Chapter 15 :: N
ummular Eczema, Lichen Simplex
Chronicus, and Prurigo Nodularis

:: Susan Burgin
NUMMULAR ECZEMA
NUMMULAR ECZEMA AT A GLANCE
Also known as discoid eczema.
A chronic disorder of unknown etiology.
Papules and papulovesicles coalesce to form
nummular plaques with oozing, crust, and
scale.
Most common sites of involvement are upper
extremities, including the dorsal hands in
women, and the lower extremities in men.
Pathology may show acute, subacute, or
chronic eczema.
EPIDEMIOLOGY
182
8. Bieber T: Atopic dermatitis. N Engl J Med 358:1483, 2008

9. Cork MJ et al: Epidermal barrier dysfunction in atopic
dermatitis. J Invest Dermatol 129:1892, 2009
10. ORegan GM et al: Filaggrin in atopic dermatitis. J Allergy Clin Immunol 122:689, 2008
36. De Benedetto A et al: Atopic dermatitis: A disease caused
by innate immune defects? J Invest Dermatol 129:14, 2009
37. Barnes KC: An update on the genetics of atopic dermatitis: Scratching the surface in 2009. J Allergy Clin Immunol
125:16, 2010
48. Boguniewicz M, Leung DY: Recent insights into atopic dermatitis and implications for management of infectious complications. J Allergy Clin Immunol 125:4,
2010
53. Akdis CA et al: Diagnosis and treatment of atopic dermatitis in children and adults: European Academy
of Allergology and Clinical Immunology/American
Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report. J Allergy Clin Immunol 118:152,
2006
58. Boguniewicz M et al: A multidisciplinary approach to
evaluation and treatment of atopic dermatitis. Semin Cutan Med Surg 27:115, 2008
67. Wollenberg A, Bieber T: Proactive therapy of atopic dermatitisAn emerging concept. Allergy 64:276, 2009
Nummular eczema is predominantly a disease of

adulthood. Men are more frequently affected than
women. The peak incidence in both males and females
is around 5065 years of age. There is a second peak in
women around 1525 years of age. Nummular eczema
is rare in infancy and childhood. The peak age of onset
in childhood is 5 years.1

The pathogenesis of nummular eczema is still
unknown. The vast majority of patients with nummular eczema do not have a personal or family history of
atopy,2,3 although nummular plaques may be seen in
atopic eczema. Numerous factors have been implicated
as causal. The state of hydration of the skin in elderly
patients has been shown to be decreased.4 The role of
infection previously received much attention in the literature. An internal focus of infection, including teeth,
upper respiratory tract, and lower respiratory tract, was
found in 68% of patients in one study.5 Eleven of thirteen
patients without a history of atopic eczema improved
after odontogenic infections were treated.6 A role for
environmental allergens, such as the house dust mite
and Candida albicans has also been touted.4 Nummular
eczema has been reported during therapy with isotretinoin and gold.7,8 Generalized nummular eczema is seen
in patients with hepatitis C undergoing combination
therapy with interferon -2b and ribavirin.9,10 Mercury
amalgam was implicated as a cause in two patients.11
CLINICAL FINDINGS
Well-demarcated coin-shaped plaques form from
coalescing papules and papulovesicles. Pinpoint
oozing and crusting eventuate, and are distinctive
(Figs. 15-1 and 15-2). Crust may however cover the
entire surface (Fig. 15-3). Plaques range from 1 to 3 cm
Chapter 15
::
Figure 15-3 Nummular eczema in a child. Crusted plaques.

(Used, with permission, from P. Lio, M.D., Northwestern
Universitys Feinberg School of Medicine, Chicago.)
in size. The surrounding skin is generally normal but

may be xerotic. Pruritus varies from minimal to severe.
Central resolution may occur, leading to annular forms.
Chronic plaques are dry, scaly, and lichenified. The
classic distribution of lesions is the extensor aspects
of the extremities. In women, the upper extremities,
including the dorsal aspects of the hands, are more frequently affected than the lower extremities.2 Exudative
discoid and lichenoid dermatitis of Sulzberger-Garbe

may represent a variant of nummular dermatitis.12
Nummular Eczema, Lichen Simplex Chronicus
Figure 15-1 Nummular eczema. Coin-shaped plaques with

pinpoint erosions and excoriations. (Image from Division of
Dermatology, University of the Witwatersrand, Johannesburg, South Africa, with permission, from Professor D. Modi.)
LABORATORY TESTS
Patch testing may be useful in chronic recalcitrant cases
to rule out a superimposed contact dermatitis. In a series
from India, just under half of 50 patients were patch-test
positive to colophony, nitrofurazone, neomycin sulfate,
and nickel sulfate.13 Serum IgE levels are normal.
SPECIAL TESTS
Histopathologic changes are reflective of the stage at
which the biopsy is performed. Acutely, there is spongiosis, with or without spongiotic microvesicles. In
subacute plaques, there is parakeratosis, scale-crust,
epidermal hyperplasia, and spongiosis of the epidermis (Fig. 15-4). There is a mixed cell infiltrate in the
dermis. Chronic lesions may resemble lichen simplex
chronicus microscopically.
Figure 15-2 Nummular eczema. Single plaque showing

pinpoint erosions and crusting.
See Box 15-1.
183
are also effective. Emollients can be added adjunctively if there is accompanying xerosis. Oral antihistamines are useful if pruritus is severe. Oral antibiotics
are indicated when secondary infection is present. For
widespread involvement, phototherapy with broador narrow-band ultraviolet B may be beneficial.
LICHEN SIMPLEX CHRONICUS/

PRURIGO NODULARIS
Section 4
Figure 15-4 Histopathology of nummular eczema. Parakeratosis containing plasma and neutrophils (scale-crust)
and psoriasiform epidermal hyperplasia with spongiosis
are present, with a superficial dermal perivascular infiltrate
of lymphocytes, macrophages, and eosinophils.
LICHEN SIMPLEX CHRONICUS

AT A GLANCE
A chronic, severely pruritic disorder
characterized by one or more lichenified
plaques.
::
COMPLICATIONS
Nummular eczema may be complicated by secondary
bacterial infection.
Pathology consists of hyperkeratosis,

hypergranulosis, psoriasiform epidermal
hyperplasia, and thickened papillary dermal
collagen.
The course is usually chronic. Recurrence at prior sites

of involvement is a feature of the disease.5
TREATMENT
Topical steroids in the mid- to high-potency range are
the mainstay of treatment. The calcineurin inhibitors,
tacrolimus and pimecrolimus, and tar preparations
Box 15-1 Differential Diagnosis

of Nummular Eczema
Most Likely
Allergic contact dermatitis
Stasis dermatitis
Atopic dermatitis
Tinea corporis
Consider
Impetigo
Psoriasis (longstanding plaques)
Mycosis fungoides (longstanding plaques)
Pagets disease, when there is unilateral involvement of nipple/areola
Other nummular dermatoses:
Fixed drug eruption
Pityriasis rotunda
184
Most common sites of involvement are scalp,

nape of neck, extensor aspects of extremities,
ankles, and anogenital area.
Always Rule Out

Tinea corporis
PRURIGO NODULARIS AT
A GLANCE
A pruritic disorder that runs a chronic
course.
Hyperkeratotic firm nodules vary in size
from 0.5 to 3 cm and may be excoriated.
Associations include atopic dermatitis, or
systemic causes of pruritus.
Pathology consists of hyperkeratosis,
hypergranulosis, psoriasiform epidermal
hyperplasia, thickened papillary dermal
collagen, and characteristic neural
hypertrophy.
EPIDEMIOLOGY
Lichen simplex chronicus affects adults, predominantly from ages 30 to 50. Females are affected more
commonly than males. Prurigo nodularis may occur
at any age, but most patients are between 20 and 60
years.14 Men and women are equally affected. Patients
with coexistent atopic dermatitis have been found to
have any earlier age of onset (mean: 19 years) as compared to the nonatopic group (mean: 48 years).15
LABORATORY TESTS
Nummular Eczema, Lichen Simplex Chronicus
HISTORY. Severe itching is the hallmark of lichen

simplex chronicus. Itching may be paroxysmal, continuous, or sporadic. Rubbing and scratching may be
RELATED PHYSICAL FINDINGS. In patients

with atopic eczema, the intervening skin is often
lichenified and xerotic. In nonatopic patients, cutaneous signs of underlying systemic disease or lymphadenopathy, signifying lymphoma, may be present.
::
CLINICAL FINDINGS
CUTANEOUS LESIONS. In lichen simplex chronicus, repeated rubbing and scratching gives rise to a
lichenified, scaly plaque with excoriations. Hyperand hypopigmentation are seen with chronicity. Usually, only one plaque is present; however, more than
one site may be involved. The most common sites of
involvement are the scalp, the nape of the neck (especially in women), the ankles, the extensor aspects of
the extremities, and the anogenital region.26 The labia
majora in women and the scrotum in men (Fig. 15-5)
are the most common sites of genital involvement.16
The upper inner thighs may also be affected.
Prurigo nodules vary in size from 0.5 to 3 cm and
are firm to hard on palpation. The surface may be
hyperkeratotic or crateriform. There is often overlying excoriation. Pruritus is usually severe. Limbs are
affected in most cases, especially the extensor aspects
(Fig. 15-6). The abdomen and sacrum were the next
most common sites of involvement in one study.22 Face
and palms are rarely involved; however, nodules may
occur on any site that can be reached by the patient.
Lesions may vary in number from few to more than
one hundred. Nodules resolve with postinflammatory
hyper- or hypopigmentation with or without scarring.
Chapter 15
Lichen simplex chronicus is induced by rubbing and

scratching secondary to itch. The prurigo nodule is
induced by picking and scratching most commonly, but
not always, in response to itch. Various factors incite itch
in both disorders and not all are well understood. A variable association between lichen simplex chronicus and
atopic disorders has been reported, ranging from around
26% to 75%.16,17 Similarly, a subset of patients with prurigo nodularis has coexistent atopic eczema. Here, prurigo nodules occur in concert with subacute prurigo,
lichenification, and xerosis. Besnier prurigo refers to
the pruriginous nodules seen in atopic dermatitis. In the
nonatopic nodular prurigo group, systemic causes of
pruritus, including renal insufficiency, hyper- or hypothyroidism, liver failure, HIV disease, parasitic infection,
or an underlying malignancy must be excluded. Hepatitis B and C have been reported as associations without
liver failure.18 Prurigo nodularis has also been reported
to occur in the setting of celiac disease in the presence or
absence of dermatitis herpetiformis.19,20 The relationship
between lichen simplex chronicus and radiculopathy
has been preliminarily investigated.21 Further studies are
needed to clarify whether an association exists.
Environmental factors have been implicated in inducing itch, such as heat, sweat, and irritation associated
with anogenital lichen simplex chronicus.17 The presence of emotional or psychological factors in patients
with prurigo nodularis and lichen simplex chronicus has
been alluded to in the literature. One study of prurigo
nodularis patients found that around half of 46 patients
had a history of depression, anxiety, or other treatable
psychological disorders.22 Lichen simplex chronicus
patients also had higher depression scores in one study.23
Whether these emotional factors are secondary to the primary dermatologic disease or whether they are primary
and causative, altering perception of itch, is unclear. It
has been postulated that neurotransmitters that affect
mood, such as dopamine, serotonin, or opioid peptides
modulate perception of itch via descending spinal pathways.14 Obsessive-compulsive disorder (OCD) has also
been associated with picking in these disorders.24
At a microscopic level, increased numbers of Merkel
cells are also seen adjacent to the dermal nerve fibers
and mast cells in prurigo nodularis. It is thought that
this complex may mediate the abnormally heightened
perception of touch and itch in these patients. Nerve
growth factor (NGF) is overexpressed in prurigo nodularis lesions and it has been implicated in the pathogenesis of the characteristic cutaneous neural hyperplasia
seen.25 NGF is produced and released by mast cells,
which are increased in number and size on histologic
sections. It upregulates the expression of neuropeptides,
such as calcitonin gene-related peptide and substance P.
These are thought to mediate inflammation and itch.17
conscious and to the point of replacing the sensation of

itch with pain, or may be unconscious, occurring during sleep. Itch severity is worse with sweating, heat, or
irritation from clothing. Itching is also worse in times
of psychological distress.18
In patients with prurigo nodularis in whom an underlying systemic cause of pruritus is suspected, a complete blood count with differential count, renal, liver,
and thyroid function tests may be ordered. A chest
X-ray may be obtained to screen for lymphoma. HIV
testing may also be indicated. The need for a more
extensive evaluation may be individualized based on
patient history and results of the aforementioned tests.
SPECIAL TESTS
On histopathologic sections, lichen simplex chronicus
shows varying degrees of hyperkeratosis with paraand orthokeratosis, hypergranulosis, and psoriasiform
epidermal hyperplasia. The papillary dermis shows
thickening of collagen with coarse collagen bundles
and vertical streaks. There is a variable inflammatory
infiltrate around the superficial vascular plexus with
lymphocytes, histiocytes, and eosinophils. A biopsy
may also reveal a primary pruritic disorder that has
led to secondary lichenification, such as psoriasis.
The epidermal findings in prurigo nodularis are
similar to lichen simplex chronicus. The lesion is more
185
Section 4
::
Figure 15-5 Lichen simplex chronicus of the scrotum:

lichenification, hyper- and hypopigmentation with excoriation. (Image from Division of Dermatology, University of
the Witwatersrand, Johannesburg, South Africa, with permission, from Professor D. Modi.)
papular with bulbous epidermal hyperplasia. Papillary dermal changes also resemble lichen simplex
chronicus. There may be cutaneous neural hypertrophy with thickened nerve bundles and an increase in
nerve fibers by S-100 staining. This finding was seen in
the minority of cases in a recent study.27
TREATMENT
Treatment is aimed at interrupting the itchscratch
cycle. Both components should be addressed. Systemic
causes of itch should be identified and addressed. In
See Boxes 15-2 and 15-3.
COMPLICATIONS
Sleep studies have shown that disturbances in the
sleep cycle in lichen simplex chronicus are present.
Non-REM sleep is disturbed and patients have an
increased arousal index (brief awakenings from sleep)
caused by scratching.28
186
Figure 15-6 Prurigo nodularis. (Used, with permission,

from Professor D. Modi, Division of Dermatology, University
of the Witwatersrand, Johannesburg, South Africa.)
Both diseases run a chronic course with persistence or

recurrence of lesions. Exacerbations occur in response
to emotional stress.

of Lichen Simplex Chronicus
Most Likely
Lichenified atopic eczema
Lichenified psoriasis
Hypertrophic lichen planus
Consider
Genital: extramammary Pagets disease
Always Rule Out
Vulva, perianally: underlying lichen sclerosus, HPV,
or tinea cruris
Scrotum: underlying HPV or tinea cruris

of Prurigo Nodularis
Most Likely
Perforating disease
Pemphigoid nodularis
Actinic prurigo
Multiple keratoacanthomas
KEY REFERENCES
Vesicular Palmoplantar Eczema
5. Krogh HK: Nummular eczema: Its relationship to internal foci of infection. A survey of 84 case records. Acta
Derm Venereol 40:114-126, 1960
9. Moore MM, Elpern DJ, Carter DJ: Severe, generalized
nummular eczema secondary to interferon alfa-2b plus
ribavirin combination therapy in a patient with chronic
hepatitis C virus infection. Arch Dermatol 140:215-217,
2004
13. Krupa Shankar DS, Shrestha S: Relevance of patch testing in patients with nummular dermatitis. Indian J Dermatol Venereol Leprol 71:406-408, 2005
15. Tanaka M et al: Prurigo nodularis consists of two distinct
forms: Early-onset atopic and late-onset non-atopic. Dermatology 190:269-276, 1995
17. Lynch PJ: Lichen simplex chronicus (atopic/neurodermatitis) of the anogenital region. Dermatol Ther 17:8-19,
2004
28. Koca R et al: Sleep disturbance in patients with lichen simplex chronicus and its relationship to nocturnal scratching: A case control study. South Med J 99:482-485, 2006
::
both conditions, first-line measures to control itch

include potent topical steroids as well as nonsteroidal antipruritic preparations such as menthol, phenol,
or pramoxine. Emollients are an important adjunct.
Intralesional steroids, such as triamcinolone acetonide, given in varying concentrations according to the
thickness of the plaque or nodule are beneficial. Topical tacrolimus has been successfully employed as a
steroid-sparing agent. Sedating antihistamines, such
as hydroxyzine, or tricyclic antidepressants, such as
doxepin, may be used to abolish nighttime itch in both
conditions. Selective serotonin reuptake inhibitors
(SSRIs) have been recommended for relief of daytime
pruritus or in patients with OCD.17
Capsaicin, calcipotriene, and cryotherapy, with or
without intralesional steroid injections, have all been
successfully used in prurigo nodularis. Both broad-
Chapter 16
Consider
Nodular scabies
and narrow-band ultraviolet B, as well as topical or

oral PUVA show efficacy and are indicated in widespread cases. The 308 nm excimer monochromatic
light, UVA1 phototherapy, and naltrexone were all
effective in small series.2931 Thalidomide and cyclosporine have also been shown to be beneficial.
The importance of avoiding scratching should be
addressed with the patient. Nails should be kept short
and occlusive measures, such as plastic films, topical
steroid tape, or Unna boots in widespread cases may
be needed.
Chapter 16 :: Vesicular Palmoplantar Eczema

:: Daven N. Doshi, Carol E. Cheng, &
Alexa B. Kimball
VESICULAR PALMOPLANTAR ECZEMA AT A GLANCE
An acute and/or chronic dermatitis
clinically characterized by small to large
blisters on the palms and soles.
Histopathology characterized by
spongiotic vesicles.
Considered an endogenous dermatitis,
distinct from dermatitis caused by
exogenous factors such as contact, allergy, or

irritation.
Can be divided into four categories: (1)
pompholyx, (2) chronic vesiculobullous
hand dermatitis, (3) hyperkeratotic hand
dermatitis, and (4) id reactions.
Does not respond well to treatment.
187
Section 4
::
Vesicular palmoplantar eczema is a dermatitis of the

hands and feet characterized by small to large blisters
clinically and spongiotic vesicles histologically. It can
manifest as either an acute or a chronic dermatitis, or
both. Because clinical and histologic presentations of
the variants of hand dermatitis, including vesicular
palmoplantar eczema, often overlap, making a precise
diagnosis can be difficult. For example, patients with
pompholyx, the most acute form of vesicular palmoplantar eczema, have been noted to have higher incidence rates of both atopy and contact dermatitis than
controls.
With the preceding caveat in mind, vesicular palmoplantar eczema can be divided into four categories: (1)
pompholyx, (2) chronic vesiculobullous hand dermatitis, (3)
hyperkeratotic hand dermatitis, and (4) id reactions (see
Chapter 17). These conditions can be grouped under
the category of endogenous hand dermatitis, in contrast to dermatitis clearly caused by exogenous factors
such as contact allergy or irritation.
Pompholyx is a term best reserved for acute explosive outbreaks of small to large vesicles and bullae on
the palms and soles. It tends to occur more often in
the spring and fall, and may be associated with stress.
Other etiologic factors are less well established. Cheiropompholyx and podopompholyx are terms occasionally
used to describe cases affecting the palms or soles,
respectively. Chronic vesiculobullous hand dermatitis, also
known as dyshidrotic hand eczema or dyshidrotic hand
dermatitis, is usually characterized by small vesicles on
the lateral aspects of the fingers. Dyshidrosis, a dysfunction of the sweat gland, was long postulated to be
a cause, but its role has been subsequently disproved.
However, the terminology persists and is commonly
used. A third category is chronic hyperkeratotic hand dermatitis, an entity that generally occurs on the central
palms. Unlike the other classifications of vesicular palmoplantar eczema, vesicles do not dominate the clinical presentation. However, the spongiosis observed
histologically is indistinguishable from the other categories. An id reaction is a vesiculobullous dermatitis,
generally appearing on the lateral aspects of the fingers, elicited by an infection elsewhere in the body. The
most common cause is a fungal infection. Treatment of
the underlying causative factor usually leads to resolution. Endogenous hand dermatitis can be exacerbated
by exogenous factors, most notably irritant dermatitis
and allergic contact dermatitis. In addition, atopy may
in some cases predispose to the development of vesicular palmoplantar eczema.
EPIDEMIOLOGY
188
Differences in classification and definition have made

it difficult to assess the true incidence of the endogenous hand disorders. Most studies have focused on
the prevalence of exogenous hand disorders as seen in
occupational settings. Pompholyx is the least common
presentation of hand dermatitis; in one population
study, the 1-year prevalence of pompholyx was estimated to be 0.5%.1 In the same study, hyperkeratotic
hand dermatitis represented 2% of all hand dermato-
ses.1 Other studies have noted prevalence rates ranging from 1% to 5%, with the variation in the frequency
of vesicular hand eczema attributable in part to the
lack of a common condition.2,3,4

With the exception of the id reaction, a direct cause
of vesicular palmoplantar eczema is rarely identified.
A number of etiologic factors have been associated
with pompholyx, including atopy (see Chapter 14),
contact allergy (see Chapter 13), psychological stress,
and hot weather.1 Pompholyx has also been reported
after ingestion of piroxicam,5 after ingestion of certain
metals in predisposed or sensitized patients most commonly nickel, cobalt, and chromate5 and after intravenous immunoglobulin therapy, with 39 cases reported
to date.6,7 There has also been a report of five cases of
photo-induced pompholyx in patients with a reported
history of photo-induced disease that was reproduced
when the patients were phototested with an ultraviolet A (UVA) source.5 Histologic evaluation confirmed
the diagnosis of pompholyx and a true photosensitivity rather than photoaggravation. Additionally, there
has been evidence of association of vesicular hand
eczema following dermatophytid from tinea pedis.8 In
a study of 398 patients with hand eczema, those with
culture positive tinea pedis were found to have an
increased relative risk of 3.58 (p < 0.05) for vesicular
hand eczema.9
EXACERBATING FACTORS
Contact allergy is common in patients affected with
vesicular palmoplantar eczema, especially the chronic
type, but the causal relationship is not always clear.
There are cases in which contact allergy has exacerbated preexisting hand dermatitis and also reports that
ingestion of certain metals, including nickel, cobalt,
and chromium, have caused flares. However, in other
cases, the causal relationship may be the reverse. The
skins impaired barrier function in vesiculobullous
hand dermatitis (see Chapter 47) may in some cases
lead to sensitization and a higher prevalence of contact
dermatitis in the affected population. Investigations
into the role of atopy (see Chapter 14) have yielded
mixed results. Some studies have shown levels of personal or familial atopy as high as 50% in affected subjects, compared to 11.5% of controls, but other studies
have demonstrated no difference in the prevalence in
people with vesiculobullous hand dermatitis versus
controls.10
CLINICAL FINDINGS
POMPHOLYX
Figure 16-1 is an algorithm showing the approach
to the patient with vesicular palmoplantar eczema.
Pompholyx can even be severe enough to neces-
Approach to patient with palmoplantar eczema
History:
recurrent rash of the hands and feet
Clinical appearance:
vesicles/bullae, plaques
Vesicles/bullae,
no plaques
Plaques,
no vesicles/bullae
Acute, explosive
self limiting
Chronic
::
Figure 16-2 Chronic dyshidrotic hand dermatitis of bilateral hands. There is hyperkeratosis of the palms and
fingers sparing the dorsal hand. Deep-seated vesicles at
different stages can be seen.
Figure 16-4 Cheiropompholyx. Apart from small vesicles,

there are large bullae, some purulent; others have collapsed and are drying up.
Consider location
Fingers:
lateral aspects
ID reaction
Chronic
vesiculobullous
Central palm
Hyperkeratotic
Figure 16-1 Approach to the patient with vesicular palmoplantar eczema.
sitate hospitalization. In true acute pompholyx,

there is an explosive outbreak of deep-seated vesicles on the palms, the lateral aspects of the fingers
(Fig. 16-2), and sometimes the soles, usually in a
symmetric pattern. Discomfort and itching usu-
ally precede the development of the blisters, which

have been described as having a tapioca appearance (see Fig. 16-3). Blisters may coalesce then
desiccate and resolve without rupture (Fig. 16-4).
Intact, large blisters can be drained, but should not
be unroofed. However, large blisters may rupture
spontaneously, leaving oozing or dried up erosions
(Fig. 16-5).
This acute phase is generally followed by desquamation of the affected areas. Individual outbreaks
are usually self-limited over 23 weeks, although
they may recur. Secondary bacterial infection is
common, often resulting in a local cellulitis, and can
sometimes potentiate the development of lymphatic
damage, resulting in lymphedema. Attacks are most
common among adolescents and young adults and
seem to be more common in the spring and summer
months. Outbreaks have been shown to be associated with dermatophyte infection, contact dermatitis, in particular cosmetic and hygiene products,
metals and internal reactivation from drugs, foods,
or metals.
Pompholyx
Chapter 16
Figure 16-3 Chronic vesiculobullous hand dermatitis.

There is a vesicular dermatitis on the lateral sides of the
fingers. Note the tapioca-like, deep-seated vesicles.
Presentation
189
Section 4
Figure 16-5 Podopompholyx. Large blisters have ruptured leaving erosions that are drying up. Note large bulla
on the arch of the right foot: The roof of the blister still contains tapioca-like vesicles. This is characteristic.
Figure 16-7 Id reaction to tinea pedis. Erythematous, partially dried up vesicles on the foot. Lesions are very pruritic.
::
CHRONIC VESICULOBULLOUS
DERMATITIS
Chronic vesiculobullous hand dermatitis is more common than pompholyx and more difficult to manage
because of its relapsing course. The clinical presentation includes small 1- to 2-mm vesicles filled with clear
fluid localizing to the lateral aspects of the fingers,
palms, and soles as in pompholyx (see Fig. 16-3). As the
condition becomes more chronic, the clinical appearance may evolve and subsequently appear more fissured and hyperkeratotic (as in Figs. 16-2 and 16-6). A
clear history of vesicles or exacerbations characterized
by blistering may help to narrow the classification of a
given presentation of hand dermatitis.
HYPERKERATOTIC HAND DERMATITIS

Patients with hyperkeratotic hand dermatitis are usually male and generally present with chronic keratotic
pruritic plaques, sometimes with fissures on the central palm (see Fig. 16-6). This condition may be the
end result of contact allergy, excoriation, and irritation,

but generally the cause is not identifiable, and contact
allergy does not seem to play an important role. This
hand dermatitis commonly occurs in middle-aged to
elderly men and is often very refractory to treatment.
Friction in lichen simplex chronicus may be an important factor in some cases. Plantar involvement is present in a minority of cases.
ID REACTION
(See Chapter 17)
In an id reaction, erythematous vesicles usually are
seen on the lateral aspects of the fingers and the palms
and are typically pruritic (Fig. 16-7). This eruption of
vesicles is usually sudden and classically occurs in
response to an intense inflammatory process, especially fungal infections, taking place somewhere else
on the body. The id reaction is thought to be an allergic reaction to fungi or to some antigen created during
inflammation. Treatment of the underlying infection
results in resolution.
LABORATORY FINDINGS
In the diagnostic workup of vesicular palmoplantar eczema, it is important to first examine the feet
to exclude a dermatophytid. Secondly, a potassium
hydroxide examination of the hand should be performed to rule out tinea manuum. Finally, patch testing
should be performed to rule out a contact dermatitis
or a systemic reaction to a contact allergen. There are
no specific laboratory findings characteristic of vesicular palmoplantar eczema, although IgE levels may be
elevated in atopic patients.
PATHOLOGY
190
Figure 16-6 Hyperkeratotic hand dermatitis. There are

pruritic keratotic plaques on the central palm: occasional
vesiculation and fissuring may occur.
The histology of these entities depends on the chronicity of the disease. The primary vesicle appears
as an intraepidermal spongiotic vesicle that does

not involve the acrosyringia on either conventional
and electron microscopy. Lymphocytic infiltration
is common in the epidermis, with a mixed infiltrate
observed in the dermis. In more chronic cases, the
epidermis may show hyperproliferation, hyperkeratosis, or even psoriasiform epidermal hyperplasia.
Periodic acid-Schiff staining can be helpful in excluding fungal elements.
DIAGNOSIS
Box 16-1 Differential Diagnosis of

Most Likely
Irritant contact dermatitis
Atopic hand dermatitis
Infections, commonly from tinea
Consider
Bazex acrokeratosis paraneoplastica
Psoriasis
Psoriasiform hand dermatitis
Pustular eruption of palms and soles
Keratolysis exfoliativa
Bullous disorders
Herpes simplex (never bilateral)
(Box 16-1)
Allergic contact dermatitis (see Chapter 13) may be
clinically indistinguishable from other forms of hand
eczema, and patch testing should be considered for
those with recurrent, atypical, or persistent forms
of the disease. In a recent study of 422 patients with
hand eczema, the ten most common allergens with
positive patch testing were nickel, cobalt, thiuram
mix, balsam of Peru (Myroxylon pereirae resin), formaldehyde, colophony, potassium dichromate, benzoyl
peroxide, fragrances methylchloroisothiazolinone/
methylisothiazolinone, and sesquiterpene lactone
::
Chapter 16
The diagnosis of vesiculobullous hand dermatitis is

usually made on the basis of clinical presentation, history, and sometimes histology. Patch testing may be
useful in helping to distinguish this entity from other
palmoplantar disorders or in eliminating other exacerbating factors such as irritant exposure and contact
allergy.
There are many other skin conditions of the hands
and feet that can be difficult to distinguish from vesiculobullous hand dermatitis. Several of the diagnoses
may also coexist.
mix.11,12 Although frequently considered, laundry

detergents rarely cause allergic contact dermatitis.
Irritants (see Chapter 48) are by far the most common
causes of hand dermatitis that are often exacerbated
by occupational exposures. The irritant dermatitis is
usually symmetric and chronic, and affects the dorsal
fingertips and web spaces.
Atopic hand dermatitis (see Chapter 14) is associated with a number of factors: hand dermatitis before
age 15 years, persistent eczema on the body, dry or
itchy skin in adult life, and widespread atopic dermatitis in childhood. The backs of the hands, particularly
the fingers, are affected with erythema, vesiculation,
crusting, excoriation, and scale.
Infections, most commonly from tinea, can mimic
endogenous hand dermatitis. In cases of asymmetric
or atypical cases, or in cases of small vesicles confined to the feet, a potassium hydroxide examination
may be useful in ruling out primary tinea infection.
In chronic cases of hand dermatitis, fungal and bacterial infections may be superimposed, and treatment
may result in improvement of clinical symptoms.
Herpes simplex may, in unusual cases, present as
blisters on the hands.
Psoriasis and psoriasiform hand dermatitis (see
Chapter 18) are most prominent over pressure
points. Psoriasis can normally be distinguished by
its sharply marginated, nummular, or circinate scaly
plaques; relative lack of itching; silvery scales; and
the presence of psoriasis elsewhere. Psoriasiform
hand dermatitis can occur without a family or personal history of psoriasis. It is a diagnosis made
primarily on clinical and histologic presentation.
At times, however, it appears as though eczematous, hyperkeratotic, and psoriatic diatheses coexist.
Repeated pressure or friction may cause hyperkeratosis in some individuals.
Pustular eruptions of the palms and soles (see Chapter 21) are generally easy to distinguish because, unlike
the presentation of clear fluid-filled blisters and bullae
of hand dermatitis, pustules are the primary lesions.
For example, in pustular psoriasis, the vesicles are
cloudy and painful.
Keratolysis exfoliativa (recurrent focal palmar peeling) is a chronic, asymptomatic, and noninflammatory
peeling of the palms and soles, most commonly seen
during the summer months. It is thought to occur more
frequently in people with hyperhidrosis in these areas.
Scaling usually starts from one to two fine points and
expands outward to larger circular areas. The condition is usually self-limited and asymptomatic, requiring only emollients.
Bazex acrokeratosis paraneoplastica is a rare, acute,
erythematous, scaling, vesiculobullous hand dermatitis with nail dystrophy associated with neoplasia,
usually squamous carcinomas of the upper digestive
or respiratory tracts, although there have been some
reports of similar findings in patients with colon cancer and genitourinary tumors.
Other blistering diseases, such as pemphigoid, pemphigus, or epidermolysis bullosa, may affect the hands
and feet, but usually do so in the setting of blisters elsewhere on the body.
191
Box 16-2 Treatments for Vesicular Palmoplantar Eczema

Topical
Physical
Systemic
Section 4
First line
Corticosteroids
Ultraviolet A-1
Psoralen and ultraviolet A
Narrowband ultraviolet B
Second line
Entanercept
Drying agents
Tacrolimus
Pimecrolimus
Retinoids
Calcipotriene
Grenz ray
Iontophoresis
Sympathectomy
Intradermal botulinum toxin
Third line
Prednisone
Cyclosporine
Mycophenolate mofetil
Methotrexate
Alitretinoin
Azathioprine
::
COMPLICATIONS
Secondary bacterial infection of the vesicles can result
in cellulitis, lymphedema, and, in rare instances, septicemia.13

COURSE
Pompholyx tends to occur as intermittent explosive
outbreaks and becomes less frequent in middle-aged
individuals. The more chronic forms of vesicular palmoplantar eczema, however, are much more persistent
and frustrating to manage and often require multiple
therapeutic approaches over time.
TREATMENT
(Box 16-2)
Treatment of vesiculobullous hand dermatitis should
be based on the acuity of the condition, the severity of
the disease, the prominence of blisters versus chronic
changes, and any relevant history that reveals possible
cofactors.
TOPICAL THERAPY
192
Topical steroids, typically high potency (class 1 or 2),

are usually first-line agents. They are often more effective if used under occlusion, although this approach
may increase the chance of infection. Topical drying
agents, such as Domeboro soaks, Burows solutions
(aluminum subacetate), or dilute potassium permanganate solution (18,000) may be useful in acute forms
with a predominance of vesicles.
Nonsteroidal topical immunomodulating agents,
such as tacrolimus and pimecrolimus, have been stud-
ied for treatment of individuals with mild to moderate chronic hand dermatitis with improvements from
baseline.5 Topical tacrolimus was shown to be as effective as momethasone furoate 0.1% ointment in a randomized, blinded trial in patients with vesicular pompholyx of the palms. After 2 weeks of treatment, the
Dyshidrotic Eczema Area and Severity Index (DASI)
was reduced by more than 50%.14
Hyperkeratotic palmar eczema is notoriously difficult to manage. Topical retinoids and calcipotriene,
both of which act to regulate epidermal cell maturation, have anecdotally been shown to improve this category of hand dermatitis.1
SYSTEMIC THERAPY
For recurrent pompholyx and chronic vesicular dermatitis, oral prednisone may be required and is often
effective if treatment is initiated early, at the onset of
the itching prodrome. However, because of significant side effects, systemic glucocorticoids are typically
inappropriate for long-term management. Intralesional and intramuscular steroid injections can also be
considered for short-term use in acute episodes when
intensive topical therapy fails.
Cyclosporine has been studied at dosing levels of
3 mg/kg/day and 5 mg/kg/day in the treatment of
chronic vesicular dermatitis. Although patients showed
improvement with treatment, relapses occurred shortly
after discontinuation of cyclosporine.15
Mycophenolate mofetil has been used in the treatment of chronic vesicular dermatitis at dosing levels
of 23 g/day (in divided doses). It has been anecdotally shown to improve chronic vesicular dermatitis
that has been otherwise recalcitrant to corticosteroids,
iontophoresis, and phototherapy. However, it has also
been anecdotally shown to induce biopsy-proven dyshidrotic eczema.
Methotrexate has proven a useful therapy of a wide
range of skin diseases. In chronic vesicular eczema,
FUTURE THERAPIES
RADIATION THERAPY AND IMMUNOTHERAPY. The use of etanercept has also been
shown in a case report to be successful in treatment of

recalcitrant dyshidrotic eczema for a 4-month period
before relapse occurred.16
Azathioprine has been shown to be efficacious in a
study that included six patients with pompholyx; however, a separate case study of its use reported development of myelotoxicity.17,18
Superficial radiotherapy (Grenz ray) is still sometimes used at a few centers. This condition may be one
of the last indications for this treatment modality, and
Iontophoresis, sympathectomy, and intradermal botulinum toxin are effective therapies for hyperhidrosis
and have been studied as treatments for chronic vesicular dermatitis.15 Tap water iontophoresis with pulsed
direct current showed no benefit for subjects with hand
dermatitis over controls in time to improvement, but
those who were treated had much longer remissions,
by a factor of months.6 Intradermal botulinum toxin A
was shown to have a beneficial effect in patients with
treatment-refractory vesicular dermatitis, especially
in those patients whose condition was aggravated by
hyperhidrosis.25 This therapy may also be used in conjunction with topical corticosteroids.26
LEUOKOTRIENE INHIBITORS. Leukotriene receptor antagonists and inhibitors are oral medications that
act by inhibiting proinflammatory mediators in the
5-lipoxygenase pathway and have been shown to block
the effects of leukotrienes successfully in asthma, allergic rhinitis, and recently in atopic dermatitis. No specific
trial has been reported yet with these medications on
pompholyx.
Phosphodiesterases-4 (PDE4) modulate the release
of inflammatory mediators and have recently been
investigated as a novel therapeutic approach in the
treatment of inflammation-associated diseases. Animal models of PDE4 inhibitors have displayed strong
anti-inflammatory action in models of allergic contact
dermatitis. The safety and efficacy in pompholyx has
yet to be evaluated.
Tumor necrosis factor inhibitors (e.g., infliximab)
have been successful for treatment of psoriatic arthritis
and psoriasis, among other chronic inflammatory diseases. No data is available on pompholyx.
Two severity indices, (1) the dyshidrosis area and
severity index and (2) the total sign and symptoms
score, have been validated and may prove useful in
clinical trials to better assess the effectiveness of these
and future therapies.
::
OTHER THERAPIES
has been shown to be successful in some patients with

resistant chronic eczema of the hand in a double-blind
study.14 Megavoltage radiation therapy (1,200 cGy) has
also been tried in patients with severe chronic vesicular hand dermatitis with moderate success in longterm remission.21,22
Chapter 16
it has been reported to partially or completely clear

lesions at low doses ranging from 12.5 to 22.5 mg/
week.15 However, its wide spectrum of potential side
effects remains a limiting factor to its use in this particular skin disease.
Alitretinoin, (9-cis-retinoic acid) is a novel retinoid with anti-inflammatory properties and one of
the newer therapies under study for palmoplantar
vesicular eczema. It is the only medication specifically approved for the treatment of adults with hand
eczema unresponsive to topical steroids in some countries outside of the United States.19 In a large controlled
study with over 1,000 patients it was successful in the
treatment of chronic hyperkeratotic hand eczema and
offers another treatment option for patients refractory
to treatments with corticosteroids, radiation therapy,
tretinoin, isotretinoin, and acitretin.20
UVB, systemic, topical, and bathwater psoralen and
UVA light with or without PUVA have been used in
severe cases of chronic vesicular hand eczema. Studies
evaluating the use of UVA-1 compared localized highdose UVA-1 irradiation against topical cream psoralen
UVA for the treatment of dyshidrotic eczema demonstrated that UVA-1 irradiation and topical PUVA
showed similar beneficial responses.23,24 In addition,
the potential side effects noted with PUVA, such as
phototoxic reactions and long-term carcinogenic risk,
are theoretically reduced with UVA-1 therapy. UV
therapy is thought to work by induction of apoptosis
of T and B lymphocytes.
PREVENTION
Prevention is a critical part of therapy in most cases,
especially when known exacerbating factors are present. Avoidance of commonly encountered allergens,
such as foods and plants, and irritants, such as soaps,
solvents, acids, and alkalis, can be helpful. Vinyl
gloves, rather than latex, are recommended because
of the risk of either having an underlying allergy or
of developing one in the setting of impaired barrier
function. Patch testing may be considered for patients
to identify relevant allergens. Modification of environmental exposure to exacerbating factors, such as
friction and cold air, may also help with persistent or
refractory disease. Frequent use of emollients, specifically novel barrier creams or ointments, help to preserve the normal skin-barrier function. Maintaining
a low-cobalt diet has been suggested to decrease the
number of dyshidrotic flares.28
KEY REFERENCES
1. Agrup G: Hand eczema and other hand dermatoses in
South Sweden [thesis]. Acta Derm Venereol 49(Suppl. 61):
1-91, 1969
193
6. Lehucher-Michel MP et al: Dyshidrotic eczema and

occupation: A descriptive study. Contact Derm 43:200,
2000
9. Meding B, Swanbeck G: Epidemiology of different types
of hand eczema in an industrial city. Acta Derm Venereol
69:227, 1989
11. Ogden S: Recalcitrant hand pompholyx: Variable response to entanercept. Clin Exp Dermatol 31:145-146,
2006
14. Polderman MCA et al. A double-blind placebo-controlled trial of UVA-1 in the treatment of dyshidrotic eczema. Clin Exp Dermatol 28:584-587, 2003
Section 4
::
Chapter 17 :: Autosensitization Dermatitis

:: Donald V. Belsito
AUTOSENSITIZATION DERMATITIS
AT A GLANCE
An acute disorder triggered by infection, stasis
and contact dermatitides, ionizing radiation,
blunt trauma, and retained suture material.
Widespread, pruritic, usually
papulovesicular eruption, most frequently
affecting the extremities.
Related features are those of the precipitating
disorder.
Pathology is nondiagnostic and most
often consistent with an acute spongiotic
process of the epidermis with a superficial,
perivascular, lymphohistiocytic infiltrate of
the dermis containing occasional eosinophils.
EPIDEMIOLOGY
Autosensitization dermatitis refers to a phenomenon
in which an acute dermatitis develops at cutaneous
sites distant from an inflammatory focus, and where
the secondary acute dermatitis is not explained by the
inciting cause of the primary inflammation. The classic presentation of autosensitization is that seen in
patients with venous stasis disease,1 where as many
as 37% of patients have been reported to develop at
least one episode of autosensitization,2 and those with
dermatophyte infections, where 45% reported having
had dermatophytid reactions.3

194
16. Scerri L: Azathioprine in dermatological practice. An overview with special emphasis on its use in non-bullous inflammatory dermatoses. Adv Exp Med Biol 455:343-348, 1999
20. Swartling C et al: Treatment of dyshidrotic hand dermatitis with intradermal botulinum toxin. J Am Acad Dermatol 47:667, 2002
23. Vecchietti G et al: Severe eczematous skin reaction after
high-dose intravenous immunoglobulin infusion: Report of 4 cases and review of the literature. Arch Dermatol
142(2):213-217, 2006
25. Veien NK: Acute and recurrent vesicular hand dermatitis. Dermatol Clin 27:337-353, 2009
The term autosensitization dermatitis was coined in

1921 by Whitfield to describe reaction patterns rang-
ing from a generalized, erythematous, morbilliform,

and urticarial eruption after blunt trauma to a generalized, petechial, papulovesicular dermatitis after
the acute irritation of chronic stasis dermatitis.4 Subsequently, the vesicular id reactions associated with
infections caused by tuberculosis,5 histoplasmosis,6
dermatophytes,7 and bacteria8 were included under
this rubric.911 Noneczematous reaction patterns,
including erythema multiforme12 and neutrophilic
lobular panniculitis,13 have also been ascribed to
autosensitization associated with various infections.
Other precipitating factors for autosensitization
have included the application of irritant or sensitizing chemicals,14 ionizing radiation,15,16 and retained
suture material.17
Although the disease was originally thought to
be due to autosensitization to epidermal antigens,11
this concept has not been experimentally verified. In
murine studies designed to determine whether keratinocyte-derived proteins can serve as antigenic carriers for hapten, Fehr et al18 derived major histocompatibility complex-restricted, T-cell receptor /, CD4+
T-cell clones that proliferated in response to keratinocyte extracts unconjugated to hapten. In these studies,
such autoreactive T-cell clones could not be derived
after treatment with irritants. Nonetheless, the authors
speculated that T cells autoreactive to keratinocyte
antigens may be generated during the course of contact hypersensitivity and lead to the development of
an id reaction.
In the most extensive study to date,1 only 4 of 81
patients with autosensitization dermatitis had serum
antibodies cytotoxic to autologous or homologous
skin. However, the role of such autoantibodies in
mediating the disorder, even in these four patients,
must be interpreted cautiously, given the high frequency of epidermal autoantibodies in the normal
adult population.19
In an experiment in which guinea pigs were injected
with autologous skin, Wilhelmj et al20 reported dermatitis in 2 of 11 guinea pigs, but it was not clear whether
these reactions were immunologic and, if so, what the
CLINICAL FINDINGS
Autosensitization Dermatitis
Typically, 1 to 2 weeks after an acute inflammation,

an extremely pruritic, symmetric, scattered, erythematous eruption with macules, papules, and vesicles
develops (Fig. 17-1). The eruption involves the forearms, thighs, legs, trunk, face, hands, neck, and feet
in descending order of frequency.2,11 During the evolution of the dermatitis, its morphology may change
in a manner consistent with the chronicity (i.e., vesicles to scale). Histopathologically, the findings are
not pathognomonic: spongiotic epidermal vesicles
::
autosensitization.26 The characteristic distribution of

the disease might perhaps be explained if the skin
overlying the arms and legs was found to contain
increased numbers of, or more avid receptors for, various cytokines than the skin of the face or hands. Such
a geographic variation in the distribution of bullous
pemphigoid antigen has been observed and hypothesized to account for the clinical patterns of this autoimmune disease.27 Application of modern biotechnological tools should provide insight into the mysteries
of autosensitization.
Chapter 17
causal allergen(s) was. Other investigators using similar techniques have been unable to induce cutaneous
disease in animals by means of epidermal extracts.21
In contrast, 19 of 24 patients with active autosensitization who were intradermally challenged with watersoluble extracts of autologous epidermal scale developed a reaction.22
The term autosensitization is probably a misnomer.
The disease is more likely due to a hyperirritability
of the skin induced by either immunologic or nonimmunologic stimuli. Factors such as irritation, sensitization, infection, and wounding, which are known
to precipitate autosensitization, have been reported
to release a variety of epidermal cytokines.23,24 Once
hematogenously disseminated in sufficient amounts,
these cytokines could heighten the sensitivity of skin
to a variety of nonspecific, but otherwise innocuous,
stimuli, producing a pattern of spillover reactions25
that have been classically termed autosensitization.
Such a hypothesis would account for (a) the results
in humans of delayed-type hypersensitivity testing
with autologous epidermal scale,22 (b) the histopathologic findings noted in the disease (see section Clinical Findings), and (c) the activated T lymphocytes
occasionally observed in the blood of patients with
Figure 17-1 Stasis dermatitis with autosensitization. An elderly woman with a long-standing history of stasis dermatitis
presented with gradual worsening of the edema; pruritus; and multiple, punctate, superficial, excoriated ulcers overlying
the medial malleoli (A). Nine days after the ulcers appeared, she developed an acute, extremely pruritic, erythematous,
papulovesicular eruption over the forearms (B), which progressively involved the upper arms, upper torso, and hands.
The acute papulovesicular dermatitis also involved the lower extremities and can be noted overlying the chronic stasis
dermatitis (A).
195

Most Likely
Atopic dermatitis
Nummular dermatitis
Consider
Polymorphous light eruption
Pityriasis rosea
Eruptive (guttate) psoriasis
Section 4
::
196
Always Rule Out

Infectious processes
Dermatophyte infections
Scabies and other mite infestations
Viral exanthems
Drug eruptions
associated with a superficial, perivascular lymphohistiocytic infiltrate of the dermis, which may contain
scattered eosinophils.28 Immunophenotypic studies
of skin have revealed that most of the lymphocytes
in the epidermis are CD3+ and CD8+ T cells, whereas
those in the dermis are primarily CD4+.25 In the majority of individuals with autosensitization,1 deposition
of antibody or complement in affected skin is not
detected.
As previously mentioned, noneczematous autosensitization patterns have also been reported. Both
erythema multiforme12 and neutrophilic lobular panniculitis13 have been reported to be induced by a
variety of infectious processes. The histology in these
cases is consistent with the reaction pattern for erythema multiforme and lobular panniculitis, respectively.
See Box 17-1.
PROGNOSIS AND
CLINICAL COURSE
The eruption often persists and spreads until the underlying causative primary site of inflammation is treated.
TREATMENT
Treatment is best directed toward the inciting disease.
The frequently weeping, vesicular eruption of autosensitization benefits from drying agents such as aluminum sulfate and calcium acetate. Given the likely
involvement of cytokines and inflammatory mediators
sensitive to glucocorticoids29 or macrolactams,30 systemic and/or topical treatment with these drugs may
be helpful. To prevent the secondary effects of excoriation, pruritus must be controlled with topical antipruritic agents or oral antihistamines. However, one must
remain alert to the possibility of inducing an allergy
in existing dermatitic skin with topical medicaments.
KEY REFERENCES
1. Parish WE et al: A study of auto-allergy in generalized
eczema. Br J Dermatol 77:479, 1965
2. Haxthausen H: Generalized ids (autosensitization)
in varicose eczema. Acta Derm Venereol (Stockh) 35:271,
1955
12. Atzori L, Pau M, Aste M: Erythema multiforme ID reaction in atypical dermatophytosis: A case report. J Eur
Acad Dermatol Venereol 17:699, 2003
13. Magro CM, Dyrsen ME, Crowson AN: Acute infectious
id panniculitis/panniculitic bacterid: A distinctive form
of neutrophilic lobular panniculitis. J Cutan Pahtol 35:941,
2008
16. Linn J et al: Radiotherapy-induced id reaction. Am J Clin
Oncol 28:105, 2005
18. Fehr BS et al: T cells reactive to keratinocyte antigens are
generated during induction of contact hypersensitivity
in mice. A model for autoeczematization in humans? Am
J Contact Dermat 11:145, 2000
23. Williams IR, Kupper TS: Immunity at the surface:
Homeostatic mechanisms of the skin immune system.
Life Sci 58:1485, 1996
Chapter 18 :: Psoriasis

:: Johann E. Gudjonsson & James T. Elder
Most common sites of involvement are scalp,

elbows, knees, hands, feet, trunk, and nails.
Psoriasis is a chronic inflammatory skin disease, with a

strong genetic basis, characterized by complex alterations in epidermal growth and differentiation and
multiple biochemical, immunologic, and vascular
abnormalities, and a poorly understood relationship
to nervous system function. Its root cause remains
unknown. Historically, psoriasis was widely considered to be a primary disorder of keratinocytes. With
the discovery that the T-cell specific immunosuppressant cyclosporine A (CsA) was highly active against
psoriasis, research became more focused on T cells and
the immune system. Nevertheless, accumulating evidence shows that keratinocytes are an integral part of
the cutaneous immune reponse in psoriasis.7
Psoriatic arthritis occurs in 10%25% of

patients; pustular and erythrodermic forms
may be associated with fever.
Pathology is characterized by uniform
elongation of the rete ridges, with dilated
blood vessels, thinning of the suprapapillary
plate, and intermittent parakeratosis.
Epidermal and perivascular dermal
infiltrates of lymphocytes, with neutrophils
occasionally in aggregates in the epidermis.
EPIDEMIOLOGY
PREVALENCE
Psoriasis is universal in occurrence. However, its
prevalence in different populations varies from 0.1%
to 11.8%, according to published reports.1 The highest
reported incidences in Europe have been in Denmark
(2.9%) and the Faeroe Islands (2.8%). A recent study of
1.3 million Germans found a prevalence of 2.5%.2 Similar prevalence (ranging from 2.2% to 2.6%) has been
measured in the United States. A higher prevalence in
East Africans as opposed to West Africans may explain
the relatively low prevalence of psoriasis in AfricanAmericans (1.3% vs. 2.5% in white Americans).3 The
incidence of psoriasis is also low in Asians (0.4%), and
in an examination of 26,000 South American Indians,
not a single case was seen. Psoriasis is equally common
in males and females.4,5
AGE OF ONSET
Psoriasis may begin at any age, but it is uncommon
under the age of 10 years. It is most likely to appear
Psoriasis
::
Erythematous scaly papules and plaques;

pustular and erythrodermic eruptions occur.
Worldwide occurrence: Affects 2%3% of

Americans; prevalence ranges from 0.1% to
3% in various populations.
Chapter 18
A chronic disorder with polygenic

predisposition combined with triggering
environmental factors such as trauma,
infection, or medication.
between the ages of 15 and 30 years. Possession of

certain HLA Class I antigens, particularly HLA-Cw6,
is associated with an earlier age of onset and with a
positive family history. This finding led Henseler and
Christophers6 to propose that two different forms of
psoriasis exist: type I psoriasis, with age of onset before
40 years and HLA-associated, and type II, with age
of onset after 40 years and lacking HLA associations,
although many patients do not fit into this classification. There is no evidence that type I and type II psoriasis respond differently to treatment.
PSORIASIS AT A GLANCE
PATHOGENESIS OF PSORIASIS
DEVELOPMENT OF LESIONS. Detailed light,
electron microscopic, immunohistochemical, and molecular studies of involved and uninvolved skin of
both newly appearing and established psoriatic lesions
provide a useful framework for inferring cause-andeffect relationships between the many cellular events
that take place in a psoriatic lesion. They are illustrated
schematically in Fig. 18-1 and with actual photomicrographs in Fig. 18-2.
Uninvolved Psoriatic Skin. The normal-appearing skin of psoriatic patients has long been known to
manifest subclinical morphologic and biochemical
changes, particularly involving lipid biosynthesis.67,68
These changes were predominantly found in the stratum corneum and included changes in the levels and
composition of phospholipids, free -amino acids,
hydrolytic enzymes, and several dehydrogenases.
These changes led to the use of the term histochemical parakeratosis to describe these findings.67 Much
more recent studies using microarray technology to
search for differences in gene expression between normal and uninvolved psoriatic skin have identified
groups of coordinately regulated genes involved in
lipid biosynthesis and innate immune defense.69
197
Development of psoriatic lesions
A
L
Section 4
::
198
C
8
MP
Figure 18-1 Development of psoriatic lesions. This figure

depicts the transition from normal skin to fully developed
lesion described in the text. Normal skin from a healthy
individual (panel A) contains epidermal Langerhans cells,
scattered immature dendritic cells (D), and skin-homing
memory T cells (T) in the dermis. Normal-appearing skin
from a psoriatic individual (panel B) manifests slight capillary dilatation and curvature, and a slight increase in the
numbers of dermal mononuclear cells and mast cells (M).
A slight increase in epidermal thickness is usually present.
In chronic plaque psoriasis, the intensity of these changes
may depend on distance from an established lesion. The
transition zone of a developing lesion (panel C) is characterized by progressive increases in capillary dilatation and
tortuosity, numbers of mast cells, macrophages (MP), and
T cells, and mast cell degranulation (small arrows). In the
epidermis, there is increasing thickness with increasingly
prominent rete pegs, widening of the extracellular spaces,
transient dyskeratosis, spotty loss of the granular layer, and
parakeratosis. Langerhans cells (L) begin to exit the epidermis, and inflammatory dendritic epidermal cells (I) and CD8+
T cells (8) begin to enter the epidermis. The fully developed
lesion (panel D) is characterized by fully developed capillary
dilatation and tortuosity with a tenfold increase in blood
flow, numerous macrophages underlying the basement
membrane, and increased numbers of dermal T cells (mainly
CD4+) making contact with maturing dermal dendritic cells
(D). The epidermis of the mature lesion manifests markedly
increased (approximately tenfold) keratinocyte hyperproliferation extending to the lower suprabasal layers, marked
but not necessarily uniform loss of the granular layer with
overlying compaction of the stratum corneum and parakeratosis, increased numbers of CD8+ T cells, and accumulation
of neutrophils in the stratum corneum (Munros microabscesses).
4
A
Chapter 18
::
Psoriasis
Figure 18-2 Histopathology of psoriasis. A. Pinpoint papule of psoriasis. In the transition from the edges to the
center of the lesion, note progressive thickening of epidermis with elongation of rete pegs, increasing dilatation and tortuosity of vessels, and increasing mononuclear cell infiltrate. Also note the transition from basketweave to compact stratum corneum with loss of granular layer in the center of the lesion. (4-mm punch biopsy,
hematoxylin and eosin, scale bar = 100 M.) B. Comparison of uninvolved versus involved skin. Four 4-mm biopsies were taken from the same individual sampled in A on the same day. Uninvolved distant skin was taken
from the upper back 30 cm from the nearest visible lesion of psoriasis. Uninvolved near edge skin was taken
0.5 cm from the edge of a 20-cm plaque, which had been present for several years, according to the patient. Center
plaque skin was taken from a relatively inactive (less red and scaly) area in the center of this plaque. Involved edge
skin was taken from an active (more red and scaly) area about 1 cm inside the edge of the same plaque. In comparing
uninvolved distant to uninvolved near edge skin, note that the latter manifests increased thickness and early elongation of the rete pegs, dilatation and early tortuosity of blood vessels, and increased numbers of mononuclear cells in the
upper dermis, many of which are in a perivascular location. In this patient, uninvolved near edge skin also manifests an
increased frequency of dyskeratotic keratinocytes, a finding that has been noted previously at the periphery of psoriatic
lesions.53 In comparing less active to more active areas of the plaque, note that the more active area manifests increased
dermal mononuclear infiltrate, increased hyperkeratosis and parakeratosis, and Munros microabscesses. (4-mm punch
biopsies, hematoxylin, and eosin, scale bar = 100 M.)
Initial Lesion. In the initial pinhead-sized macular
lesions there is marked edema, and mononuclear cell

infiltrates are found in the upper dermis.70 These findings are usually confined to the area of one or two
papillae. The overlying epidermis soon becomes spongiotic, with focal loss of the granular layer. The venules
in the upper dermis dilate and become surrounded by
a mononuclear cell infiltrate.67 Similar findings have
been described in early macules and papules of psoriasis71 and in clinically normal-appearing skin 24 cm
away from any active lesion in patients undergoing an
acute flare of guttate psoriasis.72
Developing Lesion. Studies of the clinical margins of somewhat larger lesions (0.51.0 cm) reveal an
approximately 50% increase in epidermal thickening

in the normal-appearing skin immediately adjacent
to lesions.67 There is a large increase in the metabolic
activity of epidermal cells, including the stratum corneum, increased DNA synthesis, an increased number
of mast cells and dermal macrophages, and increased
mast cell degranulation.67,73,74 Subsequent studies
revealed increased numbers of dermal T cells75 and
dendritic cells (DCs)76 in both uninvolved and involved
psoriatic skin relative to normal skin. Toward the center of the lesion, a marginal zone can be identified,
with increasing band-like epidermal thickness, increasing parakeratosis and capillary elongation, and perivascular infiltration of lymphocytes and macrophages,
without exudation into the epidermis. More centrally,
199
rete ridges begin to develop in the marginal zone,

before finally transitioning into the fully developed
psoriatic plaque. Squamous cells manifest enlarged
extracellular spaces with only a few desmosomal connections. Parakeratosis is typically mounded or spotty.
Mature Lesion.
Section 4
::
200
Mature lesions of psoriasis are

characterized by uniform elongation of rete ridges,
with thinning of the epidermis overlying the dermal
papillae.67,71 Epidermal mass is increased three to five
times, and many more mitoses are observed, frequently above the basal layer. About 10% of basal
keratinocytes are cycling in normal skin, whereas this
value rises to 100% in lesional psoriatic skin.77 Widening of the extracellular spaces between keratinocytes
persists but is less prominent than in developing
lesions and is more uniform than the typical spongiosis of eczematous skin lesions. The tips of the rete
ridges are often clubbed or fused with adjacent ones,
with thin, elongated, edematous papillae containing
dilated, tortuous capillaries. Parakeratosis, with
accompanying loss of the granular layer, is often horizontally confluent but may alternate with orthokeratosis,78 and hyperkeratosis is more extensive than in
the transitional zone. The inflammatory infiltrate
around the blood vessels in the papillary dermis
becomes more intense but still consists of lymphocytes, macrophages, DCs, and mast cells. Unlike the
initial lesion and the transitional zone, lymphocytes
are observed in the epidermis of the mature lesion.
Neutrophils exit from the tips of a subset of dermal
capillaries (the squirting papillae), leading to their
accumulation in the overlying parakeratotic stratum
corneum (Munros microabscesses) and, less frequently, in the spinous layer (spongiform pustules of
Kogoj). Collections of serum can also be seen in the
epidermis and the stratum corneum.67,71
CELLULAR PARTICIPANTS IN PSORIASIS

T Cells.79,80 In 1984, it was demonstrated that
the
eruption of psoriatic skin lesions coincided with epidermal influx and activation of T cells,75 and shortly
thereafter it was further shown that resolution of psoriasis during phototherapy was preceded by depletion
of T cells, predominantly from the epidermis.81 Several
studies found CsA to be highly effective in psoriasis,82,83
and this effect was demonstrated to be primarily
through blockade of T cells rather than keratinocytes.84
Furthermore, psoriasis has been triggered or cured by
bone marrow transplantation, depending on whether
the donor or the host was psoriatic.85,86 The role of T
cells in psoriasis was functionally demonstrated in
1996 when it was shown that the psoriasis process
could be induced by injecting activated autologous T
cells into uninvolved psoriatic skin transplanted onto
severe combined immunodeficient mice.87 Available
data indicate that the T-cell responses are antigen-specific rather than mediated by superantigens, as clonal
populations of both CD4+ and CD8+ T cells have consistently been identified in psoriatic lesions.8891 However, most of the T cells in a psoriatic lesion are not
clonally expanded and may accumulate in response to
the cytokine environment of the lesion. There is virtually no evidence for B-cell involvement or antibodymediated processes in psoriasis.
The best-characterized T cells are the CD4+ and CD8+
subsets. Predominantly of the memory phenotype
(CD45RO+), these cells express the cutaneous lymphocyte antigen (CLA), a ligand for E-selectin, which is
selectively expressed on skin capillaries and therefore
provides them with access to the skin.92 CD8+ T cells
are predominantly located in the epidermis, whereas
CD4+ T cells are predominantly located in the upper
dermis.93,94 The cytokine profile of psoriatic lesions
is rich in interferon (IFN)-,95 indicative of T helper 1
(Th1) polarization of CD4+ cells, and T cytotoxic 1 (Tc1)
polarization of CD8+ cells96 (Fig. 18-3). Two other subsets of CD4+ T cells, stimulated by IL-23 and characterized by production of IL-17 (Th17 cells) and/or IL-22
(Th22 cells), are also found in psoriatic lesions and
have been shown to play a major role in maintaining
chronic inflammation in psoriasis97,98 as well as other
autoinflammatory conditions.99101 While the majority
of CD4 T cells are Th1, about 20% of them produce
IL-17 (Th17) and 15% produce IL-22 (Th22).98 Similarly, CD8+ epidermal T cells producing IFN- (Tc1),
IL-17 (Tc17), and IL-22 (Tc22) are found in psoriasis.98
These T-cell subsets have considerable functional plasticity and conversions of Tc17 to Tc1102 and Th17 to
Th1103105 have been described. In mice most Th17 cells
also elaborate IL-22, which mediates dermal inflammation and epidermal hyperplasia after intracutaneous injection of IL-23.106 However, in humans, this
overlap is much less pronounced, with largely distinct
populations of Th17 and Th22 cells.98,107109
Regulatory T cells suppress immune responses in an
antigen-specific fashion, and are responsible not only
for downregulating successful responses to pathogens
but also for the maintenance of immunologic tolerance.110 Several different populations of regulatory T
cells (T-regs) exist but the best characterized one is the
CD4+ CD25+ subset.111 A recent study of this subset in
psoriasis demonstrated impaired inhibitory function
and failure to suppress effector T-cell proliferation,112
possibly due to a tissue environment rich in IL-6 produced by endothelial, dendritic, and Th17 cells.113
Natural killer T cells (NKT cells) are a heterogeneous
subpopulation of T lymphocytes defined by coexpression of the T-cell receptor (TCR) and natural killer
(NK) lineage markers such as CD16, CD56, CD57,
CD94, and CD161. Unlike conventional T cells, NKT
cells recognize glycolipid antigens in the context of the
MHC Class I-like antigen-presenting molecule CD1d.
NKT cells constitute only a small fraction of lymphocytes. Nevertheless, their ability to rapidly secrete
large amounts of cytokines, including IFN-, IL-4, IL-2,
IL-5, IL-10, IL-13, IL-17, and TNF-, positions them
as potentially important regulators of T-cell differentiation at sites of inflammation. While NKT cells are
increased in psoriatic lesions relative to uninvolved
or normal skin, their precise role in psoriasis remains
unclear.114
Natural Killer Cells. Like NKT cells, NK cells are

major producers of IFN- and serve as a bridge
Cytokine network in psoriasis
CD8
hBD2
TGF-
AREG
IL-20
IL-19
IL-17
IL-22
IFN-
IL-7
IL-15
KCs
TNF-
IL-18
IL-8 / hBD2
chemokines
DC
IL-23
IFN-
IL-12
CD4+
Th17/Th22
CD4+
Th1
IL-12
Chapter 18
TNF-
IFN-
IL-17
IL-22
::
between innate and acquired immunity. Unlike NKT

cells, NK cells do not express the T-cell receptor. NK
cells are present in psoriasis,115,116 and can trigger the
formation of psoriasis lesions in a xenograft model
system.117 NK cells are regulated in part by killer
immunoglobulin-like receptors (KIRs), which recognize HLA-C and other MHC Class I molecules. KIRs
are a family of 15 closely linked genes located on
chromosome 19q13.4,118 some of which stimulate and
others of which inhibit NK cell activation. KIR genes
have been associated with psoriasis119121 and psoriatic
arthritis.122,123 It has been proposed that susceptibility
to psoriatic arthritis is determined by the overall balance of activating and inhibitory genotypes.121,124
Although it is attractive to speculate that the association of psoriasis with HLA-Cw6 might reflect a KIRmediated dysregulation of NK cells, it is known that a
number of other HLA-C protein alleles recognize the
same inhibitory receptor (KIR2DL1), including HLACw2, HLA-Cw4, HLA-Cw5, HLA-Cw15, and HLACw17. Thus, it is not straightforward to explain the
action of HLA-Cw6 in psoriasis on the basis of KIR
recognition alone.
Dendritic Cells.
Treatments directed primarily

against key costimulatory molecules expressed by
professional antigen-presenting DCs markedly
improve psoriasis.79 This suggests that T cells in psoriatic lesions are in constant communication with DCs,
which have a role in both the priming of adaptive
immune responses and the induction of self-tolerance125 (see Chapter 10). Several subsets of DCs have
been defined, and many of these are found in mark-
Psoriasis
Figure 18-3 The cytokine network in psoriasis. IFN- is produced by Th1 cells, and TNF- is produced by activated T-cells
and DCs. IFN- amplifies the production of IL-23 by DC. In turn, IL-23 maintains and expands subsets of CD4+ T cells, called
Th17 and Th22 cells, which are characterized by production of IL-17 and IL-22, respectively. CD8+ T cells are predominantly
found in the epidermis, and their entry into the epidermis is necessary for lesion development. IL-17, TNF-, IFN-, and
IL-22 synergistically promote activation of the innate keratinocyte defense response involving secretion of antimicrobial
peptides such as human--defensin 2 (hBD-2), IL-8 and other chemokines, and growth factors such as TGF-, AREG, IL-19,
and IL-20. Keratinocytes also produce IL-7 and IL-15, which influence the survival and turnover of CD8+ T cells, and IL-18,
which via IL-12 causes DC to further increase the production of IFN- by T-cells.
edly increased numbers within psoriatic lesions.125128

Although DCs are believed to be central to the pathogenesis of psoriasis, the specific role of each subset is
still somewhat unclear.
Langerhans Cells. Usually defined by a Langerin+,
CD1a+ surface phenotype, Langerhans cells (LCs) are
considered to be immature DCs (iDCs). LCs have a
well-defined role as antigen-presenting cells (APCs)
in contact dermatitis,129 but their role in psoriasis is
currently somewhat unclear. While the density of
LC is decreased in lesional psoriasis in terms of cells
per unit area,126,130 the number of LC per unit length
of epidermis is similar in normal, uninvolved, and
lesional skin.128 DCs lacking the characteristic Birbeck
granule but positive for the maturation molecule DCLAMP found in the dermis of psoriatic lesions could be
derived from epidermal or dermal iDC.131 Recently, LC
have been shown to preferentially drive Th22 differentiation, relative to dermal DC.132 Interestingly, migration of LCs in response to inflammatory cytokines is
markedly impaired in uninvolved psoriatic epidermis
relative to normal skin,133 especially in type I (early
onset) psoriasis.134
Dermal Dendritic Cells. Dermal DCs do not express
activation markers in resting normal skin and in that
context can be considered as another type of iDC that
is similar to myeloid iDCs found in other tissues.128,135
Immunophenotyping studies have revealed that the
population of dermal DCs is quite complex, and that
psoriasis lesions demonstrate a marked increase in the
number and maturation state of dermal DC.126,136,137
201
Section 4
::
202
Identified initially by strong expression of MHC Class

II and/or factor XIIIa,138 it is now appreciated that factor XIIIa+ cells are macrophages rather than DCs, and
that the most reliable marker for myeloid-derived
dermal DC is CD11c.139 There appears to be three
types of myeloid-derived (CD11c+) DCs in psoriasis
lesions.128,139,140 The first is the population of resident
dermal DCs that are also seen in normal skin. These
CD11c+/CD1c+ DC account for about 10%15% of DCs
in psoriasis lesions. These cells are relatively more
mature than inflammatory DCs (see Section Inflammatory Dendritic Epidermal Cells), but less so than
fully mature DCs. The second population comprises
mature DCs that are marked by DC-LAMP or
CD83. The DC-LAMP+ DCs form large aggregates
with T cells in the dermis, whereas the CD83+ DCs
are more diffuse. It has been suggested that fully
mature DCs may be the sustaining force for chronic
T-cell activation in skin and the characteristics
of these cells are very similar to those in lymph
nodes.128,139141 The third population of myeloid
DCs are the inflammatory DCs, which are CD11c+/
CD1c, and are less mature than the resident CD1c+
subset. These cells make IL-23 and probably help
drive Th17 differentiation.142 About 80%90% of DCs
in psoriasis lesions are these relatively immature,
inflammatory DCs and, interestingly, the total number of these cells can exceed the number of T cells in
lesions. A subset of these inflammatory DC express
high levels of TNF- and iNOS, and by analogy to
similar if not identical cells in mice, have been called
TIP-DC (for TNF- and iNOS-producing DC). Consistent with our recent genetic findings,64 TIP-DCs are
increased up to 30-fold in psoriatic lesions.128 There
appears to be substantial plasticity in this population
of cells, as the cytokine milieu in atopic dermatitis
promotes the emergence of dermal DC that chemotactically attract a different subset of T cells than those
found in psoriasis.143
Inflammatory Dendritic Epidermal Cells. Thought
to be either monocyte-derived iDCs,144 or a variant of
inflammatory myeloid DC that migrate into the epidermis,145 inflammatory dendritic epidermal cells (IDECs)
are distinguished from LCs by the lack of Birbeck granules and lower expression of CD1a. Unlike LCs, IDECs
are nearly absent in normal skin, and their numbers
are markedly increased in the epidermis of active psoriasis lesions, as well as a large number of other inflammatory dermatoses.126,130
Plasmacytoid Dendritic Cells. Plasmacytoid DCs
(pDCs) are inefficient presenters of antigens to T cells.
However, they regulate inflammation and link innate
with adaptive immunity, producing large amounts
of IFN- when activated146 (see Chapter 10). Absent
from normal skin, pDCs are significantly increased in
both uninvolved and involved psoriatic skin, but activated only in involved skin.126,147 Interestingly, inhibition of pDCs was shown to prevent development of
psoriasis in a mouse xenograft model.147 Conversely,
imiquimod, which has been reported to exacerbate
psoriasis,148 likely acts through this type I IFN system
by binding to Toll-like receptor 7 on pDCs.149 Although

IFN- appears to have a role in psoriatic lesional development and exacerbations,147 its role in stable chronic
plaque psoriasis has been questioned.150
Mast Cells. Mast cells have long been observed in

initial and developing psoriasis lesions,67 with prominent mast cell degranulation in both eruptive psoriasis72 and in lesions reappearing after discontinuation
of topical corticosteroid suppression.74 Interestingly,
skin-derived mast cell release of preformed and newly
synthesized mediators is potently suppressed byCsA
and tacrolimus,151 suggesting that the antipsoriatic
effects of these compounds could be mediated by
mast cells as well as T cells. Recently, mast cells have
been shown to be a major source of IL-17 production
in both rheumatoid arthritis synovium152 and in psoriatic lesions.153
Macrophages. Macrophages are prominent in initial and developing psoriasis lesions.67 CD163 has
recently been shown to be a reliable marker for skinderived macrophages,139 and as mentioned earlier,
these cells also express Factor XIIIa.154 A population of
CD11c, CD1a+, CD68+ macrophages is found scattered
just under the basement membrane, subadjacent to
proliferating keratinocytes expressing the macrophage
chemokine MCP-1 (CCL2).155157 These phagocytically
active cells could be involved in generating fenestrations (holes) in the epidermal basement membrane.158
Recent studies in two different mouse models of psoriasis, one dependent on and the other independent of
T cells, showed that selective elimination of macrophages led to prompt improvement of lesions. These
findings suggest that macrophages may play a key role
in the pathogenesis of psoriasis, at least in part via production of tumor necrosis factor (TNF)-, iNOS, and
IL-23.154,159161
Neutrophils. Although neutrophils are commonly
seen in the upper epidermis of psoriatic lesions, they
appear late during the development of lesions, their
number is quite variable, and their role in the pathogenesis of psoriasis is unclear. Studies in one of the
same mouse models used to implicate macrophages
indicate that neutrophils are probably unnecessary for
lesional development.161
Keratinocytes. As detailed below, keratinocytes

are a major producer of proinflammatory cytokines,
chemokines, and growth factors,162 as well as other
inflammatory mediators such as eicosanoids163 and
mediators of innate immunity such as cathelicidins,
defensins, and S100 proteins.164 Psoriatic keratinocytes are engaged in an alternative pathway of keratinocyte differentiation called regenerative maturation.165
Regenerative maturation is activated in response
to immunologic stimulation in psoriasis,166 but the
mechanism by which this occurs is presently
unknown.
Other Cell Types. Other cell types, such as endo-
thelial cells and fibroblasts, are also likely to be participants in the pathogenic process. Endothelial cells are
strongly activated in developing and mature lesions of

psoriasis67,71 and in addition to delivering a tenfold
increase in blood flow to the lesion, they play a major
role in controlling the flux of leukocytes and serum
proteins into psoriatic tissue.167169 Fibroblasts support
keratinocyte proliferation in a paracrine manner,170
and this process is exaggerated in psoriasis.171 Fibroblasts produce many chemotactic factors and support
the migration of T cells out of psoriatic lesions.172 Thus,
fibroblasts may also be intimately involved in psoriasis
by directing the localization of T cells.
Psoriasis
Innate Immune Mediators. In addition to cytokines and chemokines, several mediators of innate
immunity are abnormally expressed in psoriasis.164
Prominent among the innate immune mediators are
the antimicrobial peptides human -defensin-2
(hBD-2) and cathelicidin (LL-37), both of which are
much more highly overexpressed in psoriasis than in
atopic dermatitis.192,193 Notably, expression of HBD-2
::
work in psoriasis is extremely complex, involving the

actions and interactions of multiple cytokines, chemokines, and growth factors, and their receptors in addition to other mediators produced by multiple cell
types. Combinations of cytokines and growth factors
can result in effects that are not seen when these factors
are studied individually. For example, T-cell clones isolated from psoriatic skin lesions are able to promote
keratinocyte proliferation in an IFN--dependent manner,173,174 but by itself, IFN- has an antiproliferative
effect on cultured keratinocytes.175
The most prominent cytokines currently thought to
be involved in the pathogenesis of psoriasis are summarized in Fig. 18-3. Besides IFN-,96,176 a plethora of
cytokines and chemokines are upregulated in psoriasis,
including the cytokines TNF-,177 IL-2,95 IL-6,178 IL-8,179
IL-15,180 IL-17,181 IL-18,182 IL-19, IL-20, IL-22,183 IL-21,184
IL-23,97,100,101 and the chemokines MIG/CXCL9, IP-10/
CXCL10, I-TAC/CXCL11, and MIP-3/CCL20.7,185
More complex abnormalities have been observed for
other immunomodulatory cytokines and their receptors, including IL-1 and TGF-.186188 IL-23 is currently
believed to play a central role in the pathogenesis of
psoriasis through its role in maintaining and expanding specific subsets of CD4+ T cells characterized by
production of IL-17 (Th17)189 and IL-22 (Th22).106 IFN plays a role in amplifying this process by stimulating antigen-presenting cells to produce more IL-23.190
The entry of activated, cytokine secreting, CD8+ T cells
into the epidermis promotes epidermal hyperplasia191
and activation of keratinocyte innate defense response
with resulting production of antimicrobial peptides,
cytokines, chemokines, and growth factors (see Fig.
18-3). The other major cytokine producers in psoriatic
lesions are DC and macrophages,154 with additional
contributions from mast cells, neutrophils, and endothelial cells. Overall, this creates a highly complex
network of inflammatory signals between the main
cellular participants.
Chapter 18
SIGNALING MOLECULES IN PSORIASIS

Cytokines and Chemokines. The cytokine net-
and LL-37 is increased in response to proinflammatory and type I cytokines (TNF-, IL-1, and IFN-) and
suppressed by type II cytokines (IL-4, IL-10, and
IL-13).194 These differences in antimicrobial peptide
expression help to explain why approximately 30% of
patients with atopic dermatitis have bacterial or viral
infections, as opposed to only 7% of psoriasis patients,
even though both conditions have a defective skin
barrier.195 They may also explain why psoriasis
patients, though frequently colonized with Staphylococcus aureus, are not markedly improved by antibiotic
treatment, whereas atopic dermatitis patients often
obtain dramatic benefit from antibiotic therapy. The
S100 proteins are a large family of dimeric low-molecular-weight proteins that bind calcium and other
divalent cations. S100A2, S100A7 (psoriasin), and the
S100A8/A9 heterodimer (calprotectin) are markedly
overexpressed in psoriasis lesions.196 These proteins
exert chemotactic and antimicrobial activity, the latter
through sequestration of zinc ions,197,198 and have been
shown to function as TLR4 ligands on CD8+ T cells,
upregulating IL-17 expression and inducing autoimmunity.199 Nitric oxide is produced in large amounts
by DCs in psoriasis, triggering multiple signal transduction events.137 Finally, the complement component
C5a is a potent chemoattractant for neutrophils and
may contribute to the accumulation of neutrophils in
the stratum corneum of psoriasis.200 Interestingly, it is
also the most potent chemoattractant for DCs in psoriatic scale extracts.201 Many of these mediators are regulated in response to Toll-like receptors, providing a
mechanism whereby the innate immune system can
rapidly recognize a wide variety of pathogens according to their pathogen-associated molecular patterns202
(see Chapter 10).
Eicosanoids. The role of eicosanoids in psoriasis

remains unclear.203 Levels of free arachidonic acid, leukotriene B4, 12-hydroxyeicosatetraenoic acid, and
15-hydroxyeicosatetraenoic acid are markedly increased
in lesional skin, whereas levels of prostaglandins E and
F2 are increased less than twofold.
Growth Factors. Multiple growth factors are over-
expressed in psoriasis.204 Members of the epidermal

growth factor (EGF) family induce their own production in keratinocytes, including transforming growth
factor-, amphiregulin (AREG), and heparin-binding
EGF-like growth factor.205 Studies in xenografted mice
found a reduction in epidermal hyperplasia after antibody-mediated neutralization of AREG.206 Activation
of the EGF receptor stimulates keratinocyte production
of vascular endothelial growth factor (VEGF),167 perhaps accounting for the long-standing observation that
the angiogenic properties of normal and psoriatic skin
associate with the epidermis.207 Nerve growth factor
(NGF) is also overexpressed by keratinocytes in psoriatic skin, and NGF receptors are increased in the
peripheral nerves of lesional skin. Psoriasis has been
shown to clear in denervated skin,208 and psoriasis
improved after NGF blockade in xenografted mice.209
Moreover, direct connections have been documented
between terminal nerve fibers and DCs in the skin, and
203
neuropeptides have been shown to modulate DC function.210 Paracrine growth factors produced outside the
epidermal compartment may also play an important
role in stimulating epidermal hyperplasia in psoriasis,
including insulin-like growth factor-1211 and keratinocyte growth factor.212
Proteases and Their Inhibitors. The psoriatic
Section 4
::
204
lesion is characterized by marked overexpression of

multiple classes of proteinases by both keratinocytes
and leukocytes. Metalloproteinases release TNF-,
several EGF-like growth factors, and many other cytokines and growth factors from their membraneanchored precursors.213 Leukocyte-derived elastase
has also been implicated in the release of EGF-like
growth factors.214 Serine proteases directly activate
protease-activated receptors.215 Each of these mechanisms may contribute to stimulation of keratinocyte
proliferation. The protease inhibitors elafin, serpinB3,
and serpinB13 (hurpin) are among the most markedly
overexpressed genes in psoriatic lesions,216,217 suggesting that homeostatic mechanisms are strongly engaged
in an effort to regulate the proteolytic environment of
psoriatic lesions.
Integrins. Several observations suggest an early role
for 5 integrins and their ligand fibronectin in psoriasis. Fibronectin is increased in psoriatic epidermis,218
and it has been suggested that fibronectin gains access
to the epidermis via fenestrations in the epidermal
basement membrane.219 Fibronectin receptors (5 integrins) are only weakly expressed in normal skin, but
are strongly expressed in uninvolved as well as
involved psoriatic skin,219 and fibronectin selectively
increases the proliferation of keratinocytes cultured
from uninvolved psoriatic skin.219 Receptors for collagen and laminin-5 (21 and 31 integrins, respectively) are confined to the basal layer of normal skin
but are strongly expressed in suprabasal keratinocytes
as part of the regenerative maturation program.220
Interestingly, forced expression of 1 integrins in the
suprabasal compartment results in epidermal hyperplasia.221 Finally, the entry and retention of CD8+ T cells
into the epidermis requires binding of type IV collagen
by 11 integrin and binding of E-cadherin by E7
integrin, respectively.191,222
Signal Transduction. As would be expected given
this plethora of intercellular signaling alterations, multiple signal transduction mechanisms are dysregulated
in psoriatic epidermis, including receptor tyrosine
kinase, mitogen-activated protein kinase, Akt, STAT,
Src family kinase, Wnt,223 and NF-B pathways. These
abnormalities affect immunocyte activation and trafficking as well as keratinocyte responses of proliferation, differentiation, and survival. As described below,
many of the susceptibility variants associated with
psoriasis have a role in regulating these signaling pathways, particularly the NF-B pathway.34,64 This is a
challenging area of research, as signal transduction
experiments are typically conducted on cell lines in
culture, whereas the phenotype of psoriasis requires
intercellular interactions and differentiation conditions
that can only be obtained in vivo. Animal models are
helping to define signal transduction abnormalities at

a functional level. Space does not allow detailed consideration of these pathways in psoriasis, nor of the
animal models being used to study them. Interested
readers are referred to several reviews for deta
ils.50,188,224226
PSORIASIS: INTEGRATING GENETICS AND

IMMUNOLOGY
HLA-Cw6. (Fig. 18-4). As has been made clear by
detailed fine mapping, genetic linkage, and association

studies, HLA-C is by far the major genetic risk factor
for psoriasis.30,34,35,38,57 Because it presents antigens to
CD8+ T cells, HLA-Cw6 is an excellent candidate for
functional involvement in psoriasis. Psoriasis has long
been known to be triggered by streptococcal pharyngitis, and is the only infection that has been shown to
trigger psoriasis in a prospective cohort study.227
Because tonsillar T cells are cutaneous lymphoid antigen (CLA)-positive and recognize activated skin endothelium228 they can traffic into the skin, explaining why
the same CLA-positive T-cell clones are found in the
tonsils and in the lesional skin of psoriatic patients.229
CD8+ T cells comprise at least 80% of the T cells in the
epidermis of psoriatic lesions,230 and epidermal invasion correlates with lesional development.94,231,232 CD8+
T cells selectively traffic to the epidermis because they
express integrin 11 (also known as VLA-1), which
binds to type IV basement membrane collagen,191 as
well as integrin E7, which binds to keratinocyte
E-cadherin.222 Once in the epidermis, CD8+ T cells
interrogate peptides bound to HLA-Cw6 on the surface of dendritic APCs and/or keratinocytes. In normal immune responses, CD4+ T cells provide critical
help in processing and presentation of intracellular
viral components and tumor antigens, in a process
called cross-priming. While CD4+ and CD8+ memory T
cells can traffic between the skin and lymph nodes and
blood, increasing evidence suggest that they spend
most of their time in the skin itself.233 This may help to
account for the characteristic distribution of psoriatic
plaques, which tend to recur in the same places after
therapeutic or spontaneous improvement.
As mentioned earlier, there is a very strong association between HLA-Cw6 and guttate psoriasis. This
form of psoriasis is often self-limiting5,234 but can progress to chronic plaque psoriasis, which has a fluctuating inflammatory course in the absence of ongoing
streptococcal infection. The transition from guttate to
chronic plaque psoriasis likely reflects a transition from
a self-limited cutaneous immune reaction triggered by
streptococci encountered in the tonsils during a guttate
flare, to a persistent and inappropriate immune reaction directed against host proteins in chronic plaque
disease.235 The mechanisms by which normal immunologic tolerance of self-proteins is broken during this
transition remain to be elucidated.
Non-MHC Genes. (Fig. 18-5). As reviewed earlier,

in the online edition, the advent of GWAS has identified an increasing number of convincing genetic
association signals for psoriasis outside the MHC
Proposed role of HLA-Cw6 in the pathogenesis of psoriasis
Crosspresentation
of antigens
HLA-Cw6-Ag
TCR
Activation and
proliferation of
memory T cells
in dermis
Cytokines
sublethal injury?
Chapter 18
CD8 T-cell
Ag
4
3 2m
Dermal blood vessels
Antigen
2 1
Lymphatics
HLA-Cw6
Psoriasis
V V
T-cell
receptor
::
C C
CD8
Activation and
proliferation of
naive T cells in
lymph nodes
Keratinocyte or
dendritic cell
Figure 18-4 Proposed role of HLA-Cw6 in the pathogenesis of psoriasis. Antigen (Ag) in the binding pocket of HLA-Cw6
interacts with a T-cell receptor. The role of HLA-Cw6 in psoriasis is likely to be twofold. HLA-Cw6 is active in cross-presenting peptides on the surface of dendritic cells, allowing activation and clonal expansion of antigen-specific CD8+ T cells. This
process is dependent on CD4+ T-cell help for cross-presentation of intracellular antigens and is likely to happen both in the
dermis (activation of memory resident T cells) and local lymph nodes (activation of naive T cells). Subsequently, the CD8+ T
cells are able to migrate into the epidermis where they encounter HLA-Cw6 on the surface of the keratinocytes presenting
those same pathogenic peptides. Activated CD8+ T-cells may recognize peptides presented by HLA-Cw6 on keratinocyte
cell surface. Because these T-cells express perforin, they could directly damage keratinocytes in the traditional cytotoxic
manner.435 Activated CD8+ T cells could also trigger the local release soluble factors, including cytokines, chemokines, eicosanoids, and/or innate immune mediators, which could further increase local inflammation and stimulate keratinocyte
proliferation.173 In response to either insult, keratinocytes could respond by elaborating autocrine growth factors such as
TGF- and AREG, thereby encouraging their own proliferation and survival.436
(Table 18-1). The genes contained within these associated regions fit very well with our current concepts of
psoriasis pathogenesis. This integration is further
reinforced by the pronounced clinical responsiveness
of psoriasis to biological agents that specifically target the genetically implicated pathways. Most of the
non-MHC associations identified thus far fall into
four interconnected functional axes: (1) IFN-/IL-23/
IL-17 signaling, (2) NF-B signaling, (3) inflammatory
DC function, and (4) keratinocyte differentiation.
While the actual functional genetic variations that are
ultimately responsible for these associations remain
to be determined, these discoveries provide a rationale for biological and therapeutic dissection of the
implicated pathways.
IFN-/IL-23/IL-17 Signaling. Three strong regions of
association map near genes involved in IL-23 signaling: (1) IL12B (encoding the p40 subunit of IL-23 and
IL-12), (2) IL23A (encoding the p19 subunit of IL-23),

and (3) IL23R (encoding a subunit of the IL-23 receptor).34,60,61 These associations are further supported by
the impressive efficacy of biologics targeting the p40
subunit common to IL-12 and IL-23,268 along with the
fact that IL12B and IL23A are markedly overexpressed
in psoriatic lesions, whereas IL12A is not.269 IL-23
signaling promotes cellular immune responses by
promoting the survival and expansion of a subset of
IL-17-expressing T cells that protects epithelia against
microbial pathogens.270 Given the similarities between
skin and gut as epithelial tissues, it is notable that
inflammatory bowel disease (IBD) is clinically associated with psoriasis271 and the same genetic variation
in IL23R that increases risk for both diseases.272 Ankylosing spondylitis (AS) is another HLA-Class I-associated autoimmune disorder that is clinically associated
with IBD273 and genetically associated with IL23R.274
Psoriatic arthritis (PsA) shares a number of clinical
205
Proposed model integrating the genetics and immunology of psoriasis

ERAP1
PSMA6
LCE3B/LCE3C
NF-B
DEFB CNV
Tc17
HLA-Cw6
Tc1
TRAF3IP2
IL-17R
IL-17
IL23R
Section 4
::
206
Th22
Th2
IL4/IL13
DC
KC
Tc17
Tc1
DC
Th1
Th17
IFN-
IL23A
TLR ligands
IL12B
NOS2
TNF-
Th17
Th17
TNFAIP3
TNIP1
DC
NFKBIA
FBXL19
NF-B
Figure 18-5 Proposed model integrating the genetics and immunology of psoriasis. The majority of the CD8+ T-cells
(lilac) are located in the epidermis, whereas CD4+ T-cells (blue) predominate in the dermis along with antigen presenting
cells/dendritic cells (DCs) (blue) and macrophages (Ms)(light blue). Confirmed association signals are indicated by the
likely candidate genes they contain. Please see text for additional details. (Adapted from Nair RP et al: Psoriasis bench to
bedside: Genetics meets immunology. Arch Dermatol 145(4):462-464, 2009, with permission.)
similarities with AS, and is genetically associated with

IL12B, IL23A, and IL23R34,275,276 (see Chapter 19).
IFN- is a major product of activated Th1 cells that
stimulates DC to produce IL-23.190 Several psoriasis
susceptibility loci contain genes involved in interferon
signaling (IFIH1, IL28R, and TYK2)61 Together with
IL-1, IL-23 promotes the survival and proliferation
of IL-17-expressing T cells (Th17), thereby explaining
why Th1 and Th17 are colocalized in psoriasis lesions
and in many other sites of inflammation.190 Given the
well-known reciprocal relationship between Th1 and
Th2 differentiation, it is notable that another psoriasis susceptibility region contains the IL4 and IL13
genes.34,63 In addition to biasing T-cell differentiation
away from Th1 and toward Th2, IL-4 inhibits Th17 cell
development.277 Both IL-4 and IL-13 are expressed at
high levels in atopic dermatitis, but only at very low
levels in psoriasis.278 Moreover, treatment of psoriasis with IL-4 resulted in significant clinical improvement,279 accompanied by reduced expression of IL-23
(but not of IL-12) and reduced numbers of Th17 cells.280
The fact that significant genetic signals at both ends
of this polarizing spectrum (IL-23, on the one hand,
and IL-4/IL-13, on the other), with IFN- positioned
between them, suggests that Th1-Th2-Th17 balance is
a key functional and genetic determinant of psoriasis.
NF-B Signaling. At least five psoriasis-associated

genomic regions contain genes involved with controlling signaling through the transcription factor NF-B:
(1) TNFAIP3, (2) TNIP1, (3) NFKBIA, (4) FBXL19, and
(5) TRAF3IP2.34,58,59,61,64 TNF- is a major activator of
NF-B signaling, and these associations are clinically
reinforced by the dramatic therapeutic response of
psoriasis to anti-TNF biologicals (see Section Treatment). TNFAIP3 and TNIP1, respectively encode A20
and ABIN-1, which interact with each other to regulate
the ubiquitin-mediated destruction of IKK/NEMO, a
central nexus of NF-B signaling.281 TNFAIP3 is genetically associated with rheumatoid arthritis (RA),282,283
and both TNFAIP3 and TNIP1 are associated with systemic lupus erythematosus (SLE).284287 The polymorphisms implicated in RA and SLE show no association
with psoriasis, suggesting that each of these common
autoimmune diseases is driven by a different variant
of the TNFAIP3 gene. Interestingly, in mice, Tnfaip3
is associated with atherosclerosis,288 which is now
known to be a major comorbidity of psoriasis.289 NFKBIA encodes IB, which inhibits NF-B signaling by
sequestering it in the cytoplasm. FBXL19 and TRAF3IP2
are significantly more strongly associated with PsA
than with purely cutaneous psoriasis.58,64 FBXL19 is
structurally related to FBXL11, an F-box family mem-
TABLE 18-1
Genome-wide Significant Psoriasis Susceptibility Loci
SNP ID
Chromo(rs number)a somal Band
Risk Allele
(frequency Odds
in controls)b Ratiob
pValuec
Notable
Gene(s) in
Associated
Region
rs12191877
6p21.33
T (0.147)
2.64
<1 E-100
HLA-C, CDSN
Nair et al34
rs17728338
5q33.1
A (0.054)
1.59
1 E-20
TNIP1
Nair et al34
rs2082412
5q33.3
G (0.798)
1.44
2 E-28
IL12B
Cargill et al,60
Nair et al34
rs33980500
6q21
T (0.071)
1.38
1 E-16
TRAF3IP2
Ellinghaus et al58
rs4649203
1p36
A (0.770)
1.36
7 E-8
IL28RA
Strange et al61
rs2066808
12q13.3
A (0.932)
1.34
1 E-09
IL23A, STAT2
Nair et al34
rs17716942
2p24
A (0.900)
1.29
1 E-13
IFIH1
Strange et al61
rs20541
5q31.1
G (0.790)
1.27
5 E-15
IL13, IL4
Nair et al34
rs4085613
1q21.3
C (0.421)
1.27
7 E-30
LCE3C, LCE3D
Zhang et al57
rs495337
20q13.13
C (0.551)
1.25
1 E-08
RNF114
Capon et al62
rs2431697
5q33.3
C (0.177)
1.19
1 E-08
PTTG1
Stuart et al59
rs4795067
17q11.2
G (0.349)
1.19
4 E-11
NOS2
Stuart et al59
rs610604
6q23.3
G (0.320)
1.19
9 E-12
TNFAIP3
Nair et al34
rs10782001
16p11.2
G (0.368)
1.16
9 E-10
FBXL19
Stuart et al64
rs12586317
14q13.2
T (0.751)
1.16
2 E-08
NFKBIA, PSMA6
Stuart et al64
rs3751385
13q12.11
T (0.478)
1.14
2 E-10
GJB2
Stuart et al59
rs10088247
8p23.2
C (0.183)
1.13
5 E-09
CSMD1
Stuart et al59
rs2201841
1p31.3
G (0.295)
1.13
3 E-08
IL23R
Nair et al34
rs151823
5q15
A (0.495)
1.12
9 E-09
ERAP1
Stuart et al59
rs514315
18q22.1
T (0.742)
1.12
6 E-09
SERPINB8
Stuart et al59
rs702873
2p16
G (0.620)
1.12
4 E-09
REL
Strange et al61
rs9304742
19q13.41
T (0.649)
1.11
2 E-09
ZNF816A
Stuart et al59
NAd
8p23.1
NAd
NAd
3 E-08
-defensin genes
Hollox et al66
Independently
Confirmed Reference
Chapter 18
::
Psoriasis
The most significant SNP in the associated region is shown.

Risk allele frequencies and odds ratios are computed for the replication sample (discovery sample excluded due to the winners curse phenomenon).
c
P-value is calculated for the combined discovery and replication samples. Only genes that reached a genome-wide significance criterion of p = 7
10-8 are shown.
d
Not applicable because the disease association is with copy number variation rather than SNP.
b
ber recently shown to inhibit NF-B activity by lysine

demethylation.290 FBXL11 contains domains known to
be required for demethylase activity, but FBLX19 does
not.291 Thus, FBXL19 might act as a dominant negative
inhibitor of demethylase activity, thereby serving to
activate NF-B. TRAF3IP2 encodes Act1, a ubiquitin
ligase that interacts with TRAF (tumor necrosis factor receptor-associated factors) proteins and the IKK
complex to activate NF-B. Interestingly, Act1 is a key
component of IL-17-mediated signaling through the
IL-17 receptor, allowing the incorporation of TRAF6
into the IL-17 receptor signaling complex, with consequent activation of NF-B.292 Thus, Act1 may serve as
a key link between the IFN-/IL-23/IL-17 axis on the
one hand, and the NF-B axis on the other.
Inflammatory DC Function. Beyond the major role

of HLA-Cw6 described earlier, it is noteworthy that
two other regions of association contain genes whose
products function in antigen presentation: (1) PSMA6,
which encodes a proteosomal subunit involved in
MHC Class I antigen processing,64 and (2) ERAP1,
an IFN--inducible aminopeptidase that trims peptides for optimal binding to the MHC Class I peptide
groove. As noted above, inflammatory DC produce
large amounts of TNF- and nitric oxide in addition
to their well-recognized functions in antigen presentation. Thus, it seems more than coincidental that another
novel region of association contains NOS2, which
encodes iNOS, the enzyme responsible for nitric oxide
production by DC. Reflective of the massive increase
207
Section 4
::
208
in inflammatory dermal dendritic cells characteristic of

psoriasis lesions, NOS2 is markedly overexpressed in
lesional skin.64 In addition to iNOS, these inflammatory
DC produce large amounts of TNF-, which synergizes strongly with IL-17 to induce a marked increase
expression of innate inflammatory mediators such as
hBD2 by keratinocytes.58
psoriasis, a history of onset of joint symptoms before

the fourth decade and/or a history of warm, swollen
joints should raise the suspicion of psoriatic arthritis
(see Chapter 19).
Keratinocyte Differentiation. Given that hyperproliferation and altered differentiation of keratinocytes

figure prominently in psoriasis pathophysiology, it
is perhaps surprising that relatively few of the psoriasis-associated regions highlight genes that function
primarily in keratinocytes. The most well-established association is an insertiondeletion polymorphism of the late cornified envelope genes LCE3B
and LCE3C, which was independently discovered
in European65 and Chinese57 populations. Located
in the EDC, these genes are expressed very late
during keratinocyte terminal differentiation293 and
are markedly overexpressed in psoriasis,294 wound
healing, and epidermal stress.65,293 Another reported
genetic association involving keratinocytes involves
increased DEFB4 copy number.66 Whether or not
this association is ultimately confirmed, it is notable
that DEFB4 is one of the most highly overexpressed
genes in psoriatic lesions.295 Finally, TRAF3IP2 is
known to function in epidermal cells, as shRNAmediated knockdown of TRAF3IP2 abrogates the
TNF- + IL-17-mediated upregulation of DEFB4 in
human keratinocytes.58
The classic lesion of psoriasis is a well-demarcated,

raised, red plaque with a white scaly surface (Fig.
18-7). Lesions can vary in size from pinpoint papules
to plaques that cover large areas of the body. Under
the scale, the skin has a glossy homogeneous erythema, and bleeding points appear when the scale is
removed, traumatizing the dilated capillaries below
(the Auspitz sign) (Fig. 18-8).297 Psoriasis tends to be a
symmetric eruption, and symmetry is a helpful feature
in establishing a diagnosis. Unilateral involvement can
occur, however. The psoriatic phenotype may present
a changing spectrum of disease expression even within
the same patient.
Koebner phenomenon (also known as the isomorphic
response) is the traumatic induction of psoriasis on nonlesional skin; it occurs more frequently during flares
of disease and is an all-or-none phenomenon (i.e., if
psoriasis occurs at one site of injury it will occur at all
sites of injury) (Fig. 18-9). The Koebner reaction usually occurs 714 days after injury, and approximately
25% of patients may have a history of trauma-related
Koebner phenomenon at some point in their lives.298
Estimates of lifetime prevalence rise as high as 76%
when factors such as infection, emotional stress, and
drug reactions are included.4 The Koebner phenomenon is not specific for psoriasis but can be helpful in
making the diagnosis when present.
CLINICAL FINDINGS
Figure 18-6 is an algorithm showing clinical findings
and treatment for psoriasis.
HISTORY
It is useful to determine the age at onset and the presence or absence of a family history of psoriasis, as
younger age of onset and positive family history have
been associated with more widespread and recurrent
disease.6,21 In addition, the physician should inquire
about the prior course of the disease, as major differences exist between acute and chronic disease.
In the latter form, lesions may persist unchanged for
months or even years, whereas acute disease shows
sudden outbreak of lesions within a short time (days).
Likewise, patients have great variability in regard to
relapses. Some patients have frequent relapses occurring weekly or monthly, whereas others have more
stable disease with only occasional recurrence. The frequently relapsing patients tend to develop more severe
disease with rapidly enlarging lesions covering significant portions of the body surface296 and may require
more rigorous treatment compared to those with more
stable disease. Certain medications may worsen psoriasis (see Section Treatment). The physician should
also inquire about joint complaints. Although osteoarthritis is extremely common and can coexist with
CUTANEOUS LESIONS297
CLINICAL PATTERNS OF SKIN

PRESENTATION297
PSORIASIS VULGARIS, CHRONIC STATIONARY PSORIASIS, PLAQUE-TYPE PSORIASIS.
Psoriasis vulgaris is the most common form of psoriasis, seen in approximately 90% of patients. Red, scaly,
symmetrically distributed plaques are characteristically localized to the extensor aspects of the extremities,
particularly the elbows and knees, along with scalp,
lower lumbosacral, buttocks, and genital involvement
(see Fig. 18-7). Other sites of predilection include the
umbilicus and the intergluteal cleft. The extent of involvement varies widely from patient to patient. There
is constant production of large amounts of scale with
little alteration in shape or distribution of individual
plaques. Single small lesions may become confluent,
forming plaques in which the borders resemble a land
map (psoriasis geographica). Lesions may extend laterally and become circinate because of the confluence
of several plaques (psoriasis gyrata). Occasionally,
there is partial central clearing, resulting in ring-like
lesions (annular psoriasis) (Fig. 18-10). This is usually
associated with lesional clearing and portends a good
prognosis. Other clinical variants of plaque psoriasis
have been described depending on the morphology of
Diagnosis and treatment algorithm for psoriasis

Features supporting a
diagnosis of psoriasis
Symmetry of lesions
Extensor distribution
Auspitzs sign
Sharply demarcated lesions
Silvery scale
Clinical impression
Diagnosis not obvious
Not psoriasis
(see DDX)
2nd line
Chronic plaque
psoriasis
Severe
>30% BSA
Moderate
>10% BSA
Day treatment
center
Modified Goeckerman
Mild
<10% BSA
Phototherapy
1st line
NB-UVB
BB-UVB
2nd line
PUVA
Excimer
Climatotherapy
Topical Tx
1st line
Psoriasis
Methotrexate
Acitretin
Biologicals
Alefacept
Etanercept
Adalimumab
Infliximab
Ustekinumab
Guttate psoriasis
No treatment
NB-UVB
Topical treatment
Vitamin D3 analog
Topical steroids
::
Systemic Tx
1st line
Psoriasis
Chapter 18
Erythrodermic/
pustular psoriasis
Acitretin
Cyclosporine A
PUVA, NB-UVB
Methotrexate
Anti-TNF agents
Systemic steroids**
Biopsy
Emollients
Glucocorticoids
Vitamin D3 analogs
2nd line
Salicylic acid
Dithranol
Tazarotene
Tar
FAE
Cyclosporine A
Other agents:
Hydroxyurea
6-Thioguanine
Cellcept
Sulfasalazine
Figure 18-6 Diagnosis and treatment algorithm for psoriasis. The diagnosis of psoriasis is usually based on clinical features. In those few cases in which clinical history and examination is not diagnostic, biopsy is indicated to establish the
correct diagnosis. The majority of psoriasis cases fall into three major categories: guttate, erythrodermic/pustular, and
chronic plaque, of which the latter is by far the most common. Guttate psoriasis is often a self-limited disease with spontaneous resolution within 612 weeks. In mild cases of guttate psoriasis, treatment may not be needed, but, with widespread disease, ultraviolet B (UVB) phototherapy or narrowband UVB in association with topical therapy is very effective.
Erythrodermic/pustular psoriasis is often associated with systemic symptoms and necessitates treatment with fast-acting
systemic medications. The most commonly used drug for erythrodermic and pustular psoriasis is acitretin. In occasional
cases of pustular psoriasis, systemic steroids may be indicated (**). Dotted arrows indicate that guttate, erythrodermic,
and pustular forms often evolve into chronic plaque psoriasis. Therapeutic choices for chronic plaque psoriasis are typically based on the extent of the disease. Among the main treatment regimens (topical treatment, phototherapy, day
treatment centers, and systemic treatments), first-line and second-line modalities are indicated by the solid and dashed
lines, respectively. Individuals with conditions that limit their activities, including painful palmoplantar involvement and
psoriatic arthritis, may require more potent treatments irrespective of the extent of affected body surface area. Likewise,
psychological issues and the impact on quality of life should be taken into consideration. Within each treatment regimen,
first-line and second-line choices are grouped. Cyclosporin A is not considered a first-line long-term systemic treatment
due to its side effects, but short-term treatment can be helpful for induction of remission. If patients have incomplete
response to or are unable to tolerate individual first-line systemic medications, combination regimens (Table 18-6), rotational treatments, or use of biologic therapies should be considered. BB-UVB = broadband UVB; BSA = body surface area;
DDx = differential diagnosis; FAE = fumaric acid ester; NB-UVB = narrowband UVB; PUVA = psoralen, and UVA light;
tx = therapy.
209
Section 4
::
Figure 18-7 AF. Chronic plaque psoriasis located at typical sites. Note marked symmetry of lesions. (Photos used with
permission from Dr. Johann Gudjonsson and Mr. Harrold Carter.)
the lesions; particularly those associated with gross hyperkeratosis (see Fig. 18-10). Rupioid psoriasis refers to
lesions in the shape of a cone or limpet. Ostraceous psoriasis, an infrequently used term, refers to a ring-like,
hyperkeratotic concave lesion, resembling an oyster
shell. Finally, elephantine psoriasis is an uncommon
form characterized by thickly scaling, large plaques,
210
usually on the lower extremities. A hypopigmented

ring (Woronoff ring) surrounding individual psoriatic
lesions may occasionally be seen and is usually associated with treatment, most commonly UV radiation or
topical corticosteroids (see Fig. 18-10C). The pathogenesis is not well understood but may result from inhibition of prostaglandin synthesis.299
Figure 18-8 Auspitz sign. Note point of bleeding after scale is removed. (Photos used with permission from
Dr. Johann Gudjonsson and Ms. Laura Vangoor.)
SMALL PLAQUE PSORIASIS. Small plaque pso-
riasis resembles guttate psoriasis clinically, but can be

distinguished by its onset in older patients, by its chronicity, and by having somewhat larger lesions (typically
12 cm) that are thicker and scalier than in guttate disease. It is said to be a common adult-onset presentation
of psoriasis in Korea and other Asian countries.141
Psoriasis
GUTTATE (ERUPTIVE) PSORIASIS. Guttate psoriasis (from the Latin gutta, meaning a drop) is characterized by eruption of small (0.51.5 cm in diameter)
papules over the upper trunk and proximal extremities (Fig. 18-11). It typically manifests at an early age
and as such is found frequently in young adults. This
form of psoriasis has the strongest association to HLACw6,26 and streptococcal throat infection frequently
precedes or is concomitant with the onset or flare of
guttate psoriasis.300 However, antibiotic treatment has
not been shown to be beneficial or to shorten the disease course.301 Patients with a history of chronic plaque
psoriasis may develop guttate lesions, with or without
worsening of their chronic plaques.
::
Figure 18-9 Koebner phenomenon. A. Psoriasis appearing in keratome biopsy sites 4 weeks after biopsy. (Photo
used with permission from Mr. Harrold Carter.) B. Flare
of psoriasis on the back after a sunburn. Note sparing of
sun-protected areas. (Photo used with permission from
Dr. James Rasmussen.)
ERYTHRODERMIC PSORIASIS. (See also Chapter 23). Psoriatic erythroderma represents the generalized form of the disease that affects all body sites,
including the face, hands, feet, nails, trunk, and extremities (Fig. 18-13). Although all the symptoms of
psoriasis are present, erythema is the most prominent
feature, and scaling is different compared with chronic
stationary psoriasis. Instead of thick, adherent, white
scale there is superficial scaling. Patients with erythrodermic psoriasis lose excessive heat because of generalized vasodilatation, and this may cause hypothermia. Patients may shiver in an attempt to raise their
body temperature. Psoriatic skin is often hypohidrotic
due to occlusion of the sweat ducts,303 and there is an
attendant risk of hyperthermia in warm climates. Lower extremity edema is common secondary to vasodilatation and loss of protein from the blood vessels into
the tissues. High-output cardiac failure and impaired
hepatic and renal function may also occur. Psoriatic
erythroderma has a variable presentation, but two
forms are thought to exist.304 In the first form, chronic
plaque psoriasis may worsen to involve most or all of
the skin surface, and patients remain relatively responsive to therapy. In the second form, generalized erythroderma may present suddenly and unexpectedly or
result from nontolerated external treatment (e.g., UVB,
anthralin), thus representing a generalized Koebner
reaction. Generalized pustular psoriasis [see Section
Generalized Pustular Psoriasis (von Zumbusch)]
may revert to erythroderma with diminished or absent
pustule formation. Occasional diagnostic problems
may arise in differentiating psoriatic erythroderma
from other causes (see Chapter 23).
Chapter 18
INVERSE (FLEXURAL) PSORIASIS. Psoriasis lesions may be localized in the major skin folds, such as
the axillae, the genito-crural region, and the neck. Scaling is usually minimal or absent, and the lesions show
a glossy sharply demarcated erythema, which is often
localized to areas of skin-to-skin contact (Fig. 18-12).
Sweating is impaired in affected areas.302
PUSTULAR PSORIASIS. Several clinical variants

of pustular psoriasis exist: generalized pustular psoriasis (von Zumbusch type), annular pustular psoriasis,
impetigo herpetiformis, and two variants of localized
pustular psoriasis(1) pustulosis palmaris et plantaris
and (2) acrodermatitis continua of Hallopeau. In children, pustular psoriasis can be complicated by sterile,
lytic lesions of bones305,306 and can be a manifestation
of the SAPHO syndrome (synovitis, acne, pustulosis,
hyperostosis, osteitis).307
Generalized Pustular Psoriasis (von Zumbusch). Generalized pustular psoriasis (von Zumbusch)
211
4
A
Section 4
::
212
Figure 18-10 Unusual forms of plaque-type psoriasis A. Annular psoriasis on the flank. B. Rupioid psoriasis in an infant.
Note cone-shaped lesions. C. Psoriatic patient undergoing modified Goeckerman therapy (ultraviolet B light, coal tar,
and topical steroid), demonstrating Woronoff rings. D. Elephantine psoriasis of the lower extremities. Note psoriatic involvement of toenails. (Photographs used with permission from Dr. Johann Gudjonsson, Mr. Harrold Carter, and Ms. Laura
Vangoor.)
Figure 18-11 Guttate psoriasis, involving thigh (A), hands (B), and back (C and D). The patient in
D went on to develop chronic plaque psoriasis. (Photos used with permission from Drs. Johann
Gudjonsson and Trilokraj Tejasvi, Mr. Harrold Carter, and Ms. Laura Vangoor.)
Figure 18-12 Flexural psoriasis. Note the well-demarcated, beefy-red, shiny plaques in A. The infant in B is suffering from
napkin psoriasis. (Photos used with permission from Dr. Johann Gudjonsson and Mr. Harrold Carter.)
Psoriasis
on highly erythematous skin, first as patches (Fig.

18-14C) and then becoming confluent as the disease
becomes more severe. With prolonged disease, the fingertips may become atrophic. The erythema that surrounds the pustules often spreads and becomes
confluent, leading to erythroderma. Characteristically,
the disease occurs in waves of fevers and pustules. The
::
is a distinctive acute variant of psoriasis. It is usually

preceded by other forms of the disease. Attacks are
characterized by fever that lasts several days and a
sudden generalized eruption of sterile pustules 23
mm in diameter (Fig. 18-14). The pustules are disseminated over the trunk and extremities, including the
nail beds, palms, and soles. The pustules usually arise
Chapter 18
Figure 18-13 Erythrodermic psoriasis. The patient shown in panel A rapidly developed nearcomplete involvement and complained of fatigue and malaise. Note islands of sparing. The
patient shown in panels B and C had total body involvement with marked hyperkeratosis
and desquamation. (Photos used with permission from Mr. Harrold Carter and Dr. Johann
Gudjonsson.)
213
Section 4
::
214
Figure 18-14 Pustular psoriasis. A and B, von Zumbusch-type generalized pustular psoriasis. Note tiny pustules, 12 mm
in diameter, on erythematous skin. C and D, localized pustular psoriasis of the leg and foot, respectively. E, resolving pustular psoriasis, note extensive areas of desquamation. (Photos CE used with permission from Drs. Johann Gudjonsson,
Trilokraj Tejasvi, and Neena Khanna.)
etiology of generalized psoriasis von Zumbusch type is
unknown. Various provoking agents include infections,
irritating topical treatment (Koebner phenomenon), and
withdrawal of oral corticosteroids.308 This form of psoriasis is usually associated with prominent systemic
signs and can potentially have life-threatening complications such as hypocalcemia,309 bacterial superinfection, sepsis, and dehydration.310 Severe pustular
psoriasis can be difficult to control and requires a potent
treatment regimen with rapid onset of action to avoid
life-threatening complications. Drugs commonly used
include etretinate, methotrexate (MTX), cyclosporine,
infliximab,311,312 or oral corticosteroids (see Section
Treatment).313 Cases of acute respiratory distress syndrome associated with generalized pustular psoriasis
have been reported.314 Two recent reports have identified recessive loss-of function mutations in the IL36RN
gene encoding IL-36 receptor antagonist (IL-36ra) in
patients with generalized pustular psoriasis. Consistent
with the prominent inflammation associated with generalized pustular psoriasis, IL-36ra is an anti-inflammatory cytokine that inhibits signaling by three related IL-1
like proteins (IL-36alpha, beta, and gamma).315,316
Exanthematic Pustular Psoriasis. Exanthematic

pustular psoriasis tends to occur after a viral infection
and consists of widespread pustules with generalized
plaque psoriasis. However, unlike the von Zumbusch
pattern, there are no constitutional symptoms, and the
disorder tends not to recur.297 There is an overlap between
this form of pustular psoriasis and acute generalized

exanthematous pustulosis, a type of drug eruption.
Annular Pustular Psoriasis.
SEBOPSORIASIS. A common clinical entity, sebopsoriasis presents with erythematous plaques with
greasy scales localized to seborrheic areas (scalp, glabella, nasolabial folds, perioral and presternal areas,
and intertriginous areas). In the absence of typical findings of psoriasis elsewhere, distinction from seborrheic
dermatitis is difficult. Sebopsoriasis may represent a
modification of seborrheic dermatitis by the genetic
background of psoriasis and is relatively resistant to
treatment. Although an etiologic role of Pityrosporum
remains unproven, antifungal agents may be useful.321
NAPKIN PSORIASIS. Napkin psoriasis usually begins between the ages of 3 and 6 months and first appears in the diaper (napkin) areas as a confluent red
area (see Fig. 18-12B) with appearance a few days later
of small red papules on the trunk that may also involve
the limbs. These papules have the typical white scales
of psoriasis. The face may also be involved with red
scaly eruption. Unlike other forms of psoriasis, the
rash responds readily to treatment and tends to disappear after the age of 1 year.
LINEAR PSORIASIS. Linear psoriasis is a very rare
form. The psoriatic lesion presents as linear lesion
most commonly on the limbs but may also be limited
to a dermatome on the trunk. This may be an underlying nevus, possibly an inflammatory linear verrucous
epidermal nevus (ILVEN), as these lesions resemble
linear psoriasis both clinically and histologically. The
existence of a linear form of psoriasis distinct from ILVEN is controversial.322
RELATED PHYSICAL FINDINGS
NAIL CHANGES IN PSORIASIS. (See also Chapter 89). Nail changes are frequent in psoriasis, being
Clinical Sign
Proximal matrix
Pitting, onychorrhexis, Beau lines
Intermediate
matrix
Leukonychia
Distal matrix
Focal onycholysis, thinned nail plate,

erythema of the lunula
Nail bed
Oil drop sign or salmon patch,

subungual hyperkeratosis, onycholysis,
splinter hemorrhages
Hyponychium
Subungual hyperkeratosis, onycholysis
Nail plate
Crumbling and destruction plus other

changes secondary to the specific site
Proximal and
lateral nail folds
Cutaneous psoriasis
Modified from Del Rosso JQ et al: Dermatologic diseases of the nail

unit. In: Nails: Therapy, Diagnosis, Surgery, edited by RK Scher, CR Daniel.
Philadelphia, W.B., Saunders, 1997, p. 172, with permission.
found in up to 40% of patients,21 and are rare in the

absence of skin disease elsewhere. Nail involvement
increases with age, with duration and extent of disease, and with the presence of psoriatic arthritis. Several distinct changes have been described and can be
grouped according to the portion of the nail that is affected (Table 18-2).323
Nail pitting is one of the commonest features of psoriasis, involving the fingers more often than the toes
(Fig. 18-15). Pits range from 0.5 to 2.0 mm in size and
can be single or multiple. The proximal nail matrix
forms the dorsal (superficial) portion of the nail plate,
and psoriatic involvement of this region results in pitting due to defective keratinization. Other alterations
in the nail matrix resulting in deformity of the nail
plate (onychodystrophy) include leukonychia, crumbling nail, and red spots in the lunula. Onychodystrophy has a stronger association with psoriatic arthritis
than other nail changes.21 Oil spots and salmon patches
are translucent, yellowred discolorations observed
beneath the nail plate often extending distally toward
the hyponychium, due to psoriasiform hyperplasia,
parakeratosis, microvascular changes, and trapping of
neutrophils in the nail bed.324,325 Unlike pitting, which
is also seen in alopecia areata and other disorders, oil
spotting is considered to be nearly specific for psoriasis. Splinter hemorrhages result from capillary bleeding underneath the thin suprapapillary plate of the
psoriatic nail bed. Subungual hyperkeratosis is due to
hyperkeratosis of the nail bed and is often accompanied by onycholysis (separation of the nail plate from
the nail bed), which usually involves the distal aspect
of the nail. Anonychia is total loss of the nail plate.
Although nail changes are rarely seen in the localized
pustular variant of pustulosis palmaris et plantaris,
Psoriasis
ized pustular psoriasis variants, including pustulosis

palmaris et plantaris and acrodermatitis continua (of
Hallopeau), are discussed in Chapter 21.
Nail Segment
Involved
::
Localized Pustular Psoriasis Variants. Local-
Nail Changes in Psoriasis
Chapter 18
Annular pustular
psoriasis is a rare variant of pustular psoriasis. It usually presents in an annular or circinate form. Lesions
may appear at the onset of pustular psoriasis, with a
tendency to spread and form enlarged rings, or they
may develop during the course of generalized pustular psoriasis. The characteristic features are pustules
on a ring-like erythema that sometimes resembles erythema annulare centrifugum. Identical lesions are
found in patients with impetigo herpetiformis, an
entity defined by some as a variant of pustular psoriasis occurring in pregnancy.317 Onset in pregnancy is
usually early in the third trimester and persists until
delivery.318 It tends to develop earlier in subsequent
pregnancies. Impetigo herpetiformis is often associated with hypocalcemia.309,319 There is usually no personal or family history of psoriasis.320
TABLE 18-2
215
Section 4
::
216
Figure 18-15 Nail psoriasis. Panel A demonstrates distal onycholysis and oil drop spotting. Panel B demonstrates nail pitting. Panel C demonstrates subungual hyperkeratosis. Panel D demonstrates onychodystrophy and loss of nails in a patient with psoriatic arthritis. (Photos used with permission from Drs. Johann
Gudjonsson and Allen Bruce, and Mr. Harrold Carter.)
anonychia can be seen in other forms of pustular psoriasis.
GEOGRAPHIC TONGUE. (See also Chapter 76).

Geographic tongue, also known as benign migratory
glossitis or glossitis areata migrans, is an idiopathic inflammatory disorder resulting in the local loss of filiform papillae. The condition usually presents as asymptomatic erythematous patches with serpiginous
borders, resembling a map. These lesions characteristically have a migratory nature. Geographic tongue has
been postulated to be an oral variant of psoriasis, as
these lesions show several histologic features of psoriasis, including acanthosis, clubbing of the rete ridges,
focal parakeratosis, and neutrophilic infiltrate. In addition, the prevalence of geographic tongue is increased
in psoriatic patients.326 However, geographic tongue
is a relatively common condition and is seen in many
nonpsoriatic individuals, so its relationship to psoriasis needs further clarification.
PSORIATIC ARTHRITIS. Arthritis is a common extracutaneous manifestation of psoriasis seen in up to
40% of patients. It has a strong genetic component, and
several overlapping subtypes exist. This condition is
discussed in Chapter 19.
LABORATORY TESTS
Although histopathologic examination is rarely necessary to make the diagnosis, it can be helpful in difficult cases. The histopathologic findings of guttate and
chronic plaque psoriasis have already been described
(see Section Development of Lesions). In early
lesions of pustular psoriasis, the epidermis is usually
only slightly acanthotic, whereas psoriasiform hyperplasia is seen in older and persistent lesions. Neutrophils migrate from dilated vessels in the upper dermis
into the epidermis where they aggregate beneath the
stratum corneum and in the upper Malpighian layer to
form the spongiform pustules of Kogoj.
Other laboratory abnormalities in psoriasis are usually not specific and may not be found in all patients. In
severe psoriasis vulgaris, generalized pustular psoriasis,
and erythroderma, a negative nitrogen balance can be
detected, manifested by a decrease of serum albumin.327
Psoriasis patients manifest altered lipid profiles,
even at the onset of their skin disease.328 Patients had
15% higher levels of high-density lipoproteins, and
their cholesteroltriglyceride ratio for very low-density lipoprotein particles was 19% higher. Furthermore, plasma apolipoprotein-A1 concentrations were
(Box 18-1)
COMPLICATIONS
Patients with psoriasis have an increased morbidity
and mortality from cardiovascular events, particularly
those with severe and long duration of psoriasis skin
disease.330,331 Risk of myocardial infarction is particularly elevated in younger patients with severe psoriasis.289 In a recent study of 1.3 million German health
care recipients, metabolic syndrome was 2.9-fold more
frequent among psoriatic patients, and the most common diagnoses were hypertension (35.6% in psoriasis vs. 20.6% in controls) and hyperlipidemia (29.9%
vs. 17.1%). The frequencies of rheumatoid arthritis
Psoriasis
Immunostaining techniques, fluorescence-activated

cell sorting of dissociated cell suspensions, and assessment of T-cell receptor gene rearrangements have been
::
SPECIAL TESTS
of major importance in elucidating the pathogenesis

of psoriasis and in characterizing the response to antipsoriatic therapies but are generally not required for
diagnosis or management.
Chapter 18
11% higher in psoriasis patients. Whether these differences in lipid profile can explain or are contributing
to an increased incidence of cardiovascular events in
psoriasis remains to be seen.
Serum uric acid is elevated in up to 50% of patients
and is mainly correlated with the extent of lesions and
the activity of disease. There is an increased risk of
developing gouty arthritis. Serum uric acid levels usually normalize after therapy.
Markers of systemic inflammation can be increased,
including C-reactive protein, 2-macroglobulin, and
erythrocyte sedimentation rate. However, such elevations are rare in chronic plaque psoriasis uncomplicated by arthritis. Increased serum immunoglobulin
(Ig) A levels and IgA immune complexes, as well as
secondary amyloidosis, have also been observed in
psoriasis, and the latter carries a poor prognosis.329
Box 18-1 Differential Diagnosis of Psoriasis

Psoriasis Vulgaris
Guttate
Most Likely
Discoid/nummular eczema
Cutaneous T-cell lymphoma (CTCL)
Tinea corporis
Most Likely
Most Likely
Pityriasis rosea
Drug-induced
erythroderma
Pityriasis lichenoides
chronica
Eczema
Lichen planus
CTCL/Szary
syndrome
Consider
Pityriasis rubra
Small plaque
pilaris
parapsoriasis
PLEVA
Lichen planus
Drug eruption
Consider
Pityriasis rubra pilaris
Subacute cutaneous lupus
erythematosus
Erythrokeratoderma (the fixed
plaques of keratoderma variabilis
and/or progressive symmetric
erythrokeratoderma)
Inflammatory linear verrucous
epidermal nevus
Contact dermatitis
Chronic cutaneous lupus
erythematosus/discoid lupus
erythematosus
HaileyHailey disease (flexural)
Intertrigo (flexural)
Candida infection (flexural)
Always Rule Out

Secondary syphilis
Erythrodermic Pustular
Most Likely
Impetigo
Superficial candidiasis
Reactive arthritis syndrome
Superficial folliculitis
Consider
Pemphigus foliaceus
Immunoglobulin A
pemphigus
SneddonWilkinson
disease (subcorneal
pustular dermatosis)
Migratory necrolytic
erythema
Transient neonatal pustular
melanosis
Acropustulosis of infancy
Acute generalized
exanthematous pustulosis
Always Rule Out

Bowens disease/squamous cell
carcinoma in situ
Extramammary Pagets disease
217
Section 4
::
[prevalence ratio (PR) 3.8], Crohns disease (PR 2.1),

and ulcerative colitis (PR 2.0) were also increased.2
Psoriasis remained associated with after controlling for
age, sex, smoking status, obesity, diabetes, and NSAID
use.332 Psoriasis patients have also been shown to have
increased relative risk of both Hodgkin lymphoma and
cutaneous T-cell lymphoma, especially in patients with
more severe disease.333
Psoriasis is emotionally disabling, carrying with it
significant psychosocial difficulties. Emotional difficulties arise from concerns about appearance, resulting in
lowered self-esteem, social rejection, guilt, embarrassment, emptiness, sexual problems, and impairment of
professional ability.334 The presence of pruritus and pain
can aggravate these symptoms. Psychological aspects
can modify the course of illness; in particular, feeling
stigmatized can lead to treatment noncompliance and
worsening of psoriasis.335 Likewise, psychological stress
can also lead to depression and anxiety.336 The prevalence of suicidal ideation and depression in patients with
psoriasis is higher than that reported in other medical
conditions and the general population.337 Thus, although
the disease is not threatening to life itself, psoriasis can
very significantly impair quality of life.338 A comparative
study reported reduction in physical and mental functioning comparable with that seen in cancer, arthritis,
hypertension, heart disease, diabetes, and depression.339
According to a recent survey, 79% of patients with severe
psoriasis reported a negative impact on their lives.340

COURSE
NATURAL HISTORY
297
Guttate psoriasis is often a self-limited disease, lasting

from 12 to 16 weeks without treatment.297 It has been estimated that one-third to two-thirds of these patients later
develop the chronic plaque type of psoriasis.5,234 In contrast, chronic plaque psoriasis is in most cases a lifelong
disease, manifesting at unpredictable intervals. Spontaneous remissions, lasting for variable periods of time, may
occur in the course of psoriasis in up to 50% of patients.
The duration of remission ranges from 1 year to several
decades. In two separate studies, remission ranged from
17% to 55%. In another study of patients followed for 21
years, 71% had persistent lesions, 13% were free of the
disease, and 16% had intermittent lesions.297 The cause
of spontaneous remission is unknown, but could reflect
successful generation of self-tolerance under the model
of immunologic self-reactivity discussed earlier (see Section Psoriasis as an Autoimmune Disease).
Erythrodermic and generalized pustular psoriasis
have a poorer prognosis, with the disease tending to
be severe and persistent.297
MODIFYING FACTORS
218
OBESITY. It has been demonstrated that obese indi-
viduals are more likely to present with severe psoriasis
(defined as >20% body surface area involvement).341

However, obesity does not appear to have a role in defining the onset of psoriasis.341
SMOKING. Smoking (more than 20 cigarettes daily)

has also been associated with more than a twofold
increased risk of severe psoriasis.342 Unlike obesity,
smoking appears to have a role in the onset of psoriasis.341 Recently, a geneenvironment interaction has
been identified between low activity of the cytochrome
P450 gene CYP1A1 and smoking in psoriasis.343
INFECTION. An association between streptococcal
throat infection and guttate psoriasis has been repeatedly confirmed.300,343 Streptococcal throat infections
have also been demonstrated to exacerbate preexisting
chronic plaque psoriasis.227
Severe exacerbation of psoriasis can be a manifestation of human immunodeficiency virus (HIV)
infection.345 Like psoriasis in general, HIV-associated
psoriasis has a strong association with HLA-Cw6.345
Interestingly, the prevalence of psoriasis in HIV infection is no higher than in the general population (1%
2% of patients),346,347 indicating that this infection is not
a trigger for psoriasis but rather a modifying agent.
Psoriasis is increasingly more severe with progression
of immunodeficiency but can remit in the terminal
phase.348,349 This paradoxical exacerbation of psoriasis
may be due to loss of regulatory T cells and increased
activity of the CD8 T-cell subset.300 Psoriasis exacerbation in HIV disease may be effectively treated with
antiretroviral therapy.350 Psoriasis has also been associated with hepatitis C infection.351
DRUGS. Medications that exacerbate psoriasis include antimalarials, blockers, lithium, nonsteroidal
anti-inflammatory drugs, IFNs- and -, imiquimod,
angiotensin-converting enzyme inhibitors, and gemfibrozil.352 Imiquimod acts on pDCs and stimulates IFN production,147 which then strengthens both innate
and Th1 immune responses. Exacerbations and onset
of psoriasis have been described in patients receiving
TNF inhibitor therapy. The majority of these cases are
palmoplantar pustulosis, but about one-third develop
chronic plaque psoriasis.353 Lithium has been proposed
to cause exacerbation by interfering with calcium release within keratinocytes, whereas blockers are
thought to interfere with intracellular cyclic adenosine
monophosphate levels.352 The mechanisms by which
the remaining medications exacerbate psoriasis are
largely unknown. Patients with active or unstable psoriasis should receive advice when traveling to countries where antimalarial prophylaxis is needed.
TREATMENT
GENERAL CONSIDERATIONS
A broad spectrum of antipsoriatic treatments, both
topical and systemic, is available for the management of psoriasis. As detailed in Tables 18-318-6, it
TABLE 18-3
Topical Treatments for Psoriasis359

Topical Steroids
Vitamin D
Analogs
Tazarotene
Calcineurin Inhibitors
Bind to vitamin
D receptors,
influencing the
expression of many
genes. Promote
keratinocyte
differentiation.
Metabolized to tazarotenic
acid, its active metabolite,361
which binds to retinoic
acid receptors. Normalizes
epidermal differentiation,
exhibits a potent
antiproliferative effect,
and decreases epidermal
proliferation.
Bind to FK506-binding protein

(FKBP) and inhibit calcineurin,
decreasing the activation of the
transcription factor, NF-AT, with
resultant decrease in cytokine
transcription, including IL-2.
Dosing
10,000-fold range
of potency. Highpotency steroids are
applied to affected
areas twice daily
for 24 weeks and
then intermittently
(weekends).
Calcipotriene,
0.005%, to affected
areas twice
daily. Often used
alternating with
topical steroids (i.e.,
vitamin D analogs
on weekdays,
topical steroids on
weekends).
Available in 0.05% and 0.1%

formulations, both as cream
and gels. Apply every night
to affected area.
Application to affected areas

twice daily.
Efficacy
Very effective
as short-term
treatment.
Efficacy is increased
by combination
with topical steroids.
Can be combined
with various other
therapies.
Efficacy is increased by
combination with topical
steroids.361
Effective for treatment of facial

and flexural psoriasis269 but
minimally for chronic plaque
psoriasis.268
Safety
Suppression of the
hypothalamic
pituitaryadrenal
axis (higher risk in
children). Atrophy
of the epidermis
and dermis.
Formation of striae.
Tachyphylaxis.258
Development of
irritation at the
site of application
is common.258
Isolated reports
of hypercalcemia
in patients who
applied excessive
quantities.363
When used as monotherapy,

significant proportion of
patients develop irritation at
the site of application.364
Burning sensation at the site

of application. Case reports of
development of lymphoma.
Contraindications
Hypersensitivity to
the steroid, active
skin infection.
Hypercalcemia,
vitamin D toxicity.
Pregnancy, hypersensitivity
to tazarotene.
Use only with caution for

treatment of children younger
than the age of 2 years.
Remarks/longterm use
Long-term use
increases risk of side
effects.
Calcipotriol is well
tolerated and
continues to be
clinically effective
with minimum of
adverse effects in
long-term use.365,366
Combination of steroid
with tazarotene may
reduce atrophy seen
with superpotent topical
steroids.362 If added during
phototherapy, the ultraviolet
doses should be reduced by
one-third.258
Due to anecdotal reports of

association with malignancy,
this class of medications
recently received a black-box
warning by the US Food and
Drug Administration.
Pregnancy
category
::
Bind to
glucocorticoid
receptors, inhibiting
the transcription
of many different
AP-1- and NF-Bdependent genes,
including IL-1 and
TNF-.
Chapter 18
Mechanism of
action
Psoriasis
AP = activator protein; IL = interleukin; NF = nuclear factor; NF-AT = nuclear factor of activated T cells.
is notable that most if not all of these treatments are

immunomodulatory. When choosing a treatment
regimen (see Fig. 18-6) it is important to reconcile the
extent and the measurable severity of the disease with
the patients own perception of his or her disease. In
this context, it is notable that a recent study found that

40% of patients felt frustrated with the ineffectiveness
of their current therapies, and 32% reported that treatment was not aggressive enough.350 As psoriasis is a
chronic condition, it is important to know the safety
219
TABLE 18-4
Phototherapy of Psoriasis385
Psoralen and UVA
Light (PUVA)
Excimer Laser
(308 nm)
Dosing
Dosage based on either

the Fitzpatrick skin type or
MED. Determine MED. Initial
treatment at 50% of MED
followed by three to five
treatments weekly. Lubricate
before treatment. Treatments
120; increase by 10% of
initial MED. Treatments
21; increase as ordered by
physician.385
Maintenance therapy after
>95% clearance:
1/week for 4 weeks, keep
dose the same
1/2 weeks for 2 weeks,
decrease dose by 25%
1/4 weeks, 50% of highest
dose.385
The dosage may be

administered according
to the Fitzpatrick skin
type.437 Initial treatment
at 50% of MED followed
by three to five
treatments weekly.
Treatment 110 increase
dose by 25% of initial
MED.
Treatments 1120;
increase by 10% of initial
MED. Treatments 21;
increase as ordered by
physician.385
Dose based on MPD is

recommended. If MPD testing
is impractical, a regimen
based on skin type may be
used. Initial dose 0.52.0
J/cm2, depending on skin
type (or MPD). Treat twice
weekly, increments of 40%
per week until erythema, then
maximum 20% per week. No
further increments once 15 J/
cm2 is reached.369
The dose of energy

delivered is guided
by the patients skin
type and thickness of
plaque. Further doses
are adjusted based on
response to treatment
or development of side
effects.385 Treatment
usually given twice
weekly.
Efficacy
>70% improvement in a split

body study after 4 weeks
of treatment. Nine out of
eleven patients showed
clearance.368 More effective
than BB-UVB.274,275,368
47% improvement in a
split body study after
4 weeks, only 1 out of
11 patients showed
clearance.367
Induces remission in 70%

90% of patients.370373 Less
convenient than NB-UVB but
may be more effective.278
High response rates.

In one study, 85% of
patients showed a 90%
improvement in PASI
after average 7.2 weeks
of treatment438 While in
another study showed
greater than 75%
improvement in 72% of
patients in an average of
6.2 treatments.439
Safety
Photodamage, polymorphic
light eruption, increased
risk of skin aging and skin
cancers although lower than
that for PUVA.374
Photodamage,
polymorphic light
eruption, increased risk
of skin aging and skin
cancers.
Photodamage, premature
skin aging, increased
risk of melanoma and
nonmelanoma skin cancers,
ocular damage. Eye
protection required with oral
psoralens.
Erythema, blisters,
hyperpigmentation and
erosions. Long-term side
effects not yet clear but
likely similar to NB-UVB.
Contraindications
Absolute:
Photosensitivity disorders.
Absolute:
Photosensitivity
disorders.
Relative:
Photosensitizing
medications, melanoma,
and nonmelanoma skin
cancers.
Absolute:
Light-sensitizing disorder,
lactation, melanoma.
Relative:
Age <10 years, pregnancy,
photosensitizing medications,
nonmelanoma skin cancers,
severe organ dysfunction.
Absolute:
Photosensitivity
disorders.
Relative:
Photosensitizing
cancers.
Coal tar (Goeckerman

regimen), anthralin
(Ingram regimen), or
systemic therapies may
increase effectiveness in
resistant cases.
<200 total treatments

(or <2000 J/cm2 UVA)
are recommended.375
Combination with oral
retinoids can reduce
cumulative UVA exposure.
Normal skin is spared

from unnecessary
radiation exposure, as
therapy is selectively
directed toward lesional
skin.283
Section 4
Narrowband UVB
Broadband UVB
(NB-UVB; 310331 nm) (BB-UVB)
::
Relative:
Photosensitizing
cancers.
Remarks
Effective as a monotherapy,
but coal tar (Goeckerman
regimen), anthralin (Ingram
regimen), or systemic
therapies may increase
effectiveness in resistant
cases.367
MED = minimal erythema dose; MPD = minimal phototoxic dose; UVB = ultraviolet B; PASI = Psoriasis Area and Severity Index; UVA = ultraviolet A.
220
TABLE 18-5
Systemic Treatments for Psoriasis390,398

Acitretin
Fumaric Acid Esters
Mechanism of
action
Binds cyclophilin, and the

resulting complex blocks
calcineurin, reducing
the effect of the NF-AT
in T cells, resulting in
inhibition of IL-2 and other
cytokines.
Blocks dihydrofolate
reductase, leading to
inhibition of purine and
pyrimidine synthesis.
Also blocks AICAR
transformylase, leading
to accumulation of antiinflammatory adenosine.376
Binds to retinoic
acid receptors.
May contribute
to improvement
by normalizing
keratinization and
proliferation of the
epidermis.
Interferes with intracellular

redox regulation, inhibiting
NF-B translocation. Skews the
T-cell response toward a Th2like pattern.377
Dosing
High-dose approach:
5 mg/kg daily, then
tapered.
Low-dose approach:
2.5 mg/kg daily,
increased every 24
weeks up to 5 mg/
kg daily.378 Tapering
is recommended on
discontinuation.
Start with a test dose of

2.5 mg and then gradually
increase dose until a
therapeutic level is achieved
(average range, 1015 mg
weekly; maximum, 2530
mg weekly).378
Initiate at 2550 mg
daily and escalate
and titrate to
response.378
Initiate at low dose, and

escalate dose weekly. After
treatment response is achieved,
the dose should be individually
adjusted. The maximum dose is
1.2 g/day.300
Efficacy
Very effective, up to
90% of patients achieve
clearance or marked
improvement.379,380
May reduce the severity

of psoriasis by at least
50% in more than 75% of
patients.261
Modestly effective as
monotherapy.261
80% Mean reduction in Psoriasis

Area and Severity Index.381
Safety
Nephrotoxicity, HTN,
immunosuppression.
Increased risk of
malignancy if before
PUVA.
Hepatotoxicity, chronic
use may lead to hepatic
fibrosis. Fetal abnormalities
or death, myelosuppression,
pulmonary fibrosis, severe
skin reactions. Rarely, severe
opportunistic infections.
Hepatotoxicity,
lipid abnormalities,
fetal abnormalities
or death, alopecia,
mucocutaneous
toxicity, hyperostosis.
GI symptoms, including
diarrhea. Flushing headaches.
Lymphopenia, acute renal
failure.300,381
Monitoring
BP. Obtain baseline CBC,

CMP, magnesium, uric
acid, lipids, UA. Repeat
tests every 24 weeks,
then every month along
with BP.286
Baseline CBC and LFTs.

Monitor CBC and LFTs
weekly until target dose is
achieved, then every 48
weeks.286 Liver biopsy every
1.5 g (high risk) to every 3.5
4.0 g (low risk) of cumulative
dose or use procollagen III
assay.
Baseline LFTs, CBC,

lipids, pregnancy test.
Repeat LFTs, CBC,
lipids every week for
1 month then every
4 weeks. Pregnancy
test every month for
females. Spinal X-rays
if symptoms.
Baseline CBC, CMP, UA. Repeat

tests every month for the
first 6 months and bimonthly
thereafter.300
Contraindications
Absolute:
Uncontrolled HTN,
abnormal renal
function, history/current
malignancy.
Absolute:
Pregnancy, lactation,
bone marrow dysfunction,
alcohol abuse.390
Relative:
Hepatic dysfunction,
hepatitis, renal
insufficiency, severe
infections, reduced lung
function
Absolute:
Pregnancy during
or within 3 years
after termination
of acitretin,
breastfeeding.
Absolute:
Patients with chronic disease
of the GI tract or renal disease.
Pregnant or lactating women.
Malignancy (or history of ).300
Intermittent short-course
treatments appear to be
safer than chronic longterm use.380,382
With appropriate
monitoring, long-term use
appears to be safe.
Retinoids have been

combined with PUVA
and occasionally with
UVB in an attempt
to minimize the
side effects and to
improve therapeutic
response.261
Not US Food and Drug

Administration-approved for
psoriasis but widely used in
Europe. New formulations may
reduce risk of GI symptoms.
Pregnancy
category
::
Methotrexate
Chapter 18
Cyclosporine A
Psoriasis
221
(continued)
TABLE 18-5
Systemic Treatments for Psoriasis (Continued)
Section 4
6-Thioguanine
Mechanism of
action
Inhibits ribonucleotide
diphosphate reductase,
which converts
ribonucleotides to
deoxyribonucleotides,
thus selectively inhibiting
DNA synthesis in
proliferating cells.
Purine analog that interferes

with purine biosynthesis,
thereby inducing cell cycle
arrest and apoptosis.
A noncompetitive
inhibitor of inosine
monophosphate
dehydrogenase,
blocking de novo
purine biosynthesis.
Selectively cytotoxic
for cells that rely
on de novo purine
synthesis (i.e.,
lymphocytes).
Anti-inflammatory agent,
inhibits 5-lipoxygenase,
molecular mechanism unclear.
Dosing
500 mg daily, increased to

1.01.5 g daily based on
response and tolerance.286
Starting dose is 80 mg
twice weekly, with 20-mg
increments every 24
weeks. Maximum dose, 160
mg three times weekly.286
Doses often initiated

at 500 750 mg bid
and then increased to
1.01.5 g bid.
Starting dose: 500 mg tid. If

tolerated after 3 days, increase
dose to 1 g tid. If tolerated after
6 weeks, increase dose to 1 g
qid.286
Efficacy
In a study of 85 patients
with extensive chronic
plaque psoriasis, 61% had
satisfactory remission.383
A small retrospective cohort

study demonstrated >90%
improvement in up to 80%
of patients.306
Appears to be only
moderately effective
for treatment of
psoriasis.381,382
Appears to be moderately
effective treatment for severe
psoriasis.386
Safety
Bone marrow suppression,

macrocytosis.
Teratogenicity
and mutagenicity.
Dermatologic side
effects: lichen planus-like
eruptions, exacerbation
of postirradiation
erythema, leg ulcers, and
dermatomyositis changes.
Bone marrow suppression;

GI complaints, including
nausea and diarrhea;
hepatic dysfunction.
Instances of hepatovenousocclusive disease have been
reported.306
GI, including
constipation,
diarrhea, nausea and
vomiting, bleeding.
Myelosuppression,
leukopenia.
Headaches, HTN,
peripheral edema.
Infectious disease,
lymphoma.
Headache, nausea, and

vomiting, which occur in
approximately one-third of
patients. Rashes, pruritus, and
hemolytic anemia (associated
with G6PD deficiency).
Monitoring
Baseline CBC, CMP, LFTs.

Repeat baseline tests
weekly for 4 weeks then
every 24 weeks for at
least 12 weeks. Then
repeat tests every 3
months.286 Hold dosage if
WBC <2.5 109/L, platelet
count is <100 109/L or
severe anemia.
Baseline CBC, CMP, LFTs.

Repeat baseline tests weekly
during dose escalation,
then every 2 weeks. Hold if
WBC 4.0 109/L, platelet
count is <125 109/L, or
hemoglobin <110 g/L.286
Baseline CBC
and CMP. Repeat
laboratory tests
weekly 6 weeks,
then every 2 weeks
2 months, and then
monthly. Monitor BP.
Baseline CBC, CMP, and G6PD.

Repeat CBC and CMP weekly for
1 month, then every 2 weeks
for 1 month, then monthly for
3 months, and then every 3
months.
Contraindications
Absolute:
Prior bone marrow
depression (leukopenia,
thrombocytopenia,
anemia), pregnancy,
lactation.
Relative:
Renal abnormalities.
Absolute:
Patients with inherited
deficiency of thiopurine
methyltransferase enzyme
have increased risk of
myelosuppression. Liver
toxicity. Pregnancy.
Absolute:
Patients with
severe infections,
malignancy.286
Absolute:
Hypersensitivity to
sulfasalazine, sulfa drugs,
salicylates, intestinal
or urinary obstruction,
porphyria. Precaution
in patients with G6PD
deficiency.
Limited experience with

long-term treatment.
Patients have been

effectively maintained
on treatment for up to 33
months.387
Limited experience
with long-term
treatment.
Limited experience with longterm treatment.
Pregnancy
category
::
222
Mycophenolate
Mofetil
Hydroxyurea
Sulfasalazine
AICAR = 5-Aminoimidazole-4-carboxamide ribonucleotide; BP = blood pressure; CBC = complete blood cell count; CMP = comprehensive metabolic
panel; G6PD = glucose-6-phosphate dehydrogenase; GI = gastrointestinal; HTN = hypertension; LFTs = liver function tests; NF = nuclear factor;
NF-AT = nuclear factor of activated T cells; PUVA = psoralen and UVA light; Th = T helper; UA = urinalysis; UV = ultraviolet; WBC = white blood cell
count.
TABLE 18-6
Combination Treatments for Psoriasis

Topical
Vitamin
D3
Topical
Cortico
steroids
Etaner
cept440,441
Psoralen
and UVA Metho
Light
trexate
(PUVA)
(MTX)
Dithranol
Tazarotene
Ultraviolet
B (UVB)
++
++
++
++
MTX
PUVA
++
++
UVB
+/++
+/++
+/++
++
Tazarotene
++
Coal tar
+/++
Dithranol
::
++
Chapter 18
Acitretin
CsA
Psoriasis
Topical
cortico
steroids
Cyclo
sporine
A (CSA)
Coal
Tar
+/++
= contraindicated combination; = insufficient evidence; + = recommended combination; ++ = strongly recommended combination. Blank boxes are
represented elsewhere in the table.
Reasons for contraindicated combinations: CsA with PUVA; increased risk of squamous cell carcinoma. Coal tar with PUVA, severe phototoxic responses.
Acitretin with MTX, hepatotoxicity.
Adapted from van de Kerkhof PC: Therapeutic strategies: Rotational therapy and combinations. Clin Exp Dermatol 26:356, 2001, with permission.
of a treatment during long-term use. In most treatments, the duration of a treatment is restricted because
of the cumulative toxicity potential of an individual
treatment, and, in some instances, treatment efficacy
may diminish with time (tachyphylaxis). Some treatments, such as calcipotriol, MTX, and acitretin, can be
regarded as appropriate for continuous use.354 These
treatments maintain efficacy and have low cumulative
toxicity potential. In contrast, topical corticosteroids,
dithranol, tar, photo(chemo) therapy, and cyclosporine
are not indicated for continuous chronic use, and combinatorial or rotational treatments354 are suggested.
However, patients with stable chronic plaque psoriasis
who respond well to local treatments may not require
a change of treatment.354 In cases of itchy/pruritic psoriasis, treatments with an irritative potential, such as
dithranol, vitamin D3 analogs, and photo(chemo) therapy, should be used cautiously, whereas treatments
with potent anti-inflammatory effects, such as topical
corticosteroids, are more appropriate.354
In patients with erythrodermic and pustular psoriasis,
treatments with an irritant potential should be avoided,
and acitretin, MTX, or short-course cyclosporine are the
treatments of first choice.354 See Boxes 18-2 and 18-3 for
special considerations in the treatment of women of
child-bearing potential and pregnancy and children.
TOPICAL TREATMENTS
(See Table 18-3.)355,356
Most cases of psoriasis are treated topically. As topical treatments are often cosmetically unacceptable and
time-consuming to use, noncompliance is on the order
of 40%.357 In most cases, ointment formulations are more
effective than creams but are less cosmetically acceptable. For many patients, it is worth prescribing both
cream and ointment formulations; cream for use in the
morning and ointment for nighttime.358 Topical agents
are also used adjunctively for resistant lesions in patients
with more extensive psoriasis and who are concurrently
being treated with either UV light or systemic agents.359
It is worth noting that around 400 g of a topical agent
is required to cover the entire body surface of an average-sized adult when used twice daily for 1 week.360
CORTICOSTEROIDS. Glucocorticoids exert many

if not all of their myriad effects by stabilizing and causing nuclear translocation of glucocorticoid receptors,
which are members of the nuclear hormone receptor
superfamily. Topical glucocorticoids are commonly
first-line therapy in mild to moderate psoriasis and
in sites such as the flexures and genitalia, where other
topical treatments can induce irritation. Improvement
is usually achieved within 24 weeks, with maintenance treatment consisting of intermittent applications (often restricted to the weekends). Tachyphylaxis
to treatment with topical corticosteroids is a wellestablished phenomenon in psoriasis.361 Long-term
topical corticosteroids may cause skin atrophy, telangiectasia, striae (Fig. 18-16D) and adrenal suppression.
223
Section 4
::
224
Box 18-2 Treatment of Women

of Child-Bearing Potential and
during Pregnancy
Special caution needs to be exercised when treating women of child-bearing potential and during
pregnancy.
Medications such as methotrexate and oral retinoids
should be avoided or used with extreme caution and
then only along with appropriate contraception.
In selected cases, isotretinoin rather than acitretin
may be the preferred agent due to its much shorter
half-life.
As methotrexate is fetotoxic and an abortifactant and
retinoids are potent teratotoxins, the use of these
agents is absolutely contraindicated in pregnancy.
Many women experience improvement or remission during periods of pregnancy, thus decreasing
the need for the more potent agents.
If treatment is needed, emollients and other topical agents are first-line agents, often in association
with ultraviolet B phototherapy.
Many of the topical agents, such as topical steroids
and calcipotriene, are pregnancy category C agents,
and caution should be exercised with their use.
Several of the biologic agents are category B and
can be used in pregnancy. Likewise, cyclosporine
A may be considered, as it is pregnancy category C
and is nonteratogenic.
Systemic psoralen and ultraviolet A light (PUVA)
has been used on occasion in selected cases and
appears to be safe.
Another concern is that when topical steroids are discontinued, patients may rebound, sometimes worse
than it was prior to treatment.359 This class of agents is
discussed in detail in Chapter 216.
VITAMIN D3 AND ANALOGS.362 Vitamin D ex-
erts its actions by binding to the vitamin D receptor,

another member of the nuclear hormone receptor superfamily. Vitamin D3 acts to regulate cell growth, differentiation, and immune function, as well as calcium
and phosphorous metabolism. Vitamin D has been
shown to inhibit the proliferation of keratinocytes in
culture and to modulate epidermal differentiation.
Furthermore, vitamin D inhibits production of several
proinflammatory cytokines by psoriatic T-cell clones,
including IL-2 and IFN-.363
Analogs of vitamin D that have been used for the treatment of skin diseases are calcipotriene (also known as
calcipotriol), tacalcitol, and maxacalcitol. In short-term
studies, potent topical corticosteroids were found to be
superior to calcipotriene. When compared with shortcontact anthralin or 15% coal tar, calcipotriene was the
more effective agent. The efficacy of calcipotriene is
Box 18-3 Treatment of Children

Children represent a large fraction of psoriasis
patients, as the disease commonly presents during
childhood or adolescence.
As for adults, first-line treatment is with topical
agents, often in association with ultraviolet B
phototherapy.
Due to its carcinogenic risk and opportunity for
long-term exposure, psoralen and ultraviolet A
light is generally contraindicated in childhood.
Likewise, the decision to treat with systemic agents
should be carefully assessed, as the long-term
potential side effect profile of many of the systemic
agents is still unknown. However, many of the systemic agents have been used successfully in severe
recalcitrant cases.
not reduced with long-term treatment.364 Calcipotriene

applied twice daily is more effective than once-daily
use. Hypercalcemia is the only major concern with
the use of topical vitamin D preparations. When the
amount used does not exceed the recommended 100 g/
week, calcipotriene can be used with a great margin of
safety.365 Vitamin D analogs are often used in combination with or in rotation with topical corticosteroids in
an effort to maximize therapeutic effectiveness while
minimizing steroid-related skin atrophy.
ANTHRALIN (DITHRANOL). Dithranol (1,8dihydroxy-9-anthrone) is a naturally occurring substance found in the bark of the araroba tree in South
America. It can also be synthesized from anthrone. Dithranol is made up in a cream, ointment, or paste. Dithranol is approved for the treatment of chronic plaque
psoriasis. Its most common use has been in the treatment of psoriasis, particularly on plaques resistant to
other therapies. It can be combined with UVB phototherapy with good results (the Ingram regimen). Most
common side effects are irritant contact dermatitis and
staining of clothing, skin, hair, and nails. Anthralin
possesses antiproliferative activity on human keratinocytes along with potent anti-inflammatory effects.
Classic anthralin therapy starts with low concentrations (0.05%0.1%) incorporated in petrolatum or zinc
paste and given once daily. To prevent autooxidation,
salicylic acid (1%2%) should be added. The concentration is increased weekly in individually adjusted increments up to 4% until the lesions resolve. Scalp psoriasis should be treated with great caution as anthralin
can stain hair purple to green.
COAL TAR. The use of tar to treat skin diseases dates
back nearly 2000 years. In 1925, Goeckerman introduced the use of crude coal tar and UV light for the
treatment of psoriasis. Tar is the dry distillation product of organic matter heated in the absence of oxygen.
Its mode of action is not understood, and, because of
Chapter 18
::
Psoriasis
Figure 18-16 Positive and negative outcomes of psoriasis treatment. Panel A illustrates nearcomplete improvement of psoriasis after 10 weeks of infliximab therapy. Panel B illustrates
marked improvement after 28 days of oral cyclosporine A treatment. Panel C illustrates marked
reduction in nail dystrophy after 16 weeks of cyclosporine A treatment. Panel D illustrates severe
atrophy with striae distensae after several years of treatment with potent topical steroid creams.
(Photos used with permission from Mr. Harrold Carter.)
its inherent chemical complexity, tar is not pharmacologically standardized. It was recently suggested
that carbazole, a coal-derived chemical, is the main
active ingredient in tar.366 Tar appears to exert its action through suppression of DNA synthesis and consequent reduction of mitotic activity in the basal layer
of the epidermis, and some components in tar appear
to have anti-inflammatory activity. Coal tar, in concentrations up to 20% (5%20%) can be compounded in
creams, ointments, and pastes. It is often combined
with salicylic acid (2%5%), which by its keratolytic
action leads to better absorption of the coal tar.297 Occasionally, patients become sensitive to the coal tar and
develop allergic reactions. A folliculitis may occur after
the use of coal tar. Furthermore, it has an unwelcome
smell and appearance and can stain clothing and other
items. Coal tar is carcinogenic.
TAZAROTENE. Tazarotene is a third-generation

retinoid for topical use that reduces mainly scaling
and plaque thickness, with limited effectiveness on
erythema. It is thought to act by binding to retinoic
acid receptors, but its molecular targets are unknown.
It is available in 0.05% and 0.1% gels, and a cream formulation has been developed. When this drug is used
as a monotherapy, a significant proportion of patients
develop local irritation. This retinoid dermatitis is
worse with the 0.1% formulation. Efficacy of this drug
can be enhanced by combination with mid- to highpotency glucocorticoids or UVB phototherapy. When
used in combination with phototherapy, it lowers the
minimal erythema dose (MED) for both UVB and UVA.
It has been recommended that UV doses be reduced by
at least one-third if tazarotene is added in the middle
of a course of phototherapy.367
225
TOPICAL CALCINEURIN INHIBITORS.
Section 4
::
(See
Chapter 221.) Tacrolimus (FK-506) is a macrolide antibiotic, derived from the bacteria Streptomyces tsukubaensis that, by binding to immunophilin (FK506binding protein), creates a complex that interacts and
inhibits calcineurin, thus blocking both T-lymphocyte
signal transduction and IL-2 transcription. Pimecrolimus is also a calcineurin inhibitor and works in a manner similar to tacrolimus and CsA.
In a study of 70 patients with chronic plaque psoriasis treated with topical tacrolimus, there was no
improvement beyond that seen for placebo.368 However, for treatment of inverse and facial psoriasis, these
agents appear to provide effective treatment.369,370 The
main side effect of these medications is a burning sensation at application site. Anecdotal reports of lymph
node or skin malignancy require further evaluation in
controlled studies, and these drugs have a US Food
and Drug Administration (FDA) black-box warning.
SALICYLIC ACID. (See also Chapter 222.) Salicylic

acid is a topical keratolytic agent. Its mechanism of action includes reduction of keratinocyte adhesion and
lowering the pH of the stratum corneum. This results
in reduced scaling and softening of the plaques,371
thereby enhancing absorption of other agents. Therefore, salicylic acid is often combined with other topical
therapies such as corticosteroids and coal tar. Topical
salicylic acid decreases the efficacy of UVB phototherapy359 and systemic absorption can occur, particularly in
patients with abnormal hepatic or renal function and
when applied to more than 20% of the body surface
area. No placebo-controlled studies have been performed to verify the efficacy and safety of salicylic acid
as a monotherapy.359
BLAND EMOLLIENTS.
Between treatment periods, skin care with emollients should be performed to

avoid dryness. Emollients reduce scaling, may limit
painful fissuring, and can help control pruritus. They
are best applied immediately after bathing or showering. The addition of urea (up to 10%) is helpful to
improve hydration of the skin and remove scaling of
early lesions. The use of liberal bland emollients over a
thin layer of topical prescription treatments improves
hydration while minimizing treatment costs.
PHOTOTHERAPY372
226
(See Table 18-4) (See Chapters 237 and 238.)

Phototherapy of psoriasis with artificial light
sources dates back to 1925 when Goeckerman introduced a combination of topical crude coal tar and subsequent UV irradiation. In the 1970s, it was shown that
broadband UVB radiation alone, if given in doses that
produce a faint erythematous reaction, could clear the
milder clinical forms of psoriasis. Major steps forward
were the introduction of photochemotherapy with
psoralen and UVA light (PUVA) in the 1970s and narrow band UVB (311313 nm) in the 1980s.
The mechanism of action of phototherapy appears
to involve selective depletion of T cells, predominantly
those that reside in the epidermis.166,230 The mechanism

of depletion appears to involve apoptosis373 and is
accompanied by a shift from a Th1 immune response
toward a Th2 response in the lesional skin.374
ULTRAVIOLET B LIGHT (290320 nm). The

initial therapeutic UVB dose lies at 50%75% of the
MED. Treatments are given two to five times per
week. As peak UVB erythema appears within 24
hours of exposure, increments can be performed at
each successive treatment. The objective is to maintain
a minimally perceptible erythema as a clinical indicator of optimal dosing. Treatments are given until total
remission is reached or until no further improvement
can be obtained with continued treatment. The main
side effects of UVB phototherapy are summarized in
Chapter 237.
Narrowband (312 nm) UVB (NBUVB) phototherapy is
superior to conventional broadband UVB (290320 nm)
with respect to both clearing and remission times.375,376
Although early studies found NB-UVB to be as effective as psoralen and UVA light (PUVA),377,378 a recent
controlled trial found that PUVA was more effective,
albeit less convenient.379 On clearing, treatment is either
discontinued or patients are subjected to maintenance
therapy for 1 or 2 months. During this period, the frequency of UVB treatments is reduced while maintaining the last dose given at the time of clearing.372
Systemic drugs, such as retinoids, increase the efficacy of UVB light, particularly in patients with chronic
and hyperkeratosis plaque-type psoriasis.380,381 Because
they are known to inhibit carcinogenesis in experimental animals, retinoids may possibly reduce the carcinogenic potential of UVB phototherapy.
PSORALEN AND ULTRAVIOLET A LIGHT. (See
Chapter 238.) PUVA is the combined use of psoralens
(P) and long-wave ultraviolet A radiation (UVA).
The combination of drug and radiation results in a
therapeutic effect, which is not achieved by the single
component alone. Remission is induced by repeated
controlled phototoxic reactions. A detailed account of
PUVA therapy and its short-term and long-term side
effects is to be found in Chapter 238.
EXCIMER LASER.362 (See Chapter 239.) Supraery-
themogenic fluences of UVB and PUVA are known to

result in faster clearing of psoriasis,383 however, the limiting factor for the use of such high fluences lies with
the intolerance of the uninvolved surrounding skin
as psoriatic lesions can often withstand much higher
UV exposures.384 The monochromatic 308-nm excimer
laser can deliver such supraerythemogenic doses of
light (up to 6 MED, usually in the range of 26 MEDs)
to lesional skin, however, only focally. The dosing is
guided by the patients skin type and thickness of the
plaque with subsequent doses based on the response
to therapy or development of side effects.385 In a study
on 124 patients, 72% of study subjects achieved at least
75% clearing in an average of 6.2 treatments delivered
twice weekly.384 The role of this treatment seems to be
indicated for patients with stable recalcitrant plaques
particularly in the elbows and knee region.
PHOTODYNAMIC TREATMENT.386
(See Chapter 238.) Photodynamic therapy has been tried for several inflammatory dermatoses, including psoriasis. In
a randomized study on the effect of topical aminolevulinic acid-based photodynamic therapy, 29 patients
demonstrated unsatisfactory clinical response and frequent occurrence of pain during and after treatment,
prompting the authors to declare this as an inadequate
treatment option for psoriasis.
CLIMATIC THERAPY.387 It is well known that go-
METHOTREXATE. MTX is highly effective for

chronic plaque psoriasis389 and is also indicated for the
long-term management of severe forms of psoriasis,
including psoriatic erythroderma and pustular psoriasis.388 For mechanisms of action, see Chapters 227
and 233. When first used for the treatment of psoriasis,
MTX was thought to act directly to inhibit epidermal
hyperproliferation via inhibition of dihydrofolate reductase (DHFR). However, it was found to be effective
at much lower doses (0.10.3 mg/kg weekly) in the
management of psoriasis, psoriatic arthritis, and other
inflammatory conditions such as rheumatoid arthritis. At these concentrations, MTX inhibits the in vitro
proliferation of lymphocytes, but not proliferation of
keratinocytes.391 It is now thought that the inhibition of
DHFR is not the main mechanism of anti-inflammatory
action of MTX, but rather the inhibition of an enzyme
involved in purine metabolism [AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) transformylase].
This leads to accumulation of extracellular adenosine,
which has potent anti-inflammatory activities, particularly for neutrophils.392 Consistent with a DHFRindependent mechanism of action, concomitant administration of folic acid (15 mg/day) reduces certain
side effects, such as nausea and megaloblastic anemia,
without diminishing the efficacy of antipsoriatic treat-
Psoriasis
(See Table 18-5.)
::
SYSTEMIC ORAL AGENTS388390
Chapter 18
ing to a sunny climate can improve psoriasis, although

a small proportion of patients actually deteriorate. Patients should be warned not to overexpose themselves
in the first few days, as sunburn may actually progress
to psoriasis (Koebner phenomenon). The best-studied
effects are from the Dead Sea area, and those therapeutic effects may be attributed, at least partially, to the
unique climatic characteristic of that location. As it
is situated 400 m below sea level, the evaporation of
the sea forms an aerosol that stays in the atmosphere
above the sea and surrounding beaches. This aerosol
screens out the majority of the UVB rays but not the
UVA. This mixture of UV light appears to be sufficient
to clear psoriasis but without sunburn. Thus, patients
can stay on the shores of the Dead Sea for long periods of time with greatly reduced risk of sunburn. This
treatment is carried out over a period of 34 weeks,
and improvements comparable to NB-UVB or PUVA
treatments are observed. The main disadvantages of
this treatment are time and expense.
ment.393 The cellular targets of MTX action in psoriasis

are still under investigation, but its mechanism of action may involve modulation of adhesion molecules,
such as intercellular adhesion molecule 1, rather than
induction of lymphocyte apoptosis.394
The very long half-life of MTX may account for its
efficacy after weekly administration and may also help
to explain why its onset of action is rather slow (therapeutic effects usually require 48 weeks to become
evident). MTX is renally excreted and should therefore
not be administered to patients with impairment in
renal function, as MTX side effects are generally doserelated. Short-term toxicity and long-term concerns are
In the most recent guidelines395,396 it is suggested that
patients be divided into two separate groups based on
their risk factors for liver injury: the low-risk patients
follow the American College of Rheumatology (ACR)
guidelines and are not asked to undergo liver biopsy
until they have reached a cumulative MTX dose of 3.5
4.0 g. In contrast, those patients with one or more risk
factors continue to follow the previously published397
more stringent guidelines requiring baseline liver
biopsy either before treatment or after 26 months of
treatment, and then at each cumulative MTX dose of
1.01.5 g.395,398 The risk factors include current or past
alcohol consumption, persistent abnormalities of liver
function enzymes, personal, or family history of liver
disease, exposure to hepatotoxic drugs or chemicals,
diabetes mellitus, hyperlipidemia, and obesity.395
Some groups have recommended the use of amino
terminal type III procollagen peptide (PIIINP) assay
for screening of liver fibrosis.292 Specific guidelines
have been developed for monitoring PIIINP levels in
psoriatic patients,292 but the FDA has not yet approved
the use of this assay for diagnostic use within the
United States.
Another well-known side effect of MTX is myelosuppression, especially pancytopenia, which usually
occurs in the setting of folate deficiency. Leucovorin
calcium (folinic acid) is the only antidote for the hematologic toxicity of MTX. When an overdose is suspected, an immediate leucovorin dose of 20 mg should
be given parenterally or orally, and subsequent doses
should be given every 6 hours.399 Pneumonitis can
develop, and mucosal and skin ulcerations have also
been reported in patients treated with MTX.399,400
Discontinuation of MTX treatment is required in
the event of hepatotoxicity, hematopoietic suppression, active infections, nausea, and pneumonitis. MTX
is also teratogenic and should therefore not be prescribed for women who are pregnant or breastfeeding.
Several classes of drugs, including nonsteroidal antiinflammatory drugs and sulfonamides, may interact
with MTX to increase toxicity.
ACITRETIN.401 Acitretin is a second-generation, sys-
temic retinoid that has been approved for the treatment

of psoriasis since 1997 and is discussed in Chapter 228.
The clinical forms most responsive to etretinate or
acitretin as monotherapy include generalized pustular and erythrodermic psoriasis. Acitretin induces
clearance of psoriasis in a dose-dependent fashion.
227
Section 4
::
228
Overall, higher starting doses appeared to clear psoriasis faster.402 The mechanism of action of retinoids for
psoriasis is not fully understood.
The optimal initial dose of acitretin for psoriasis is
reported at 25 mg/day, with a maintenance dose of
2050 mg/day. Adverse effects, such as hair loss and
paronychia, occur more frequently with higher initial
dose (i.e., 50 mg/day). Most patients relapse within 2
months after discontinuing etretinate or acitretin. Acitretin should be discontinued if liver dysfunction, hyperlipidemia, or diffuse idiopathic hyperostosis develops.
CYCLOSPORINE A. Cyclosporine A (CsA) is a

neutral cyclic undecapeptide derived from the fungus Tolypocladium inflatum Gams. Its mechanism of action and side effects are discussed in Chapter 233. The
only formulation approved for treatment of psoriasis is
available as an oral solution or in capsules. It is highly
effective for cutaneous psoriasis and can also be effective for nail psoriasis (see Fig. 18-16B). CsA is particularly useful in patients who present with widespread,
intensely inflammatory, or frankly erythrodermic psoriasis. Dosage ranges from 2 to 5 mg/kg/day.403 Because
the nephrotoxic effects of CsA are largely irreversible,
CsA treatment should be discontinued if kidney dysfunction and/or hypertension occur. CsA-induced
hypertension may be treated with calcium antagonists
such as nifedipine.404 The most common adverse effects
noted in patients using CsA for short periods of time
are neurologic, including tremors, headache, paresthesia, and/or hyperesthesia. Long-term treatment of psoriasis with low-dose CsA was found to increase risk of
nonmelanoma skin cancers.405 However, unlike organ
transplant patients treated with higher doses of CsA,
there is little or no increased risk of lymphoma.
FUMARIC ACID ESTERS. Fumaric acid was first
reported in 1959 to be beneficial in the systemic treatment of psoriasis406 and is licensed in Germany for
treatment of psoriasis. Because fumaric acid itself is
poorly absorbed after oral intake, esters are used for
treatment. The esters are almost completely absorbed
in the small intestine, and dimethyl fumarate is rapidly hydrolyzed by esterases to monomethyl fumarate,
which is regarded as the active metabolite. The mode of
action of fumaric acid esters (FAEs) in the treatment of
psoriasis is not fully understood, but experimental data
point toward a skewing of the Th1-dominated T-cell response in psoriasis to a Th2-like pattern and inhibition
of keratinocyte proliferation.406 Patients with severe
concomitant disease, chronic disease of the gastrointestinal tract, chronic kidney disease, or with bone marrow disease leading to leukocytopenias or leukocyte
dysfunction should not be treated. Likewise, pregnant
or lactating women and patients with malignant disease (including positive history of malignancy) should
be excluded from treatment. Prolonged therapy (up to
2 years) to prevent relapse in psoriasis patients with
high disease activity is possible. Another therapeutic
option is short-course intermittent therapy. FAEs are
given until a major improvement is achieved and are
then withdrawn. If a patient remains lesion-free during
prolonged treatment, the FAE dose should be gradu-
ally decreased to reach the individuals threshold.406

Therapy with FAEs can be stopped abruptly. Rebound
phenomena have not been observed.406
SULFASALAZINE. Sulfasalazine is an uncommonly

used systemic agent in the management of psoriasis.
In the only prospective double-blind study on the efficacy of sulfasalazine in psoriasis, moderate effects
were seen, with 41% of the patients showing marked
improvement, 41% with moderate, and 18% with minimal improvement after 8 weeks of treatment.407
SYSTEMIC STEROIDS. (See Chapter 224.) In general, systemic steroids should not be used in the routine care of psoriasis. When systemic steroids are used,
clearance of psoriasis is rapid, but the disease usually
breaks through, requiring progressively higher doses to
control symptoms. If withdrawal is attempted, the disease tends to relapse promptly and may rebound in the
form of erythrodermic and pustular psoriasis.408 However, systemic steroids may have a role in the management of persistent, otherwise uncontrollable, erythroderma and in fulminant generalized pustular psoriasis
(von Zumbusch type) if other drugs are ineffective.
MYCOPHENOLATE MOFETIL. (See Chapter 233.)
Mycophenolate mofetil is a prodrug of mycophenolic
acid, an inhibitor of inosine-5-monophosphate dehydrogenase. Mycophenolic acid depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation. The
drug is usually well tolerated with few side effects. Few
studies have been done on this medication for psoriasis, but, in a prospective open-label trial on 23 patients
with dosage between 2 and 3 g daily, a 24% reduction of
the Psoriasis Area and Severity Index (PASI) was seen
after 6 weeks, with 47% improvement at 12 weeks.409
6-THIOGUANINE. 6-Thioguanine is a purine analog
that has been highly effective for psoriasis.410 Apart from

bone marrow suppression, gastrointestinal complaints
including nausea and diarrhea can occur, and elevation
of liver function tests is common.388 Isolated instances
of hepatic veno-occlusive disease have been reported.411
HYDROXYUREA. Hydroxyurea is an antimetabolite that has been shown to be effective as monotherapy, but nearly 50% of patients who achieve marked
improvement develop bone marrow toxicity with
leukopenia or thrombocytopenia. Megaloblastic anemia is also common but rarely requires treatment.388
Cutaneous reactions affect most patients treated with
hydroxyurea, including leg ulcers, which are the most
troublesome.412
COMBINATION TREATMENTS
(See Table 18-6.)
Combination treatment may increase efficacy and
reduce side effects, and so may result in a more substantial improvement, or alternatively, may permit
reduced doses to reach the same improvement as

compared with monotherapy.354 Data on combination
of biologics with other systemic or topical agents are
not yet widely available, but some combinations commonly used in the treatment of inflammatory arthritides, such as a combination of MTX and anti-TNF
agents,413 may be appropriate for treatment of recalcitrant psoriatic disease.
BIOLOGIC TREATMENTS414417
Psoriasis
EFALIZUMAB. Efalizumab (anti-CD11a) is a humanized monoclonal antibody developed for treat-
in inflammatory diseases has exploded on the clinical

realm in a manner reminiscent of the discovery of the
activity of corticosteroids.423 TNF- is a homotrimeric
protein that exists in both transmembrane and soluble
forms, the latter resulting from proteolytic cleavage
and release. It is still unclear which form is more important in mediating its proinflammatory activities
or the relative importance of the two p55- and p75-kd
TNF--binding receptors.424
Currently, four anti-TNF biologics are available in
the United States. Infliximab is a chimeric monoclonal
antibody that has high specificity, affinity, and avidity for TNF-. An example of an excellent treatment
outcome with infliximab is shown in Fig. 18-16A.
Etanercept is a human recombinant, soluble, TNF-
receptor-Fc IgG fusion protein that binds TNF- and
neutralizes its activity. Adalimumab and golimumab
are fully human recombinant IgG1 monoclonal antibodies and specifically targets TNF-. Currently golimumab is only FDA-approved for psoriatic arthritis.
Clinical trials have shown that each of these agents is
well tolerated and appears suitable for long-term use in
chronic plaque psoriasis. However, like all the targeted
biologic therapies, they carry risks of immunosuppression, and their long-term safety requires further study.
Clinical studies have found infliximab and adalimumab to be slightly more effective than etanercept in
the treatment of psoriasis. It is likely that the differential effects of these agents are associated with selectivity in their ability to perturb these receptor ligand
interactions. It is known that infliximab, adalimumab,
golimumab, and etanercept bind TNF differently; infliximab and adalimumab bind to both soluble and
membrane-bound TNF, whereas etanercept binds primarily to soluble TNF.425 Binding to membrane-bound
TNF can induce a dose-dependent increase in apoptosis of T cells, but the relevance of this mechanism in
psoriasis has not been evaluated.
::
ALEFACEPT. Alefacept is a human lymphocyte

function-associated antigen (LFA)-3-IgG1 fusion protein designed to prevent the interaction between LFA3 and CD2. The LFA-3-CD2 signal plays an important
role in activation of T cells. The LFA-3 portion of alefacept binds to the CD2 receptor on T cells, blocking the
interaction between LFA-3 and CD2, thus interfering
with the activation of T cells, inducing apoptosis and
modifying the inflammatory process. CD2 is upregulated on memory effector T cells, explaining the preferential depletion of these cells by alefacept.418 One-third
to one-half of psoriatic patients do not respond to alefacept; the reasons for this remain unclear. However,
evidence indicates that repeated administration of alefacept leads to improved response, and that responses
to alefacept are durable.415
TUMOR NECROSIS FACTOR- ANTAGONISTS. The clinical application of TNF antagonists
Chapter 18
(See Table 18-7.) (See also Chapter 234.)

Based on the continuous progress in psoriasis
research and advances in molecular biology, a new
class of agentstargeted biologic therapieshas
emerged.414,415 These agents are designed to block specific molecular steps important in the pathogenesis of
psoriasis or have been transferred to the psoriasis arena
after being developed for other inflammatory diseases.
Currently, three types of biologics are approved or are
in development for psoriasis: (1) recombinant human
cytokines, (2) fusion proteins, and (3) monoclonal antibodies, which may be chimeric or humanized. Due to
the risk of the development of antibodies to mouse
sequences, humanized or fully human antibodies are
preferred for clinical use.
Using internationally acknowledged safety and efficacy endpoints, the overall utility and benefit of biologics have been demonstrated based on the percentage
of patients achieving at least a 50% improvement in
PASI (PASI-50), a 75% improvement in PASI (PASI-75),
the impact of treatment on quality of life, and safety
and tolerability.417 In general, these agents have antipsoriatic activity roughly comparable to that of MTX
and lack its risk of hepatotoxicity. However, they are
far more expensive, carry risks of immunosuppression, infusion reactions, and antibody formation, and
their long-term safety remains to be evaluated. In the
opinion of the authors, use of biologic agents should be
reserved for treatment of severe psoriasis that is either
unresponsive to MTX or in patients for whom the use
of MTX is contraindicated.
ment of plaque psoriasis. It is directed against CD11a,

the subunit of LFA-1, and thus blocks the interaction of LFA-1 with its ligand intercellular adhesion
molecule 1. This blockade inhibits T-cell activation,
cutaneous T-cell trafficking, and T-cell adhesion to keratinocytes.419,420 Some patients have shown evidence
of exacerbation of the disease at the end of the dosing
period.421 This medication is not longer in clinical use
as it was withdrawn from the market in 2009 after reports of an increased incidence of progressive multifocal leukoencephalopathy of approximately one in 500
treated patients.422
ANTI-p40 (IL-12/IL-23 ANTAGONIST)

Ustekinumab is a human monoclonal antibody that
binds the shared p40 subunit of IL-12 and IL-23 and
prevents interaction with their receptors.426 This treatment blocks IL-12, which is critical for Th1 differentiation, but its inhibitory effect on IL-23 may be more
important. As described earlier, IL-23 supports chronic
229
TABLE 18-7
Biologic Treatments for Psoriasis390,442

Ustekinumab
Etanercept
Infliximab
Adalimumab
Mechanism
Binds CD2 on T cells,

blocking the CD2LFA3 interaction,
thus interfering with
T-cell activation
and causing T-cell
apoptosis.
Binds p40 (the

common subunit
of IL-12 and
IL-23). Blocks
Th1 and Th17
differentiation and
proliferation.
Human
recombinant,
soluble TNF-
receptor. Binds
TNF- and
neutralizes its
activity.
Chimeric
monoclonal
antibody that has
high specificity,
affinity, and avidity
for TNF-.
Fully human
recombinant
monoclonal antibody
that specifically
targets TNF-.
Dosing
15 mg IM once
weekly for 12 weeks.
Multiple subsequent
12-week courses
are possible in
responders, with a
minimum interval of
12 weeks between
courses.
Subcutaneous
injections. Weight
based dosing.
Individuals
weighing <100 kg
(220 lbs); 45 mg,
>100 kg 90 mg.
Injections at week
0, 4, and then
every 12 weeks.
25- to 50-mg
injections
subcutaneously
twice weekly.
Commonly given
as 50 mg BIW for 12
weeks followed by
50 mg weekly.
Intravenous
infusions over 2
hours. 510 mg/kg
at weeks 0, 2, and 6.
Initial dose of 80 mg,

followed by 40 mg
given every other
week starting one
week after the initial
dose.
Efficacy
PASI-75 at 14 weeks (2
weeks after last dose)
24%. Patients who
respond maintain
improvement for
extended periods of
time. Repeat courses
are safe and well
tolerated.388
PASI-75 at 12
weeks, 67% and
71%78% at week
28443
PASI-75 at 12
weeks, 34% and at
24 weeks, 44%.393
For the 25 mg BIW
vs. 49% and 59%
for the 50 mg BIW
dosing.444
PASI-75 at 10 weeks,
82% (5 mg/kg)
and 91% (10 mg/
kg).394 At week 26
(following a single
course), 57% of
patients maintained
PASI-50, and 50%
maintained PASI75.394
PASI-75 at 16 weeks,
71%445
Safety
Lymphopenia,
malignancy, serious
infections. Not
recommended
for human
immunodeficiency
virus-positive
patients.
Effects of live
vaccines not studied.
Serious infections,
increased risk
of malignancy,
reversible
posterior leukoencephalopathy
syndrome. Live
vaccinations not
recommended.
Serious infections,
exacerbation of
MS, pancytopenia,
malignancy,
worsening
congestive heart
failure. Lupus-like
symptoms (antidsDNA positive).
Live vaccinations
should not be
given.
Infusion-related
reactions, infections,
worsening of MS,
malignancy or
lymphoproliferative
disease, worsening
heart failure. Lupuslike symptoms (antidsDNA positive).
Live vaccinations
should not be given.
Injection site
reactions, infections,
lupus-like syndrome,
worsening heart
failure, cytopenias,
neurologic events.396
Live vaccinations
should not be given.
Monitoring
CD4+ T-cell counts

every 2 weeks during
treatment.
Baseline PPD/
QuantiFERON-TB
Gold
Baseline PPD/
QuantiFERON-TB
Gold
Baseline PPD/
QuantiFERON-TB
Gold.
Baseline PPD/
QuantiFERON-TB
Gold.
Long-term
administration
Up to nine
courses have been
administered over
45 years in small
number of patients
with incremental
benefits.
Clinical trials have

established safety
up to 76 weeks.443
Appears to be
similar to TNF-
inhibitors
PASI response
continues to
increase to week
24. Large databases
in patients with
other immunologic
diseases indicate
safety.
As intermittent
therapy. Large
databases in
patients with other
immunologic
diseases indicate
relative safety.
Similar to other
TNF- inhibitors.
Pregnancy
category
Section 4
Alefacept
::
BIW = twice weekly; dsDNA = double-stranded DNA; LFA = lymphocyte function-associated antigen; MS = multiple sclerosis; PASI-50 = 50%
improvement in Psoriasis Area and Severity Index; PASI-75 = 75% improvement in Psoriasis Area and Severity Index; PPD = purified protein
derivative (of tuberculin); TNF = tumor necrosis factor.
230
PREVENTION

7. Nestle FO et al: Skin immune sentinels in health and disease. Nat Rev Immunol 9(10):679-691, 2009
10. Elder JT et al: The genetics of psoriasis. Arch Dermatol
130(2):216-224, 1994
30. Nair RP et al: Sequence and haplotype analysis supports
HLA-C as the psoriasis susceptibility 1 gene. Am J Hum
Genet 78(5):827-851, 2006
34. Nair RP et al: Genome-wide scan reveals association
of psoriasis with IL-23 and NF-B pathways. Nat Genet
41(2):199-204, 2009
57. Zhang XJ et al: Psoriasis genome-wide association study
identifies susceptibility variants within LCE gene cluster
at 1q21. Nat Genet 41(2):205-210, 2009
69. Gudjonsson JE et al: Global gene expression analysis reveals evidence for decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin. J
Invest Dermatol 129(12):2795-2804, 2009
71. Ragaz A, Ackerman AB: Evolution, maturation, and regression of lesions of psoriasis. New observations and
correlation of clinical and histologic findings. Am J Dermatopathol 1(3):199-214, 1979
79. Nestle FO, Kaplan DH, Barker J: Psoriasis. N Engl J Med
361(5):496-509, 2009
106. Zheng Y et al: Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
Nature 445(7128):648-651, 2007
108. Trifari S et al: Identification of a human helper T cell population that has abundant production of interleukin 22
and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat
Immunol 10(8):864-871, 2009
110. Wing K, Sakaguchi S: Regulatory T cells exert checks and
balances on self tolerance and autoimmunity. Nat Immunol 11(1):7-13, 2010
Psoriasis
KEY REFERENCES
::
There is no known prevention for psoriasis.
128. Zaba LC, Krueger JG, Lowes MA: Resident and inflammatory dendritic cells in human skin. J Invest Dermatol
129(2):302-308, 2009
159. Clark RA, Kupper TS: Misbehaving macrophages in the
pathogenesis of psoriasis. J Clin Invest 116(8):2084-2087,
2006
164. Braff MH et al: Cutaneous defense mechanisms by antimicrobial peptides. J Invest Dermatol 125(1):9-13, 2005
183. Sa SM et al: The effects of IL-20 subfamily cytokines on
reconstituted human epidermis suggest potential roles
in cutaneous innate defense and pathogenic adaptive
immunity in psoriasis. J Immunol 178(4):2229-2240,
2007
190. Kryczek I et al: Induction of memory IL-17+ T cell trafficking and expansion by IFN-gamma: Mechanism and
pathological relevance. J Immunol 181:4733-4741, 2008
191. Conrad C et al: Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of
psoriasis. Nat Med 13(7):836-842, 2007
193. de Jongh GJ et al: High expression levels of keratinocyte
antimicrobial proteins in psoriasis compared with atopic
dermatitis. J Invest Dermatol 125(6):1163-1173, 2005
226. Gudjonsson JE et al: Mouse models of psoriasis. J Invest
Dermatol. 127(6):1292-1308, 2007
232. Boyman O et al: Spontaneous development of psoriasis
in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. J Exp Med
199(5):731-736, 2004
233. Clark RA: Skin-resident T cells: The ups and downs of on
site immunity. J Invest Dermatol 130(2):362-370, 2010
247. Suarez-Farinas M et al: Evaluation of the psoriasis transcriptome across different studies by gene set enrichment analysis (GSEA). PLoS One 5(4):e10247, 2010
257. Besgen P et al: Ezrin, maspin, peroxiredoxin 2, and heat
shock protein 27: Potential targets of a streptococcalinduced autoimmune response in psoriasis. J Immunol
184(9):5392-5402, 2010
289. Gelfand JM et al: Risk of myocardial infarction in patients with psoriasis. JAMA 296(14):1735-1741, 2006
359. Menter A et al: Guidelines of care for the management of
psoriasis and psoriatic arthritis. Section 3. Guidelines of
care for the management and treatment of psoriasis with
topical therapies. J Am Acad Dermatol 60(4):643-659, 2009
385. Menter A et al: Guidelines of care for the management
of psoriasis and psoriatic arthritis: Section 5. Guidelines
of care for the treatment of psoriasis with phototherapy
and photochemotherapy. J Am Acad Dermatol 62(1):114135, 2010
395. Kalb RE et al: Methotrexate and psoriasis: 2009 National
Psoriasis Foundation Consensus Conference. J Am Acad
Dermatol 60(5):824-837, 2009
of psoriasis and psoriatic arthritis: Section 4. Guidelines
of care for the management and treatment of psoriasis
with traditional systemic agents. J Am Acad Dermatol
61(3):451-485, 2009
of psoriasis and psoriatic arthritis: Section 1. Overview
of psoriasis and guidelines of care for the treatment of
psoriasis with biologics. J Am Acad Dermatol 58(5):826850, 2008
443. Leonardi CL et al: Efficacy and safety of ustekinumab,
a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised,
double-blind, placebo-controlled trial (PHOENIX 1).
Lancet 371(9625):1665-1674, 2008
Chapter 18
inflammation mediated by Th1799101 and Th22 cells.427

Clinical studies have found ustekinumab to be slightly
more effective than etanercept in the treatment of psoriasis,428 but direct comparison to infliximab or adalimumab has not been reported.
Numerous new drugs are currently in clinical trials
for treatment of psoriasis as outlined in a comprehensive review.429 As would be predicted from the immunological and genetic studies depicted in Figs. 18-3
and 18-5, a humanized monoclonal antibody directed
against the IL-17 receptor appears to be highly effective in early clinical trials.430
Extensive guidelines are available for specific clinical scenarios, including severe scalp psoriasis,431 intertriginous psoriasis,432 concomitant hepatitis C or HIV
infection,396,433 and in erythrodermic psoriasis.434
231
Chapter 19 :: Psoriatic Arthritis

:: Dafna D. Gladman & Vinod Chandran
PSORIATIC ARTHRITIS AT A GLANCE
Psoriatic arthritis (PsA) is an inflammatory
arthritis associated with psoriasis and
seronegative for rheumatoid factor.
Section 4
::
232
Genetic and environmental factors underlie

susceptibility to PsA and immune-mediated
inflammation leads to inflammation in
musculoskeletal structures.
Clinical features of PsA include peripheral
and axial arthritis, enthesitis, dactylitis, and
tenosynovitis.
Extra-articular involvement in addition
to skin and nail involvement may include
conjunctivitis, uveitis, and inflammatory
bowel disease.
Investigations may reveal elevated acute
phase reactants, although conventional tests
such as erythrocyte sedimentation rate and
C-reactive protein are normal in up to 50% of
patients.
Radiographs may reveal soft-tissue swelling,
periostitis, erosions, pencil-in-cup change,
ankylosis, sacroiliitis, or syndesmophytes.
Pharmacotherapy is the mainstay of
treatment, and antitumor necrosis factor
agents are safe, efficacious, and effective.
DEFINITION AND CLASSIFICATION

Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease that affects people with psoriasis or
their near relatives. It affects musculoskeletal structures such as the peripheral and axial joints, entheses,
and tendon sheaths. The eye and mucous membranes
are also often involved. Thus, the disease has varied
manifestations that make diagnosis and assessment
sometimes difficult.
The original case definition for PsA was provided
by Moll and Wright in 1973.1 They defined PsA as an
inflammatory arthritis associated with cutaneous psoriasis, seronegative for rheumatoid factor. Rheumatoid factor is a marker for rheumatoid arthritis (RA);
thus, the definition was meant to help distinguish PsA
from RA, which at that time was a more recognized
form of inflammatory arthritis. The CASPAR study
group recently developed a new set of criteria for classification of PsA using data collected prospectively in
patients with long-standing disease (Box 19-1).2 The
CASPAR criteria had specificity of 98.7% and sensitivity of 91.4% in the original study, with excellent sensitivity in both early and late disease. The criteria allow
classifying patients even when they do not have current, past, or family history of psoriasis and are now
used in epidemiologic and genetic studies in PsA.

GENETICS
PsA has a strong genetic component. The estimated
recurrence risk ratio () in first-degree relatives (FDRs)
of probands with PsA ranges from 30.4 to 55, indicating a high genetic contribution to disease susceptibility.8 Strong heritability was also demonstrated in a
recent study from Iceland where patients known to
have PsA in Reykjavik were linked to the Icelandic
genealogy database.9 FDRs to fourth-degree relatives
of patients with PsA had relative risks of 39, 12, 3.6, and
2.3, respectively, reflecting a strong genetic component.
The decrease of -1 more rapidly than by a factor of 2
with the degree of relationship indicates that multiple
genes contribute to susceptibility with some interaction of effects. Genes associated with PsA include
HLA alleles, MHC Class I related chain (MIC) genes,
TNFA, IL23R, IL1, and killer-cell immunoglobulin-like
receptor (KIR) genes. HLA-B13, -B16 and its splits -B38
and -B39, -B17, and -Cw6 are associated with psoriasis, with or without arthritis, -B27 and -B7 are specifically associated with PsA.8 However, since most
patients with PsA have cutaneous psoriasis it is difficult to determine whether genetic associations found
in patients with PsA when compared to healthy controls is associated with psoriasis or with PsA. A recent
genome-wide association study was able to investigate
association with PsA and differences between PsA and
psoriasis alone.10 HLA-C, IL12B, and TNIP1 were associated with PsA when compared to normal controls.
There was a statistically significant difference between
PsA and psoriasis alone at three loci [(1) HLA-C, (2)
IL12B, and (3) IL23R]. HLA-C and IL23R were more
strongly associated with psoriasis alone, and IL12B
with PsA. A smaller GWAS also identified a novel PsA
(and potentially psoriasis) locus on chromosome 4q27
that harbors the interleukin 2 (IL2) and interleukin 21
(IL21) genes.11
Genetic polymorphisms can also influence PsA phenotype. HLA-B39 alone, HLA-B27 in the presence of
HLA-DR7, and HLA-DQ3 only in the absence of HLADR7, confers increased risk for disease progression.12
TNF polymorphisms are associated with erosive disease and joint damage progression in early PsA.13 The
BOX 19-1 The CASPAR criteria

To meet the CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria*, a patient must have inflammatory articular disease (joint, spine, or entheseal) with
three points from the following categories:
Evidence of current psoriasis, a personal history of
PATHOGENESIS
The immune system, especially the lymphocytes, play
an important role in the pathogenesis of PsA. The
traditional model of the pathogenesis is that autoimmunity directed against a common skin and joint
autoantigen(s) leads to chronic autoreactive T-cell
driven inflammation. Genetic susceptibility predisposes the T-cell receptor repertoire to recognition of
target self-peptides expressed in target tissues. Prior
response to exogenous ligands encoded by pathogens
as well as prior episodes of inflammation result in
expansion of memory effector CD8+ T cells that recognize stress-related self-antigens and initiates and
maintains pathways of inflammation mediated by
the expression of transcription factors such as nuclear
factor-B and activator protein-1, resulting in skin and
Psoriatic Arthritis
interleukin-4 receptor gene (IL4R) I50V SNP is associated with erosive PsA, although the association was
not consistently shown.14,15
::
*Current psoriasis is assigned a score of 2; all other features are

assigned a score of 1. From Taylor W et al: Classification criteria
for psoriatic arthritis. Arthritis Rheum 54(8):2665-2673, 2006.
Chapter 19
psoriasis, or a family history of psoriasis. Current

psoriasis is defined as psoriatic skin or scalp disease present today as judged by a rheumatologist
or dermatologist. A personal history of psoriasis
is defined as a history of psoriasis that may be obtained from a patient, family physician, dermatologist, rheumatologist, or other qualified health care
provider. A family history of psoriasis is defined as
a history of psoriasis in a first- or second-degree
relative according to patient report.
Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis observed
on current physical examination. A negative test
result for the presence of rheumatoid factor by any
method except latex but preferably by enzymelinked immunosorbent assay or nephelometry,
according to the local laboratory reference range.
Either current dactylitis, defined as swelling of an
entire digit, or a history of dactylitis recorded by a
rheumatologist. Radiographic evidence of juxtaarticular new bone formation, appearing as illdefined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of
the hand or foot.
synovial inflammation.18 The primary defects in this

model involve expression of an autoantigen, binding
of autoantigen peptides by MHC Class 1 molecules
leading to initial clonal activation and expansion of an
adaptive immune response. However, recent imaging,
histological, and genetic studies have made us reconsider this view, especially with respect to joint and nail
diseases. Clinically unrecognized enthesitis is commonly seen in PsA and in psoriasis without arthritis.19
Enthesitis is associated with adjacent osteitis or bone
and synovial inflammation. Nail disease is a marker
for PsA in patients with psoriasis, since it occurs in
almost 90% of patients with PsA, but less than 50% of
those with psoriasis alone. The nail is closely related to
the distal interphalangeal (DIP) joints and the related
extensor tendon insertion sites, and the association
between DIP joint disease, adjacent nail lesions, and
entheseal inflammation was recently demonstrated.20
It is proposed that the synovial membrane and entheses form a synovioentheseal complex, and that
enthesitis is the unifying pathologic lesion that may
explain the varied clinical manifestations of PsA.21 In
this model, tissue specific factors, including microtrauma, lead to regional innate immune activation and
persistent inflammation. The genetic association of
PsA with Class 1 HLA alleles and KIR genes as well
as the association between juvenile PsA and Mediterranean Fever (MEFV) and NLR family, pyrin domain
containing 3 (NLRP3) genes indicate that PsA is closer
to the autoinflammatory end rather than the autoimmune end of the spectrum of immune-mediated
diseases.22 Disease localization in autoinflammatory
diseases is determined predominantly by the innate
immune response to local tissue specific factors.
There is also evidence that the monocytemacrophage system plays a major role in the initiation and
perpetuation of joint inflammation. Monocytes differentiate into macrophages, osteoclasts, Langerhans
cells, or dendritic cells in response to microenvironmental signals.23 In entheseal tissues, monocytes are
the principal cells that infiltrate fibrocartilage. Monocytes are also present in the synovial lining of psoriatic joints, and they infiltrate the subsynovial lining.
An increased frequency of circulating osteoclast precursors was identified in the circulation and synovial
tissues of PsA patients. These precursors, derived from
circulating CD14+ monocytes, differentiate into osteoclasts after exposure to monocyte colony stimulating
factor (M-CSF) and receptor activator of nuclear factor
B ligand (RANKL) expressed by synovial lining cells
in inflamed psoriatic synovium, and is responsible for
bone erosions. The frequency of circulating osteoclast
precursors in PsA patients decline rapidly following
treatment with anti-TNF agents and may explain its
antierosive effects.
CLINICAL FINDINGS
The CASPAR classification criteria define PsA as an
inflammatory musculoskeletal disease that can involve
the joints, spine or entheses. Clinical features of PsA
include peripheral arthritis, axial arthritis (spondylitis),
233
Section 4
Figure 19-1 Swelling and erythema of the left third metacarpophalangeal joint (arrow) indicating inflammatory arthritis in a patient with psoriatic arthritis.
::
234
enthesitis, dactylitis, and tenosynovitis. The typical features of inflammatory arthritis are joint pain, swelling,
stiffness, redness, and reduction in mobility. The arthritis of PsA is often of gradual onset and involves one or
more joints. Typically early PsA is oligoarticular (affecting less than five joints) (Fig. 19-1). Early PsA often
involves the joints of the lower limbs, but any joint of the
body may be affected. Oligoarticular PsA subsequently
evolves into polyarthritis. Joints that are typically
affected in patients with PsA include the DIP joints (Fig.
19-2). Commonly the nails near these affected joints
Figure 19-2 Psoriatic nail dystrophy and arthritis of the

fifth distal interphalangeal joint (arrow) in a patient with
psoriatic arthritis.
demonstrate the nail changes that are typical for psoriasis. The distribution of the joint involvement in PsA
is often asymmetric. However, as the number of joints
affected increases, there is a tendency toward symmetry.26 Patients with PsA have less pain than those with
RA.27 Therefore, they may be oblivious to the degree
of inflammation in their joint. In addition to peripheral arthritis, PsA affects the axial joints in 30%50% of
patients with PsA. Axial inflammatory arthritis presents with inflammatory back and/or neck pain, typically associated with stiffness and worse after periods
of prolonged inactivity such as nighttime sleep. Inflammatory axial pain and stiffness usually improve with
activity. However, evidence of radiographic involvement of the axial joints may be present in a substantial
proportion of patients presenting with peripheral PsA
in the absence of axial symptoms.28 Axial arthritis leads
to restriction in the mobility of the spine. The process
can lead to a completely fused and immobile spine,
sometimes called bamboo spine.
Dactylitis, defined as inflammatory swelling of an
entire finger or toe, is a characteristic manifestation
of PsA (Fig. 19-3). This is due to inflammation of the
joints, tendons, bones, and soft tissues in the digit(s).
Persistent dactylitis leads to destruction of the joints
in that digit. Dactylitis is a marker of severity of psoriatic arthritis. Enthesitis, defined as inflammation at
the entheses (site where ligaments or tendons attach to
bone), is another important manifestation of PsA. The
most common sites to be affected by enthesitis are the
plantar fascia on the sole of the feet (plantar fasciitis)
and Achilles tendon insertion at the back of the heel
(Achilles enthesitis). Enthesitis can also affect other
sites including tendon insertion sites on the patella,
shoulder, elbows, pelvis, spinous processes, and chest
wall. Tenosynovitis, or inflammation of the tendon
sheath, may affect tendons in the hands, wrists, and
around the ankles. (Box 19-2).
The category of asymmetric oligoarthritis includes
those patients with four or less joints affected by arthritis. The joints involved are usually of the lower limbs
and there is lack of symmetry. In the category of sym-
Figure 19-3 Dactylitis of the third toe (arrow) in a patient

with psoriatic arthritis.
BOX 19-2 Patterns of PsA

According to Moll and Wright*
Five patterns of PsA were originally described by Moll
and Wright.* These include the following:
1. Asymmetric oligoarthritis
2. Symmetric polyarthritis similar to rheumatoid arthritis
3. Spondyloarthritis
4. Distal interphalangeal joint arthritis
5. Arthritis mutilans
*From Moll JM, Wright V: Psoriatic arthritis. Semin Arthritis
Rheum 3:55, 1973.
NAIL INVOLVEMENT. Psoriatic nail dystrophy

usually manifests as pitting and onycholysis (see Chapter 18). Although 40% of patients with psoriasis without PsA have nail lesions, nail involvement is much
more frequent in patients with PsA affecting close to
90% of patients.31 Thus, nail lesions are the only clini-
Psoriatic Arthritis
Most patients with PsA

have psoriasis vulgaris. In about 70% of people with
PsA, psoriasis develops first and the arthritis manifests
itself after a variable duration, on average within 10
years. However, in about 15%, both arthritis and psoriasis develops simultaneously, and in the remaining, the
arthritis develops first, and cutaneous psoriasis manifests itself a few years later. Patients seen in dermatology clinics and those hospitalized with psoriasis have
high prevalence of PsA compared to patients with psoriasis seen in the community. Patients reporting greater
extent of psoriasis also reported a higher prevalence of
PsA when surveyed in a telephone interview.30 Thus,
patients with more severe psoriasis may have a higher
prevalence of PsA. However, most patients attending
rheumatology clinics for their arthritis have only mild
to moderate psoriasis.
LABORATORY INVESTIGATIONS. Laboratory

tests are usually done at diagnosis and periodically
thereafter. However, there is to date no diagnostic test
for PsA. The acute phase reactants [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)] are
often normal. ESR and/or CRP are raised in less that
50% of people with PsA. Rheumatoid factor is usually
negative and helps exclude RA. HLA-B*27 is positive
in 20% of patients with PsA. Radiological investigations (X-ray, ultrasonography, and magnetic resonance
imaging) can provide important clues to diagnosis and
to the extent of inflammation and damage. However,
only the presence of periostitis and new bone formation near joint margins may be considered reasonably
specific to PsA.2 Although, these tests are not by themselves diagnostic, they help in ruling out other conditions that may mimic PsA. Synovial fluid if obtained
demonstrates inflammation and helps exclude crystal arthritis and infections. Investigations such as
blood count, and liver and kidney functions are often
obtained to monitor side effects of drug therapy.
::
SKIN INVOLVEMENT.
EXTRA-ARTICULAR MANIFESTATIONS. Apart

from the involvement of the skin, nails, and joints, people with PsA also have involvement of other important
organs. Eye involvement is not infrequent. Conjunctivitis is occasionally seen and uveitis may occur in 2.3% of
patients.32 Mucous membrane inflammation presents
with painful mouth ulcers and urethritis. Inflammatory bowel disease in PsA may resemble Crohn disease and/or ulcerative colitis and can cause abdominal
pain, loose stools, and bleeding.
Chapter 19
metric polyarthritis, five or more joints are involved in

a symmetric fashion. Therefore, it is sometimes difficult
to distinguish it from RA. The spondyloarthritis category includes patients with predominant involvement
of the spine (axial arthritis), similar to the involvement
in patients with AS. As the name suggests, the category of distal interphalangeal joint arthritis includes
those patients with predominant involvement of the
DIP joints. Arthritis mutilans describes a category with
severe arthritis leading to shortening and destruction
of fingers and toes (see eFig. 19-3.1 in online edition).
Although, these categories were described initially, it
was soon realized that as the longer the duration of
the disease the higher the number of joints involved
and the involvement becomes more symmetric. Distal joint involvement also is common and is seen in
all categories. Arthritis mutilans is also a manifestation of severity of the arthritis process and not an
exclusive category. Therefore, experts nowadays tend
to classify the disease as peripheral arthritis alone,
peripheral arthritis with axial arthritis, and axial
arthritis alone.29
cal feature that distinguishes patients with psoriatic

arthritis from those with uncomplicated psoriasis. The
nail bed is closely linked to the DIP joints; nail involvement is associated with arthritis of these joints.
RADIOLOGIC FEATURES OF PsA. Imaging is

an important modality in the assessment of patients
with PsA. Imaging complements clinical assessment
and helps in confirming the diagnosis as well as in
determining disease severity. The various modalities
used in assessment of PsA include X-rays, ultrasound,
computerized-tomography scan (CT scan), magnetic
resonance imaging (MRI), and bone scan.
Plain Radiographs (X-rays). X-rays are the
mainstay in the radiologic assessment of PsA. X-rays
are relatively cheap, easily available, and can be read
by most physicians. Once PsA is suspected clinically,
radiographs of the hands, feet, pelvis, spine, and other
affected joints are done to look for changes suggestive
of PsA. X-rays are also used to assess disease severity,
as well as to follow disease progression. Radiographic
changes generally reflect damage to the joints rather
than acute inflammation. In early disease, X-rays of
the hands and feet show soft tissue swelling around
the joints involved. If dactylitis is present, soft tissue
swelling will involve the whole finger or toe. In more
severe disease, erosions develop near the joint margin
and are markers of disease severity (Fig. 19-4). Erosions may be paramarginal, in contrast to RA were
235
Section 4
::
Figure 19-5 Radiograph of the hands of a patient with

psoriatic arthritis showing erosions, joint space narrowing and new bone formation at the wrists, carpometacarpal, metacarpophalangeal, proximal interphalangeal, and
distal interphalangeal joints.
Figure 19-4 Radiograph of the feet of a patient with psoriatic arthritis showing solitary large erosion at the head of
the fourth metatarsal bone (arrow).
the erosions are usually marginal. In PsA erosions are
often accompanied by new bone formation. The combination of erosions and new bone formation at joint
margins is characteristic of PsA (Fig. 19-5). Following
the development of erosions there may be joint space
narrowing, and finally total joint destruction may
occur, either total joint lysis and the so called pencilin-cup change or complete bony bridging through the
joint termed ankylosis (Fig. 19-6).
X-rays of the pelvis often show changes reflecting the
presence of sacroiliitis. Earliest notable changes include
widening of the joint space, which is often difficult to
appreciate (eFig. 19-6.1 in online edition). Subsequently,
erosions develop, followed by sclerosis and subsequent

bony bridging across the joints, ultimately leading to
complete fusion of the joint (eFig. 19-6.2 in online edition).
X-rays of the neck and the back often show changes that
reflect consequences of inflammation at the spinal joints.
The earliest changes on lateral view of the spine include
shiny vertebral corners, erosions, and squaring of vertebrae. This is followed by bone bridging, or marginal syndesmophytes, beginning from the ends of the vertebrae
across the disc space. Complete bony bridging can occur.
If most of the vertebrae are bridged, it is called bamboo spine. These changes closely resemble the changes
in AS (Fig. 19-7). Often in PsA, the syndesmophytes can
develop from sites away from the vertebral body. The
presence of these nonmarginal syndesmophytes is
characteristic of PsA (eFig. 19-7.1 in online edition). The
changes described can at occur at any sitecervical and
lumbar vertebrae are frequently involved. In the cervical spine, occasionally atlanto-axial subluxation may be
present and can lead to serious consequences.
Ankylosis
236
Pencil-in-cup change
Figure 19-6 Advanced destructive changes in

the hand joints including pencil-in-cup change
and ankylosis in a patient with psoriatic arthritis.
Facet joint fusion
Classical marginal
syndesmophyte
Chapter 19
::
ULTRASOUND IMAGING. Ultrasound combined

with Doppler evaluation, can detect active inflammation
in joints and entheses. Ultrasound can also detect erosions before they appear on X-rays especially in the hand
joints. It can also be used to guide injections into joints.33
MAGNETIC RESONANCE IMAGING (MRI).
MRI scans along with contrast can detect active inflammation. MRI can also show erosions in the bone even
before they are seen on plain X-rays.34 Bone edema
which often precedes the development of overt erosions is also detected easily. MRI scans are also very
useful in detecting active inflammation in the spine
and MRI changes are usually evident much before
any abnormality is visualized on X-rays.34 Thus, MRI
evaluation is crucial in the diagnosis of early disease,
especially affecting the spine.
COMPUTERIZED TOMOGRAPHY. CT scans are

most useful when joints or the spine need to be evaluated in detail, especially when an MRI is unavailable or
contraindicated. CT scans also give a detailed view of the
joints. Bones are viewed better than in MRIs. However,
CT scans involve considerable exposure to radiation.
COURSE AND PROGNOSIS

PsA has a variable course and prognosis. While some
patients do well with small number of joints involved,
and no significant damage, others progress very
Psoriatic Arthritis
Figure 19-7 Lateral radiograph of the cervical spine showing anterior marginal syndesmophytes and fusion of the facet joints in a patient with psoriatic arthritis.
quickly, developed marked joint damage and disability.35 Over 10 years of follow-up, 55% of the patients
had at least five clinically damaged joints.36 By the time
patients present to a PsA clinic, 67% have at least one
erosion.31 Even in early disease, of 129 patients seen
within 5 months of onset of symptoms 47% developed erosions within the first 2 years.37 Factors associated with progression of joint damage include the
number of actively inflamed and damaged joints at
presentation, the ESR at presentation, and the number
of actively inflamed joints at each visit.3841 There are
patients with PsA who achieve remission, defined as
no actively inflamed joints for 12 months.42 In a longitudinal observation cohort 17.6% of the patients
achieved remission, but only six patients had a complete remission with no actively inflamed joints, no
damage, and off therapy. The period of remission
lasted for 2.6 years, after which 52% of the patients
flared. Thus, active disease must be treated aggressively, particularly in the presence of erosive changes.
Quality of life and function of patients with PsA are
reduced compared to the general population.43,44 PsA
patients have worse quality of life and function than
patients with psoriasis alone.45
COMORBIDITIES. Patients with psoriasis and PsA

have an increased prevalence of cardiovascular disease
(CVD). In patients with PsA, the standardized prevalence ratio of hypertension, myocardial infarction, and
angina is higher than the general population.4648 For
other comorbidities, see Chapter 18.
237
MORTALITY IN PsA. Although population-based
studies have shown that PsA is not associated with

increased mortality, clinic-based studies have shown
that patients with PsA have an elevated mortality risk,
although the risk seems to have declined over the last
decade.49 The four leading causes of death are diseases
of the circulatory or respiratory system, malignancies,
and injuries/poisoning. Evidence of previously active
and severe disease, as manifested by the prior use of
medications and by radiologic changes as well as an
elevated ESR at presentation, are prognostic indicators
for death.50
Section 4
::
238
EARLY DIAGNOSIS
PsA has an unpredictable clinical course. Radiographic
damage can occur within 2 years of disease onset in
almost half of patients with PsA, and the disease usually follows a chronic, progressive course.37,51 With the
availability of effective therapy it is hoped that early
diagnosis will help prevent damage. Since cutaneous
psoriasis precedes or occurs simultaneously with joint
disease in 85% of patients with PsA, screening patients
with psoriasis for PsA has the potential to help detect
PsA early.52
Several screening tools have been recently developed.53 The Psoriasis and Arthritis Questionnaire
(PAQ) and its modification, Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire, Psoriasis
Epidemiology Screening Tool (PEST) questionnaire,
and Psoriasis and Arthritis Screening Questionnaire
(PASQ) were developed specifically to screen for PsA
in patients with psoriasis, whereas the Toronto Psoriatic Arthritis Screen (ToPAS) was developed for use in
the general population as well as in patients with psoriasis. The PASE, PEST, and ToPAS questionnaires have
high sensitivity and specificity. Imaging studies using
scintigraphy, MRI, and ultrasound have also shown
abnormalities in subjects with psoriasis, who do not
have overt PsA.19,54,55 Soluble biomarkers have also
been evaluated as a marker for screening for PsA in
patients with psoriasis; C-reactive protein and Matrix
Metalloproteinase-3 have shown promise.56,57 Circulating osteoclast precursors are elevated in patients with
PsA and psoriasis, and decrease with anti-TNF therapy.58 In prospective studies, clinical predictors for PsA
in patients with psoriasis include presence of scalp or
intergluteal/perianal psoriasis, 3 affected sites, and
presence of nail dystrophy.59
DIFFERENTIAL DIAGNOSIS. A number of

arthritic conditions may occur in patients with psoriasis and these must be differentiated from PsA (Table
19-1). Since psoriasis is a common condition, occurring
in 2%3% of the population, and rheumatoid arthritis,
the most common form of inflammatory arthritis, may
occur in 1% of the population, the co-occurrence of
rheumatoid arthritis and psoriasis would be expected
by chance alone in 2 in 10,000 people. Since RA, like PsA
is inflammatory in nature, the differentiation may be
difficult. Osteoarthritis, which is the commonest form
of arthritis, occurs in about 5% of the population and it
may coexist with psoriasis. While osteoarthritis is not
usually an inflammatory form of arthritis, it affects the
DIP joints, a site commonly affected in patients with
PsA. Patients with PsA also have increased prevalence
of hyperuricemia and gout, and occasionally gouty
arthritis may mimic PsA. PsA also has to be distinguished from other SpA.60
Table 19-1
Differential Diagnosis of Arthritis in Patients With Psoriasis

Manifestation
PsA
RA
Gout
Osteoarthritis
Age at onset
36s
40s
Any age
Over 50
M:F
1.1:1
1:3
3:1
1:1
Joint affected
Proximal and distal

interphalangeal joints,
small and large
Proximal
interphalangeal and
metacarpophalangeal
joints, small and large
Toes, knees ankles
Weight bearing, distal

hands
Symmetry
Usually asymmetric
Symmetric
Usually asymmetric
May be symmetric
Redness over joint
Yes
No
Yes
No
Spinal disease
Yes, inflammatory
No
No
Yes, degenerative
Dactylitis
Yes
No
Podagra
No
Enthesitis
Yes
No
No
No
Nodules
No
Yes, extensor surfaces
Tophi
Heberdens and
Bouchards
Psoriasis
100%
13%
13%
13%
Nail lesions
87%
No
No
No
of the arthritis and severity of skin disease. Patients

should ideally be under the care of a team of health
professional comprising rheumatologists, dermatologists, physiotherapists, and occupational therapists.
However, if the primary problem is skin disease and
the arthritis is mild, the subject may be managed by a
dermatologist after a complete assessment by a rheumatologist. Periodic assessment by a rheumatologist in
such cases would be ideal. On the other hand, if the
primary problem is joint disease, the rheumatologist
should primarily manage the patient, with the dermatologist confirming the diagnosis of psoriasis and providing input if skin disease remains poorly controlled.
Drug therapy for psoriatic arthritis may be classified
as in Box 19-3.
NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDs)
Psoriatic Arthritis
Pharmacotherapy is the cornerstone of management of

PsA. Drug therapy depends on the severity and stage
Symptom modifying therapy

Therapy with Disease modifying Antirheumatic
Drugs (DMARDs)
Therapy with biologic agents
::
TREATMENT
BOX 19-3 Drug Therapy for PsA
Chapter 19
The diagnosis of PsA is considered when a patient

presents with inflammatory musculoskeletal disease.
This may be in the form of arthritis, dactylitis, enthesitis,
or spondylitis. The presence of cutaneous psoriasis is an
important clue and this should be looked for carefully,
especially in hidden regions such as the scalp, umbilicus, below breasts, or in the natal cleft. Nails should be
carefully inspected for changes of nail psoriasis as the
evidence of psoriasis may be present in the nail only.
The pattern of involvement in PsA is often asymmetric.
This is not usually the case in RA, which tends to be
symmetric. A characteristic pattern of PsA is the ray
patterninvolvement of all joints in a particular finger or toe, as opposed to joints beside one another. The
ray distribution is typical for PsA, and is not usually
seen in either RA or OA. The presence of dactylitis is an
important feature. It is a typical feature for PsA and is
not seen in RA. The only other arthritic condition that
may manifest with dactylitis is reactive arthritis, which
is not associated with psoriasis but where psoriasis-like
lesions can occur (see Chapter 20). Spinal involvement
presenting as inflammatory neck or back pain with or
without restriction of mobility is present in about half
of the patients with PsA, especially in well-established
disease. It is not a feature of RA. The presence of spinal and peripheral arthritis makes the diagnosis of PsA
very likely, and virtually rules out RA.
The diagnosis of PsA may sometimes be made even
in the absence of psoriasis. If the above characteristic
features are present even without cutaneous psoriasis,
the diagnosis may be considered. The diagnosis is especially likely if there is a family history of psoriasis or
PsA. The diagnosis may also be made if characteristic
radiographic features such as pencil-in-cup changes,
bony ankylosis, new bone formation close to sites of erosions, and nonmarginal syndesmophytes are present.
Laboratory tests have only a minor role to play in
making the diagnosis of PsA. Characteristically, rheumatoid factor test is negative, although a positive test
does not rule out the diagnosis. Elevated erythrocyte
sedimentation rate (ESR) or C-reactive protein (CRP) is
present only in about half of the patients. However, these
are markers of severity. ESR is a predictor of progression
of joint damage and mortality, and CRP is a predictor
of progression of radiological damage.38,41,50 Other tests
usually done are routine tests such as blood counts, and
liver and kidney function tests. Although these tests are
not important in making a diagnosis, they give important information on the presence of comorbid conditions
and are important in monitoring treatment. If synovial
fluid can be aspirated from the joint, it can be tested to
confirm inflammation and to rule out other causes of
inflammation like infection and crystals. Synovial biopsies, usually done using an arthroscope, show evidence
of chronic inflammation, and are sometimes required to
rule out chronic infection. As outlined above, imaging is
most important in making a diagnosis of PsA.
NSAIDs are useful in the treatment of PsA and give

relief to symptoms such as pain and stiffness. However,
NSAIDs do not prevent disease progression, and may
worsen skin lesions. They may be used as sole therapy
in treating mild PsA and for symptomatic management of pain, inflammatory swelling and morning
stiffness. With the recent reports of increased risk of
myocardial infarction and stroke with long term use
of COX-2 inhibitors, the use of nonselective NSAIDs
like naproxen, ibuprofen, diclofenac, indomethacin,
or aspirin (with or without misoprostol/H2-blockers/
proton pump inhibitors) is preferable. If symptoms
persist, or if more joints accrue after adequate trials
with two different NSAIDs, Disease Modifying Antirheumatic Drug (DMARD) use should be considered.
CORTICOSTEROIDS
Corticosteroid therapy in the form of intra-articular
injections of corticosteroids (triamcinolone, methylprednisolone) into the joints either at the bedside in the
clinic or under ultrasound guidance is often used for
rapid relief of symptoms when only one or a few joints
are affected. This form of therapy has been proven
effective in PsA.66 Oral corticosteroids are used occasionally for symptom relief when there is polyarthritis
or when there is inadequate response to NSAIDs and
there is significant disability. However, glucocorticosteroids need to be used with extreme caution with
slow taper, since psoriasis worsens in many instances
and could occasionally evolve into more severe forms
like pustular psoriasis. Treatment with oral steroids is
usually resorted to as short-term therapy, until other
239
longer acting drugs take effect. Long-term steroid therapy is associated with significant toxicity such as high
blood pressure, cataracts, weight gain, diabetes, osteoporosis, and avascular necrosis of bone.
DISEASE MODIFYING
DRUG THERAPY
Section 4
::
240
There is a paucity of clinical trials with traditional disease modifying agents (DMARDs) in PsA.67 A recently
published systematic review and meta-analysis of efficacy and toxicity of DMARDs and biological agents
for PsA showed that treatment was more effective than
placebo (RR = 0.35; 95% CI 0.25, 0.49) but caused more
toxicity (RR = 2.33; 95% CI 1.61, 3.37).67
METHOTREXATE. Although methotrexate is used

most commonly to treat PsA, oral methotrexate (MTX)
has been evaluated in only one RCT.68 This 12-week
placebo-controlled trial of low-dose oral MTX given at
a dose of 2.55.0 mg every 12 hours in three consecutive doses per week was terminated early after recruiting only 37 patients. MTX significantly improved
physician global assessment, but there were no significant effects on tender and swollen joint scores,
patient global assessment, and ESR. However, a retrospective analysis of PsA patients treated with MTX
for 24 months therapy compared to a matched cohort
not thus treated did not show any difference in radiographic progression scores in the two groups.69 A reappraisal from the same cohort showed that in the last
decade treatment with MTX has changed to include
patients with shorter disease duration and less damage, at increased dose, and that there may be better
response with less progression of damage.70 In spite of
lack of evidence from RCTs, based on efficacy in RA
and psoriasis, rheumatologists have been using MTX
as a first-line DMARD. Patients on MTX require regular monitoring of blood counts, liver function tests,
and creatinine. Significant test abnormalities require
adjustment of dose or treatment cessation. Although
liver toxicity can occur in the absence of abnormal
serum liver function tests, regular liver biopsies are
not typically ordered by rheumatologists as they may
be by dermatologists. The occurrence of liver fibrosis
and cirrhosis seem to be higher in patients with psoriasis when compared to patients with RA, reflected in
the differing guidelines in rheumatology and dermatology. There is increased prevalence of obesity, metabolic syndrome and type-2 diabetes in patients with
psoriasis. Patients with psoriasis treated with MTX
and having risk factors for liver disease, especially diabetes type 2 or obesity, are at higher risk of developing
severe liver fibrosis compared to those without such
risk factors, even when lower cumulative methotrexate doses are given.71 These risk factors are important
for nonalcoholic steatohepatitis even when there is no
exposure to MTX. Thus it is unclear whether weekly
low-dose MTX independently increases risk for cirrhosis. In clinical practice, it will thus be prudent to
get serial liver biopsies after a cumulative MTX dose of
1.5 g especially in those patients who have risk factors
for fibrosis and cirrhosis such as obesity, metabolic

syndrome, type 2 diabetes, viral hepatitis, and significant alcohol use.
SULFASALAZINE. Five RCTs have evaluated

sulfasalazine (SSZ) in the treatment of PsA; its benefits were moderate.67 In the largest of these, 221 PsA
patients were treated with SSZ, 2 g/day, for 36 weeks.72
The psoriatic arthritis response criteria (PsARC) developed specifically for this study showed statistically
significant improvement in the treatment group (57.8%
for SSZ compared with 44.6% for placebo, P = 0.05).
But, the only individual measure within the responder
index to do so was the patient global assessment, and
longitudinal analysis revealed only a trend favoring
SSZ treatment. A systematic review revealed that the
effect size for SSZ was less than 0.2, the level required
to confirm response.73 SSZ has not been shown to prevent progression of joint damage.74
CYCLOSPORINE A. Cyclosporine A (CsA) is effective in controlling psoriasis. A three-arm RCT comparing CsA 3 mg/kg/day added to standard therapy, SSZ
2 g/day added to standard therapy, and standard therapy alone, showed that CsA was well tolerated and was
more efficacious that standard therapy and SSZ.76 In
the most recently published RCT, CsA was compared
to placebo as an add-on treatment, in patients with
PsA demonstrating an incomplete response to MTX
monotherapy. There was significant improvement at
12 months in the swollen joint count, C-reactive protein, PASI, and synovitis detected by high-resolution
ultrasound. There was no improvement in the Health
Assessment Questionnaire or pain scores.77 Thus, CsA
has a role in the management of PsA either on its own
or as an add-on treatment to MTX. However, it is not
well tolerated. Its effect on joint damage has not been
assessed.
GOLD. Although not shown to protect from progression of joint damage, Gold has been used in the
treatment of PsA, with intramuscular gold being more
efficacious.78 With significant concern about toxicity,
slow mode of action, problems with availability, and
availability of more effective drugs, it is seldom used
nowadays.
ANTI-TNF AGENTS. (See also Chapter 234.) AntiTNF agents have revolutionized the management of
PsA. There are currently four agents marketed for the
treatment of PsA. In the placebo-controlled portion of
the phase 3 Etanercept trial in PsA (n = 205), ACR 20
response was achieved by 59% of Etanercept treated
patients versus 15% in the placebo group (P < 0.0001).81
Skin response, as measured by the PASI score in
patients with body surface area (BSA) involvement at
least 3% showed a 75% improvement in 23% and 3%,
respectively at 24 weeks (P = 0.001). Measures of function and quality of life significantly improved. Significant inhibition of progression of joint space narrowing
and erosions was shown. In the open label extension
of this study, at 2 years, effectiveness was maintained.
::
Psoriatic Arthritis
least with gold and leflunomide, and poor with SSZ.67

There are no direct head-to-head trials comparing the
efficacy of various anti-TNF agents in PsA. However, a
meta-analysis of anti-TNF RCTs showed that the three
anti-TNF agents [(1) Infliximab, (2) Etanercept, and (3)
Adalimumab] were significantly more effective than
placebo.88 There were no significant differences between
anti-TNF agents and placebo in the proportions of
patients experiencing withdrawal for any reason, due
to adverse events, serious adverse or upper respiratory
tract infections. Pooled rates for injection site reactions
were significantly higher for Adalimumab and Etanercept than for placebo, but there was no significant difference in the proportion of patients experiencing infusion
reactions with Infliximab compared against placebo.
Indirect analysis did not demonstrate any significant
differences between the anti-TNF agents.88
Data from biologics registries that have been maintained in Europe suggest that drug survival (the length
of time a patient continues to take a particular drug)
of anti-TNF agents is significantly higher in SpA compared to RA.89,90 Concomitant MTX was associated
with better drug survival in RA and PsA, but not for
AS.90,91 There is a tendency toward shorter persistence
with treatment for Infliximab when compared with
Etanercept and Adalimumab.91,92 Risk factors for drug
discontinuation include female sex, comorbidity, using
Infliximab rather than Etanercept, and absence of concomitant therapy with MTX.91,92
Chapter 19
The drug was well tolerated. A more recent trial compared Etanercept 50 mg twice weekly for 12 weeks, followed by 50 mg weekly, compared with 50 mg weekly
throughout in 752 patients with psoriasis affecting
>10% of body surface area and at least two swollen and
tender joints.82 There was no difference in the response
to arthritis at week 12 or 24, although the skin response
was better at week 12. No difference in skin response
was evident at week 24. Dactylitis and enthesitis also
showed improvement from baseline.
In the IMPACT II phase 3 study, Infliximab in 200
PsA patients showed significant benefit. At week 14,
58% of Infliximab-treated patients and 11% of placebo
patients achieved an ACR 20 response (P < 0.001). Presence of dactylitis and enthesitis decreased significantly
in the Infliximab group. At 24 weeks, PASI 75 was
achieved by 64% of the evaluable treatment group and
2% of the placebo group (P < 0.001).83 Infliximab also
significantly inhibits radiographic progression, and
improves function and quality of life.83,84
In the phase 3 Adalimumab Effectiveness in Psoriatic
Arthritis Trial (ADEPT), 313 subjects were studied.85
At 12 weeks, 58% of patients receiving Adalimumab
40 mg every other week achieved ACR 20 response
compared with 14% of patients receiving placebo
(P < 0.001). PASI 75 was achieved by 59% in the Adalimumab-treated group and 1% in the placebo group
(P < 0.001) in those 69 patients in each group who were
evaluable for PASI scoring. Radiographic progression
of disease was significantly inhibited, and there was
improvement in disability and quality of life scores.85
The latest anti-TNF agent to be approved for PsA
is Golimumab. In the GO-REVEAL trial, 405 patients
active PsA were randomly assigned to receive subcutaneous injections of placebo (Golimumab 50 mg or
Golimumab 100 mg every 4 weeks.86 At week 14, 51%
of patients receiving Golimumab 50 mg and 45% of
patients receiving Golimumab 100 mg achieved an ACR
20 response, compared with 9% of patients receiving
placebo (P < 0.001 for all comparisons). Among the 74%
of patients in whom at least 3% of the body surface area
was affected by psoriasis at baseline, 40% of those in the
Golimumab 50 mg group and 58% of those in the Golimumab 100 mg group had at least 75% improvement
in the PASI at week 14, compared with 3% of placebotreated patients (P < 0.001 for both doses). Improvement
was also demonstrated in the HAQ score, SF-36, NAPSI,
and enthesitis. There was no difference in the arthritis
outcomes between the two doses of Golimumab and
it is marked only for PsA at a monthly dose of 50 mg.
Significant improvement in dactylitis was seen only in
the 100 mg dose, although a trend was evident with the
50 mg dose.86 Golimumab was also shown to inhibit
progression of radiographic damage.87
Thus, the anti-TNF agents have shown the greatest
efficacy of any treatment to date in the various clinical
aspects of PsA. Their efficacy in joint disease activity,
inhibition of structural damage, function, and quality of life are similar, and they are well tolerated, with
injection site reactions being the most significant. On
comparing with traditional DMARDs, anti-TNF agents
had the best efficacy/toxicity ratio (number needed to
harm/number needed to treat = 0.25); tolerability was
USTEKINUMAB. (See also Chapter 234.) Ustekinumab

is a human monoclonal antibody that inhibits receptor
binding of IL-12 and IL-23 has been shown to be very
efficacious in treating psoriasis and is marketed for
this indication.93 A phase 2 trial in 146 subjects with
PsA showed that at week 12, 42% of patients in active
arm and 14% in the placebo arm achieved an ACR
20 response (p = 0.0002).94 Of 124 participants with
psoriasis affecting 3% or more body surface area, 52%
in the active arm and three of 5% in the placebo arm
had a PASI 75 response (p < 0.0001). The drug was well
tolerated.94 A larger phase 3 trial is underway.
ANTI T CELL AGENTS. (See also Chapter 234.)
Alefacept is a fully human lymphocyte function
associated antigen-3/immunoglobulin G1 fusion
protein that targets memory-effector T cells is an
effective therapy for psoriasis.95 In combination with
MTX, Alefacept is efficacious in PsA. In a phase 3 trial
with 185 patients, 54% of patients in the Alefacept plus
MTX group achieved an ACR 20 response, compared
with 23% of patients in the placebo plus MTX group
(P 0.001) at week 24.96 In patients with psoriasis
involving 3% BSA (n = 87), a PASI 50 response at
week 14 was achieved by 53% of patients receiving
Alefacept plus MTX compared with 17% of those
receiving placebo plus MTX (P < 0.001).96 Alefacept in
combination with MTX is thus a treatment option in
patients failing standard therapy.
Abatacept (CTLA4-Ig) is a recombinant human
fusion protein that binds to the CD80/86 receptor on
an antigen-presenting cell, thus blocking the second
241
signal activation of the CD28 receptor on the T-cell. It is

approved for use in RA.97 Results from a phase 2 study
using Abatacept in PsA show that Abatacept at 10 mg/
kg significantly improved ACR 20 and physical function in PsA patients. Abatacept treatment also resulted
in less joint damage by MRI evaluation.98
SURGICAL PROCEDURES
Section 4
::
242
There are few studies addressing surgery in patients

with PsA. It has been reported that about 7% of the
patients with PsA require surgery and that the likelihood of surgery increased with disease duration.99 The
average disease duration at the time of surgery was
13 years. The most common surgical procedure was
total hip replacement followed by total knee replacement. Joint replacement in the metacarpophalangeal
joints was also performed, followed by fusion surgery
for the fingers, wrists, and ankles. Few patients had
synovectomies, including knee, wrist, and elbow. The
majority of the patients had only one procedure, but
in 28% several procedure were performed. The upper
and lower extremities were involved in a similar number of patients with few patients having both upper
and lower extremity surgery. Surgery was predicted by
the number of actively inflamed joints and the extent
of X-ray damage at presentation to the clinic. Patients
with the highest number of severely affected joints
both clinically and on radiographs were more likely
to have surgery. Although patients who had surgery
had more severe disease, their health outcomes were
not worse than those who did not have surgery.99 In
another study of the type and outcome of reconstructive surgery for different patterns of psoriatic arthritis
over a 10-year period was studied.100 The patients were
divided into three groups: (1) distal joint involvement,
(2) oligoarticular, and (3) polyarticular. It was shown
that the majority of patients had polyarticular disease.
The majority of the operations done in this group of
patients included complex hand and foot reconstruction, followed by hip replacements, and surgical fusion
of different joints. In the oligoarticular group most of
the procedures involved joint replacement, usually the
hip or knee. Patients with distal arthritis had fusions
in the distal joints. Patients with polyarticular disease
had lower level of physical functioning according to
the scores on the physical function domain of a quality
of life questionnaire. Patients with severe axial arthritis may develop marked deformity of the spine and
on occasion require surgery to correct this deformity.
While there are no reported studies specifically describing spinal surgery in patients with PsA, the procedures
are similar to those performed in patients with AS.
RECOMMENDATIONS FROM GRAPPA

Based on formal literature reviews of therapies for
peripheral joints, spine, skin and nails, enthesitis, and
dactylitis, the GRAPPA group has developed a treatment grid categorizing each domain as mild, moderate, or severe based on measures of disease severity
and impact on function and quality of life in order to
help clinicians with treatment decisions.101 GRAPPA
recommends that all domains of the disease be considered to define severity of psoriatic disease. The
worst individual domain should guide the management of all domains of PsA. Thus, if the skin domain is
severe, but the peripheral arthritis is mild, the patient
is classified as heaving severe disease and treated for
severe psoriasis as appropriate. GRAPPA has also
suggested treatment strategies applicable to patients
worldwide.
KEY REFERENCES
2. Taylor W et al: Classification criteria for psoriatic arthritis: Development of new criteria from a large international study. Arthritis Rheum 54:2665, 2006
3. ONeill T, Silman AJ: Psoriatic arthritis. Historical background and epidemiology. Baillieres Clin Rheumatol
8:245, 1994
7. Chandran V, Raychaudhuri SP: Geoepidemiology and
environmental factors of psoriasis and psoriatic arthritis. J Autoimmun 34:J314, 2010
8. Duffin KC et al: Genetics of psoriasis and psoriatic
arthritis: Update and future direction. J Rheumatol
35:1449, 2008
10. Nair RP et al: Genome-wide scan reveals association
of psoriasis with IL-23 and NF-kappaB pathways. Nat
Genet 41:199, 2009
21. McGonagle D et al: The concept of a synovio-entheseal
complex and its implications for understanding joint
inflammation and damage in psoriatic arthritis and
beyond. Arthritis Rheum 56:2482, 2007
41. Bond SJ et al: Predictors for radiological damage in psoriatic arthritis: Results from a single centre. Ann Rheum
Dis 66:370, 2007
46. Gladman DD et al: Cardiovascular morbidity in psoriatic arthritis. Ann Rheum Dis 68:1131, 2009
68. Ravindran V, Scott DL, Choy EH: A systematic review
and meta-analysis of efficacy and toxicity of disease
modifying anti-rheumatic drugs and biological agents
for psoriatic arthritis. Ann Rheum Dis 67:855, 2008
89. Saad AA et al: Risks and benefits of tumor necrosis
factor-alpha inhibitors in the management of psoriatic
arthritis: Systematic review and metaanalysis of randomized controlled trials. J Rheumatol 35:883, 2008
102. Ritchlin CT et al: Treatment recommendations for psoriatic arthritis. Ann Rheum Dis 68:1387, 2009
Chapter 20 :: Reactive Arthritis

:: John D. Carter
REACTIVE ARTHRITIS AT A GLANCE
Reactive arthritis is one of the
spondyloarthritides. It is an inflammatory
syndrome that typically begins 14 weeks
after certain genitourinary or gastrointestinal
infections.
HLA-B27 appears to increase disease

susceptibility and chronicity of reactive
arthritis, but recent data suggest it might
portend more fulminate symptoms thereby
serving as a diagnostic bias.
Chlamydia, Salmonella, Campylobacter, Shigella,
and Yersinia are definitive triggers of reactive
arthritis, but other infections may also act as
initiators.
Although reactive arthritis often is selflimited in weeks to months, as many as
30%50% of patients will develop chronic
disease that often waxes and wanes.

TRIGGERING ORGANISMS
Bacteria that commonly cause ReA are Salmonella,
Shigella, Campylobacter, Yersinia, and Chlamydia trachomatis. Indeed, these organisms represent the definitive triggers of ReA; however many other infectious
agents have been implicated as potential causes
(Box 20-1). Chlamydia trachomatis (Ct) is the most
Reactive Arthritis
Psoriasiform lesions on the soles

keratoderma blenorrhagicumor penis
circinate balanitisoccur in one-third of
patients and inflammatory eye disease is
present in a similar proportion. Urethritis
may occur with or without urogenital
infection.
::
Key clinical features are asymmetric arthritis

of a few joints, most often large joints of
the lower extremities, often accompanied
by axial arthritis and enthesitis typically at
the Achilles tendon or plantar fascia and
sacroiliac joints.
Chapter 20
Most patients do not have the classic triad

of symptoms (synovitis, urethritis, and
conjunctivitis) and other organs are often
involved (namely the skin).
common etiologic agent causing ReA in the United

States.14,22 Despite the obvious difference of initial
route of infection (i.e., gastrointestinal vs. genitourinary), another distinction exists. The postdysentery
form of ReA is always preceded by a symptomatic
infection, and recent data suggest the more severe the
initial gastrointestinal infection, the more likely ReA
develops.2325 However, an initial Ct infection is often
asymptomatic.2628 Recent data suggest that an initial
asymptomatic Ct infection is a common cause of ReA.29
In this study, the majority of patients diagnosed with
uSpA, because of no known preceding infection prior
to the onset of their arthritis, were found to be polymerase chain reaction (PCR) positive for Chlamydiae
on synovial tissue analysis. This is in keeping with
previous data suggesting that 78% of subjects who
develop ReA after a venereal infection had an asymptomatic infection.30 A number of published studies also
indicate that Chlamydophila (Chlamydia) pneumonaie
(Cpn), a related respiratory pathogen, is another causative agent in ReA, albeit at a lower frequency.3133
Chlamydiae are Gram-negative, obligate intracellular organisms. The attack rate of ReA after a Ct infection is approximately 5%.30 Synovial tissue analyses
from patients affected with postchlamydial ReA have
shown that these organisms traffic from the initial site
of infection to the synovium. These synovium-based
Chlamydiae exist in a morphologically aberrant but
metabolically active viable state termed chlamydial
persistence.34,35 The pattern of gene expression is
attenuated and significantly different than that seen
during normal active infection. For example, during
persistence of Ct expression of the major outer membrane protein (omp1) gene and several genes required
for the cell division process are severely downregulated. This is coupled with differential regulations of
the three paralog genes specifying Chlamydia trachomatis heat shock proteins (HSP)-60 [(1) Ct110, (2) Ct604,
and (3) Ct755].36 The exact role that these synoviumbased persistent Chlamydiae play in terms of disease
pathogenesis or disease propagation is not completely
understood. Of note, it has been demonstrated that
these same persistent Chlamydiae traffic to other end
organs, specifically the skin in patients with suspect
keratoderma blenorrhagicum.37
Other recent data relating to Chlamydia-induced
ReA force us to reconsider our traditional paradigms.
Because these pathogens are responsible for genital
infections, it was logical to assume that the genital
strains of C. trachomatis were responsible for triggering
ReA. However, there are several serovars of C. trachomatis, specifically serovars A through K. Serovars A, B,
and C are ocular (trachoma) serovars and the remainders (serovars D through K) are genital. Remarkably, a
recent study analyzing the chlamydial serovars of 36
subjects with known C. trachomatis-induced ReA demonstrated that all 36 synovial tissue samples were positive for the ocular serovars, not the genital serovars.38 It
243
Box 20-1 Triggering Microbes of

Reactive Arthritis
DEFINITE CAUSES
Postvenereal
Chlamydia trachomatis
Section 4
Postenteric
Salmonella (S. enteritidis, S. typhimurium,
S. bovismorbificans, S. blockley)
Shigella (S. flexneri, S. dysenteriae, S. sonnei,
S. boydii)
Campylobacter (C. jejuni, C. coli)
Yersinia (Y. enterocolitica, Y. pseudotuberculosis)
PROBABLE CAUSES
::
Chlamydophila (Chlamydia) pneumoniae

Ureaplasma urealyticum
Bacille Calmette-Gurin (intravesicular)
POSSIBLE CAUSES
Bacillus cereus
Brucella abortus
Clostridium difficile
Escherichia coli
Helicobacter pylori
Hafnia alvei
Lactobacillus
Neisseria meningitidis serogroup B
Pseudomona
Intestinal parasites (Strongyloides stercolis, Taenia
saginata, Giardia lamblia, Ascaris lumbricoides, Filariasis, and Cryptosporidium)
OTHER TYPES OF INFLAMMATORY ARTHRITIS IN
WHICH BACTERIA MAY PLAY A CAUSATIVE ROLE
Borrelia burgdorferi (Lyme disease)
Propionbacterium acnes (SAPHO)
Streptococcus sp. (poststreptococcal reactive
arthritis)
Trophyrema whippelii (Whipples disease)
Reprinted with permission from Carter JD: Reactive arthritis:
Defined etiologies, emerging pathophysiology, and unresolved
treatment. Infect Dis Clin North Am 20:827, 2006.
is known that genital infection with the ocular strains

do occur, but are rare.39,40 The infrequent rate of genital
infections with the ocular strain might explain the low
attack rate of ReA in patients with acute chlamydial
infections.
HOST FACTORS
244
Reactive arthritis represents the classic interplay of

host and environment. The environmental triggers
outlined above play and undeniable role in disease

genesis; the concept of bacterial persistence lends
speculative support that these pathogens might also
play a role in disease propagation. Certain bacterial
serovars or species might be particularly arthritogenic
or more prone to dissemination. However, genetic susceptibility also clearly plays a role. Because ReA is one
of the spondyloarthritides, much of the focus on host
genetics has centered on HLA-B27. There are also data
indicating that patients with HIV are at increased risk
for ReA and the symptoms can improve with antiretroviral HIV therapy.57
The prevalence of HLA-B27 and reactive arthritis
varies around the world.58 In Caucasian populations,
HLAB27 is present in 7%9% of individuals. Older literature suggested that as many as 70%80% of patients
with ReA were HLA-B27 positive.59,60 However, several large epidemiological studies of ReA now dictate
that, in reality, about 30%50% of ReA patients are
positive for this antigen.45,6167 More recent data even
suggest there might be no association with HLA-B27
and ReA.25,47,64 The vast majority of data regarding the
prevalence of HLA-B27 in ReA comes from epidemiological studies of postenteric ReA after outbreaks with
certain enteric pathogens. Therefore, the true prevalence of HLA-B27 in postchlamydial ReA is less well
defined.
The possibility exists that HLA-B27 plays more of
a role with phenotypic disease expression rather than
a true genetic susceptibility locus. Several large ReA
studies demonstrate that HLA-B27 positive patients
have more severe symptoms, thereby making the
condition more clinically apparent.23 This haplotype
might also increase ones risk for developing the complete triad of symptoms.68 It should also be noted that
the variation in the prevalence of HLA-B27 in various studies described above could, at least in part, be
explained by the potential role that HLA-B27 plays on
phenotypic expression. The studies cited above suggesting that HLA-B27 has little to no role in disease
susceptibility include patients with milder symptoms,
whereas the previous studies demonstrating a higher
HLA-B27 prevalence only include patients with more
fulminate symptoms sometimes requiring the complete triad of symptoms.
Whether HLA-B27 is more important in disease
susceptibility or clinical expression, it clearly plays a
role in ReA. Many theories exist regarding its pathophysiologic role, but none are proven. Since HLA-B27
is a Class I histocompatability antigen, it has been
postulated that HLA-B27 presents arthritogenic microbial peptides to T cells stimulating an autoimmune
response, so called molecular mimicry.69 Conversely,
B27 itself may serve as the autoantigen that is targeted
by the immune system.70 It is also possible that exposure to the triggering bacteria may subvert self-tolerance to the B27 antigen.71 Another theory suggests that
the role of HLA-B27 may be to enhance invasion of
the causative organisms into human intestinal epithelial cells in patients with postenteric ReA.72 Vast data
demonstrate that misfolding of HLA-B27 can lead to
the unfolded protein response enhancing the production of interleukin-23;73 however this unfolded pro-
Reactive Arthritis
It is apparent that the causative bacteria of ReA are

incorporated intracellularly, either in-part or in-whole,
then taken from the site of initial infection and trafficked to the synovium. However, what governs this
process is not yet evident. It is also not clear if their
presence in the affected organs represents a trigger for
an autoimmune response, or if these organisms are the
source for the inflammatory process. It appears that
this phenomenon of cellular uptake, trafficking, and
host tolerance is multifactorial in nature.
Although the causative organisms are intracellular pathogens, the process of cellular uptake is not
entirely apparent. Indeed the specific mechanisms for
cellular uptake of these microbes are probably different for each organism. In the case of Chlamydiae, the
quest to find a specific extracellular ligand has been
unsuccessful. Intriguing recent data suggest that there
might not be a specific chlamydial ligand, rather these
pathogens might utilize a different ligand entirely.
Apolipoprotein E (ApoE4) that is adherent to the surface of chlamydial elementary bodies (EB) attaches to
the host cell low-density lipoprotein (LDL) receptor
family carrying the EB with it.77 However, this only
appears to be true of C. pneumoniae, not C. trachomatis. In the case of Salmonella, type 1 fimbriae mediate
the attachment of this organism to the cell leading to
internalization.78
Toll-like receptors (TLR) are a key component of the
innate immune system. Because they are among the
first line of defense against microbes and they recognize extracellular pathogens, they could play a role
in ReA. All of the definitive triggering organisms are
Gram-negative with a lipopolysaccharide (LPS) component to their cell wall, and TLR-4 recognizes LPS.
TLR-4 deficient mice exposed to Salmonella demonstrate dramatically increased bacterial growth and
demise.79 Other animal data have shown that effective
host clearance of Ct depends on appropriate TLR-4
expression by neutrophils.80 However, recent human
data suggest that TLR-2, not TLR-4, is important in
determining ReA disease susceptibility after a Salmonella infection.81
::
PATHOPHYSIOLOGY
In terms of cytokine response in ReA, it appears

that both Th1 and Th2 are important, but the Th2
pathway predominates. Although ReA patients have
higher serum TNF- (Th1) than normal controls,82
lower levels of TNF- have been demonstrated in ReA
compared to other types of inflammatory arthritis.8385
Synovial fluid analyses from patients with ReA demonstrate higher levels of IL-10 and lower levels of TNF and IFN- (favoring a Th2 profile).84,85 Interestingly,
in terms of postchlamydial ReA, lower levels of these
same two cytokines (TNF- and IFN-) have been
associated with increased chlamydial replication and
overall bacterial burden in vitro.8688 The suppression
of Th1 cytokines is likely mediated through suppression of IL-12 synthesis.
Data also exist suggesting that these cytokine levels can change over time. ReA patients with a disease
duration of greater than 6 months secreted significantly less TNF-.83 Temporal relationships of these
different Th1 and Th2 cytokines might also be important in disease manifestations. Slight changes in the
Th1/Th2 balance may explain the relapsing course
that is frequently seen chronic ReA. Animal data also
suggest that blunting of the initial cytokine response
of TNF-, IFN-, and Interleukin-4 (IL-4) to an acute
chlamydial infection leads to decreased bacterial clearance.89 Therefore, lower initial responses of these Th1
cytokines may increase the likelihood of developing
ReA. These animal data provide an interesting potential correlate to the fact that asymptomatic chlamydial
infections in humans can often lead to ReA.
Chapter 20
tein response has not been definitively linked to ReA.

HLA-B27 has multiple alleles that could influence host
response and disease susceptibility. One study suggests that although HLA-B*2705 is the most common
allele observed in B27-positive ReA patients, this allele
is seen less frequently than in the other SpAs and in
B27 healthy controls.74
While HLA-B27 is important to pathogenesis in
ReA, it is not the sole determinant. Clearly patients
who are HLA-B27 negative can develop ReA. It has
been suggested that HLA-B*5703 increases the risk for
the classic triad of symptoms in patients who develop
ReA.75 Gene expression analyses suggest that proangiogenic factors account for genetic susceptibility of
ReA.76 Much remains to be learned about other HLA
loci or even non-HLA genes that might be important in
the pathophysiology of ReA.
In spite of the fact that ReA has several distinct etiologic agents and the apparent differences in the pathophysiology depending on the triggering microbe, the
clinical features of ReA are congruent regardless of the
initiating infection. The clinical syndrome that encompasses ReA can involve many different organ systems,
although it has a predilection for the synovium, urethra, eye, and the skin (Box 20-2). The symptoms start
within 14 weeks of the initial infection. However, as
stated with Chlamydiae, the inciting infection could be
asymptomatic obfuscating the diagnosis. It has traditionally been felt that the vast majority of cases of ReA
resolve spontaneously within weeks to months, but
more recent data suggest that 30%50% of cases can
become chronic.45,6167 One series suggested that 63% of
patients develop chronic symptoms.18 In general, if a
patient experiences symptoms of longer than 6 months
duration, then they are felt to have chronic disease
(Box 20-3). Typically, patients have more significant
symptoms during the acute phase; these can include
constitutional symptoms (malaise, fatigue) and fever.
If the symptoms persist, then the long-term manifestations tend to be milder. In these chronic cases, it is not
unusual for the symptoms to wax and wane.
ReA is often misdiagnosed or underdiagnosed. The
reasons are varied, but an overreliance on the classic
clinical triad of symptoms lends to this underdiagnosis. Some of the earliest descriptions of ReA included
245
Box 20-2 Clinical Manifestations of ReA

ACUTE SYMPTOMS
Articular
Most commonly present with oligoarthritis, but can also present with polyarthritis or monoarthritis
Section 4
Axial
Frequently involved
Sacroiliac joints
Lumbar spine
Occasionally involved
Thoracic spine (usually seen in chronic ReA)
Cervical spine (usually seen in chronic ReA)
Cartilaginous joints (symphysis pubis; sternoclavicular and costosternal joints)
Peripheral
Frequently involved
Large joints of the lower extremities (especially knees)
Dactylitis (sausage digit)
Very specific for a spondyloarthropathy
::
Enthesitis
Hallmark feature: inflammation at the transitional zone where collagenous structures such as tendons and
ligaments insert into bone.
Common sites: plantar fasciitis, Achilles tendonitis; but any enthesis can be involved.
Mucosal
Oral ulcers (generally painless)
Sterile dysuria (occurs with both postvenereal and postdysentery forms)
Cutaneous
Keratoderma blenorrhagicum
Pustular or plaque-like rash on the soles and/or palms

Grossly and histologically indistinguishable from pustular psoriasis
Can also involve nails (onycholysis, subungal keratosis, nail pits), scalp,
extremities
Circinate balanitis
Erythema or plaque-like lesions on the shaft and/or glans of penis
Ocular
Conjunctivitis
Anterior uveitis (iritis)
Rarely described
Typically during acute stages only

Often recurrent
Scleritis, pars planitis, iridocyclitis, and others
Cardiac
Pericarditis (uncommon)
patients with this triad of symptoms. For many years,

clinicians felt this triad was necessary for the diagnosis. In 1976, the concept of Incomplete Reiter syndrome was introduced describing a case series of 13
patients, who were predominately HLA-B27 positive,
and presented with oligoarthritis, heel pain, periostitis,
dactylitis, and mucocutaneous lesions, but no urethritis
or conjunctivitis.90 It is now apparent that the majority
of cases do not involve the three classic organ systems.
ARTICULAR
246
ReA nearly always involves an inflammatory arthritis.

It is unclear if some patients with other symptoms of
ReA, such as recurrent uveitis or enthesitis without

arthritis, might represent cases of ReA as well. Patients
with ReA can develop an inflammatory arthritis that
involves the axial skeleton and/or the peripheral
joints.
The axial arthritis of ReA (Box 20-2) presents as pain
and stiffness in the low back and/or buttocks. A classic
feature is prolonged pain and stiffness in the morning or
after periods of rest or inactivity. These symptoms tend
to improve with activity or exercise. The cause of the
pain includes inflammation in the synovial portion of
the sacroiliac joints and enthesitis of these same joints,
pelvis, and lumbar spine. The combination of synovitis
and enthesitis of the sacroiliac joints results in one of the
classic features of ReA, i.e., sacroiliitis. These symptoms
Box 20-3 Clinical Manifestations

of ReA
CHRONIC SYMPTOMS (6 MONTHS)
Articular
Large joints of the lower

extremities (especially
knees)
Dactylitis
(sausage digit)
Very specific for a spondyloarthropathy
Enthesitis
Chronic inflammation can cause collagen fibers
to undergo metaplasia forming fibrous bone
Chronic enthesitis leads to radiographic findings:
Plantar/Achilles spurs
Periostitis
Nonmarginal syndesmophytes
Syndesmoses of the sacroiliac joints
Mucosal
Sterile dysuria
Cutaneous
Keratoderma blennorrhagicum
Circinate balanitis
Ocular
Anterior uveitis
(iritis)
Rarely described
Often recurrent
Scleritis, pars planitis,
iridocyclitis, and others
Cardiac
Aortic regurgitation
Valvular pathologies
Reprinted with permission from Carter JD, Hudson AP: Reactive
arthritis: Clinical aspects and medical management. Rheum Dis
Clin North Am 35:21, 2009.
might be more pronounced during the acute phase of

the illness. It is important to note that sacroiliitis can
often be documented on plain radiographs, but these
imaging studies might be of lesser utility in patients
with acute symptoms since radiographic evidence of
sacroiliitis can take weeks to months to develop. In
patients with a high index of suspicion of acute disease and normal plain radiographs, advanced imaging
with magnetic resonance imaging (MRI) might prove
useful (Fig. 20-1). Such advanced imaging can show
evidence of early inflammatory sacroiliitis that might
Reactive Arthritis
Peripheral
::
Sacroiliac joints
Lumbar spine
Thoracic spine
Cervical spine
Cartilaginous joints
(symphysis pubis;
sternoclavicular joints)
Chapter 20
Axial
be otherwise missed by conventional radiographs.91

Plain radiographs remain the imaging investigation of
choice for patients with chronic disease. ReA patients
with radiographic sacroiliitis typically have unilateral
or bilateral asymmetric findings.
The axial inflammatory arthritis of ReA involves the
thoracic and cervical spine less often than the lumbar
spine. If present, symptoms are similar including prolonged pain and stiffness in the morning and improvement with activity. In addition to sacroiliitis, patients
can also develop spinal changes on plain radiographs.
The most typical finding is nonmarginal syndesmophytes (eFig. 20-1.1 in online edition). These are thick,
bridging, comma-shaped bony growths between vertebral bodies. These are most often seen in patients
with chronic disease. Finally, the axial symptoms can
include inflammation in cartilaginous joints, such as
the symphysis pubis or sternoclavicular joints, with
resultant radiographic changes.
The peripheral arthritis of ReA most often is an inflammatory oligoarthritis; there is a predilection for the large
joints of the lower extremities. However, patients can
also present with a polyarthritis or even monoarthritis.
This clinical picture involving one or a few joints, particularly of the lower extremities contrasts with other
types of inflammatory arthritis, such as rheumatoid
arthritis, that typically present with a symmetrical polyarthritis. As with the axial symptoms, these tend to be
more pronounced during the acute stage and can relapse
and remit. In patients with more chronic or severe cases
the small joints of the hands and feet can be involved.
Radiographic features of peripheral joints in patients
with chronic disease can include erosive changes, periostitis, and possibly even pencil-in-cup deformities most
often associated with psoriatic arthritis.
Dactylitis (sausage digit) is a valuable diagnostic
clue for potential ReA (Fig. 20-2). Dactylitis represents
diffuse inflammation of an entire finger or toe. While
not specific to ReA, if present, it is strongly suggestive
of a spondyloarthropathy. Besides the spondyloarthropathies, only a few conditions, namely sarcoidosis
and gout, cause dactylitis. One series suggested that
ReA was the most common diagnosis in patients presenting with dactylitis; 28% of ReA patients had this
finding as part of their constellation of symptoms.92
ENTHESITIS
Enthesitis, or fibrocatilagenous enthesitis, is inflammation at the transitional zone where collagenous structures such as tendons, ligaments, and joint capsules
insert into bone. This is a hallmark feature of ReA (as
well as for other types of spondyloarthritis). There are
two main phases of enthesitis: (1) subchondral osteitis
and (2) reparative ossification. The inflammation starts
in the intraosseous portion of the enthesis, eventually
destroying the bone and cartilage plate. The defect is
rapidly filled with newly formed bone that extends to
the terminal part of the tendon producing an enthesophyte (eFig. 20-2.1 in online edition). Common types
of enthesitis in ReA are Achilles tendonitis and plantar
fasciitis, but inflammation can occur at any enthesis.
247
Section 4
::
248
Figure 20-1 Magnetic resonance image showing unilateral sacroiliitis.
Sacroiliitis represents a combination of synovitis and

enthesitis.93 A recent report of >6,000 cases of cultureconfirmed infections with bacterial enteric pathogens
revealed that enthesitis was the most common finding
in those individuals who developed ReA.25
CUTANEOUS
Dermatologic manifestations of ReA are several. The
two most common are keratoderma blenorrhagicum
and circinate balanitis. Keratoderma blenorrhagicum
is a pustular or plaque-like rash that most often occurs
in a palmoplantar distribution (Fig. 20-3). These
Figure 20-2 Dactylitis of second toe (sausage toe).
Figure 20-3 Keratoderma blennorrhagicum.
(Boxes 20-2 and 20-3)

Although the original classic triad of symptoms
of ReA included eye involvement, conjunctivitis was
specifically mentioned. Not only do patients with ReA
develop conjunctivitis, they often develop iritis/anterior uveitis. Although both conditions can occur at any
time during the condition, it has traditionally been felt
that conjunctivitis most often occurs during the early
stage and less frequently becomes chronic whereas iritis/anterior uveitis occurs both as an acute and chronic
(intermittent) problem. However, a long-term study of
25 ReA subjects with eye involvement at the time of
diagnosis demonstrated that long-term ocular complications included conjunctivitis and anterior uveitis in
96% and 92% of patients, respectively.102 Other longterm complications were seen in this study including
posterior uveitis (64%), keratitis (64%), cataract (56%),
intermediate uveitis (40%), scleritis (28%), cystoid
macular edema (28%), papillitis (16%), and glaucoma
(16%). These data suggest that patients with ocular
involvement at the time of diagnosis are at increased
risk for many long-term ocular complications; perhaps
this risk is higher than previously appreciated.
Reactive Arthritis
OCULAR
::
occur in about 20%30% of ReA patients.96 The relationship between distal interphalangeal arthritis and
nail involvement is well recognized in psoriatic arthritis,97 the same is also likely to be true for ReA, but there
are no definitive data in this regard.
The true prevalence of keratoderma blenorrhagicum and circinate balanitis in patients ReA remains
somewhat uncertain. Previous data have suggested
that they occur in about 10%98 and 50%99 of patients,
respectively and it was felt that they are more common in patients who are HLA-B27 positive.100 However, as is the case with ReA in general, it is not clear
if this genetic marker truly increases the occurrence
of these cutaneous manifestations or if it has served
as a diagnostic bias. More recent data demonstrate
that circinate balanitis more strongly correlates with
a previous chlamydial infection than previously
thought.101 In this same study, there was no apparent association with HLA-B27 and the majority of
patients had no other signs or symptoms of ReA. The
fact that these lesions are also clinically and histological indistinct from pustular psoriasis can also obfuscate the diagnosis.
Chapter 20
typically begin as erythematous macules or vesicles.

These vesicles are often pustular in nature, but they
can also be hemorrhagic; over time they can become
thickened or papular forming a horny excrescence.
These chronic lesions can become hyperpigmented
and may coalesce. Rarely these lesions can occur in a
more general distribution involving the entire body94;
this is felt to be more likely in the setting of HIV. Interestingly, keratoderma blenorrhagicum is clinically
and histologically indistinct from pustular psoriasis.95 Histologic findings include hyperkeratosis and
parakeratosis, elongation and hypertrophy of the rete
ridges, general epidermal hyperplasia, and extensive
neutrophilic infiltration with formation of microabscesses and spongiform pustules. Recently it has been
demonstrated that these lesions are PCR positive for
Chlamydia trachomatis in patients with suspected Chlamydia-induced ReA.37
Circinate balanitis is a cutaneous manifestation
of ReA involving the penis. These are erythematous, pustular, or plaque-like lesions that most
often involve the glans of the penis, but they can
include the shaft and rarely the scrotum (Fig. 20-4).
It has been suggested that these lesions on the glans
can exhibit different characteristics depending on
whether the patient is circumcised or not. In circumcised males, hyperkeratotic plaques are most typical
and in uncircumcised patients they often begin as
vesicles or pustules that may coalesce into a circinate
pattern (Fig. 20-4).96 Females with ReA can rarely get
ulcerative vulvitis that has similar appearance to circinate balanitis.
Patients with ReA may also have nail involvement,
which is similar to psoriasis and presents as onycholysis, subungal keratotic debris, transverse ridges, periungual scaly lesions, and nail pitting. These changes
MUCOSAL
Figure 20-4 Circinate balanitis.
(Boxes 20-2 and 20-3)

Mucosal involvement of the mouth, oral pharynx,
and tongue can occur in patients with ReA, but these
are infrequent. If they occur, typical lesions on the
oropharnyx include diffuse erythema, macules, and
plaques. They are often painless and might go unnoticed by the patient. Such lesions will sometimes present with bleeding. Lesions involving the tongue are
most often circinate or annular in appearance. More
249
common mucosal manifestations include intestinal

inflammatory lesions that resemble those of inflammatory bowel disease. One study found that 67% of subjects with ReA had histologic evidence of ileocolitis,
even in the absence of gastrointestinal symptoms.103
This finding might be higher in patients with postenteric ReA. Finally, it is well described that patients with
ReA develop sterile dysuria. Interestingly this occurs
with equal frequency in both postvenereal and postenteric ReA. This sterile dysuria can become a chronic
intermittent problem for some patients. Prostatitis,
cystitis, and pelvic inflammatory disease have also
been described.104,105
Section 4
CARDIAC
::
(Boxes 20-2 and 20-3)

Cardiac involvement from ReA is rare. There are
sparse reports of ReA patients developing pericarditis, aortic regurgitation, or valvular pathologies. When
they occur, they are more likely in chronic disease.
These manifestations are rare enough in the acute
setting that routine echocardiography is not recommended.106 Electrocardiographic abnormalities can
occur in the acute setting with significant arrhythmias
occurring in approximately 5% of patients.107
DIAGNOSIS
Diagnostic criteria are broad and rely on clinical symptoms.100,108 Difficulties with these diagnostic criteria
have been raised.109 The traditional disease definition
also suggests that ReA represents a sterile inflammatory arthritis, but data presented above, specifically
pertaining to Chlamydiae, challenge this paradigm.
Although not pathognomonic for the condition, the
documentation of the DNA presence of one of the
causative organisms by PCR in synovial tissue or fluid
of patients who fulfill the clinical criteria for ReA represents the most accurate means of diagnosing the condition.110 Unfortunately, such synovial tissue analysis is
not readily available for the majority of clinicians. Stool
and urogenital sampling for the causative organisms in
patients with chronic disease have been analyzed, but
many patients test negative limiting the utility of this
approach.111,112 Serologic testing for antibodies to the
causative organisms is unreliable. Because more than
half of affected patients are HLA-B27 negative, this
genetic antigen should not be utilized as a diagnostic
tool. Therefore, at the current time we are left without a
practical diagnostic test. Recognition of an underlying
spondyloarthritis and identifying one of the triggering
infections remains the most practical means of diagnosis ReA until better diagnostic tests are widely available. A diagnostic algorithm is shown in Figure 20-5.
TREATMENT
250
In the setting of acute or mild ReA, treatment is most

often symptomatic and conservative. It is important to
remember that many of the symptoms of acute ReA

are self-limiting. The initial treatment of choice for the
arthritis is nonsteroidal anti-inflammatory (NSAIDs).
Not only is there a breadth of clinical experience
with NSAIDs demonstrating their efficacy, there are
also two randomized trials that have formally evaluated their use in ReA. The first was a double-blind
crossover study comparing azapropazone to indomethacin in patients with both psoriatic arthritis and
ReA.113 Both medications were efficacious with a trend
favoring indomethacin. Neither medication helped
with the skin manifestations of either condition. The
second was another double-blind crossover study
comparing ketoprofen to indomethacin in 50 patients
with ReA.114 Both drugs were efficacious in treating
the articular symptoms with no significant difference
between the two. There were slightly more adverse
events with indomethacin in both studies. Corticosteroids are quite helpful in patients with more severe
articular symptoms. It has been suggested that systemic corticosteroids might be more efficacious in the
treatment of peripheral articular symptoms rather than
the axial symptoms.115 Because ReA often involves one
or few joints, intra-articular corticosteroids are often a
useful treatment strategy.
Initial treatment of many of the extra-articular features of ReA includes topical corticosteroids. These
have been utilized to treat iritis/uveitis, keratoderma
blenorrhagicum, and circinate balanitis.115 Given the
similarities between the cutaneous manifestations of
ReA and psoriasis, it is not surprising that other medications used to treat psoriasis have been advocated as
potential treatments for keratoderma blenorrhagicum
and/or circinate balanitis. Data suggest that topical
calcipotriene is a useful treatment modality for keratoderma.116 Emollients, keratolytics, coal tar, and phototherapy have also been advocated for keratoderma
blenorrhagicum. In severe cases of keratoderma
blenorrhagicum and circinate balanitis methotrexate
(low-dose regimen as for psoriasis) and etretinate
(0.5 mg/kg body weight) have been found to be
beneficial but no formal clinical trials have been performed!
In spite of the fact that ReA often remits, as many
as 30%50% of patients will develop chronic disease.
Both the articular and extra-articular features can persist. Because ReA can lead to pathologic sequelae (e.g.,
joint damage, visual impairment, skin disfigurement)
resulting in decreased health-related quality of life,
more definitive treatments have been sought. Paralleling the opposing schools of thought regarding the true
role bacterial persistence plays in the pathophysiology of the disease, both traditional disease modifying
antirheumatic drugs (DMARDs) and antibiotics have
been assessed as potential therapeutic options. The latter have been studied in both acute and chronic disease, whereas the former are most often reserved for
patients with chronic symptoms.
Several DMARDs have been advocated as treatments for ReA. These include sulfasalazine, methotrexate, azathioprine, and cyclosporine. Surprisingly,
only one of these, sulfasalazine, has been formally
evaluated in prospective clinical trials. Sulfasalazine
Diagnosis algorithm making the diagnosis
Is it spondyloarthropathy?
History
joint or enthesis pain
a few sites
lower limbs
buttock pain
heel pain
past history knee swelling, iritis, heel pain
family history psoriasis, IBD, back pain
Chapter 20
::
Examination
mono or oligoarthritis
achilles tendonitis, plantar fasciitis
psoriasis, IBD, inflammatory eye disease
acute phase response

radiographs/MRI sacroiliac joints
chest radiograph normal
ophthalmologic exam
HLA-B27
synovial fluid culture - positive

synovial fluid microscopy - positive
chest radiograph - abnormal
YES
YES
Spondyloarthropathy
Not a spondyloarthropathy
Reactive Arthritis
Investigations
Is it reactive arthritis?
YES
History
recent new sexual contact
contact with diarrheal illness
dysuria or diarrhea
sore throat or cough
Investigation
urethral/cervical smear
genital tract cultures/PCR/antigen detection
stool culture
Yersinia serology, ASOT, antiDNAse B
NO
Undifferentiated
spondyloarthropathy
YES
Reactive arthritis
Figure 20-5 Diagnostic algorithm making the diagnosis. Anti-DNAse B = antideoxyribonuclease B; ASOT = antistreptolysin O titer; IBD = inflammatory bowel disease; MRI = magnetic resonance imaging; PCR = polymerase chain reaction.
251
Section 4
::
252
has been studied as a potential treatment for both

acute and chronic ReA. In the acute ReA study, there
was no significant difference between sulfasalazine
and placebo in terms of pain, number of swollen
joints, and erythrocyte sedimentation rate (ESR) after 6
months of therapy.117 In addition, there was no apparent efficacy difference in patients regarding the initial
triggering infection, HLA-B27 status, or presence/
absence of axial arthritis. However, it is important to
remember that acute ReA often remits spontaneously,
so this potentially confounds these data. Sulfasalazine
has also been studied in the setting of chronic ReA.118
In this study, all patients had failed NSAIDs and were
followed for 36 weeks duration. There was a trend
favoring sulfasalazine over placebo in terms of overall
response. Sulfasalazine fared significantly better than
placebo in some of the secondary endpoints including
a longitudinal analysis and ESR.
The tumor necrosis factor (TNF)- antagonists have
demonstrated remarkable success treating several
types of inflammatory arthritis including other types
of spondyloarthritides, namely ankylosing spondylitis
and psoriatic arthritis. Therefore it might seem logical
that they would be useful therapeutic agents for ReA.
However, several studies suggest that ReA is more of a
Th2 driven disease.8385 Conversely, ReA patients have
higher serum TNF- levels than normal controls.82
Adding to this complexity, it has been suggested that
the Th1 versus Th2 predominance depends on the
cell analyzed (synovial fluid derived T-cell clones vs.
synovial fluid mononuclear cells).82 It should also be
noted that, in the case of chlamydial persistence, chlamydial replication is inversely proportional to TNF-
levels.8688 There are no randomized trials in ReA to
accurately assess the efficacy of anti-TNF therapy, but
several case reports and a small open label study suggest clinical benefit with these drugs in the treatment
of ReA.119122 It might also be noteworthy that a rare,
but defined, adverse event of anti-TNF therapy, in
general, includes the onset of de novo psoriasis.123 The
similarities of keratoderma blenorrhagicum and pustular psoriasis are well described. The majority of these
cases of anti-TNF therapy induced psoriasis occurs on
the palms and/or soles and is pustular in nature. Three
reported cases have been shown to be PCR positive for
Chlamydia trachomatis on lesional skin biopsies.37 The
exact pathophysiology of these de novo cases of psoriasiform lesions remains unknown.
The fact that certain bacterial organisms are responsible for the genesis of ReA makes the notion of using
antibiotics plausible. Data have demonstrated that the
causative bacterial organisms traffic to the synovium
and in the case of persistent synovium-based Chlamydiae, specifically, these organisms exist in a viable,
albeit aberrant, state. This important difference in postchlamydial and postenteric ReA suggests a potential
difference in antimicrobial response.
The first prospective, double-blind trial assessed
antibiotics in the setting of acute ReA.124 In this trial,
3 months of therapy with lymecycline significantly
decreased the duration of illness in those subjects with
postchlamydial ReA, but not those with the postenteric variety. This led to several studies assessing the
utility of long-term treatment with various antibiotics,

including ciprofloxacin, azithromycin, and doxycycline, in the ensuing years that produced negative
results.67,125128 However, the initial concept that postchlamydial and postenteric ReA might behave differently in terms of therapeutic response was somewhat
lost in these follow-up studies. More recently, data
have suggested that a prolonged course of combination antibiotics is an efficacious treatment specifically
for chronic postchlamydial ReA. Initially, an openlabel comparison of doxycycline with rifampin versus doxycycline monotherapy suggested superiority
with the former.65 A double-blind, placebo-controlled
follow-up study demonstrated that 6-month courses
of doxycycline with rifampin and azithromycin with
rifampin were significantly better than placebo.129
In this study, all patients had to be PCR positive for
Chlamydiae in order to be randomized to treatment.
Significantly more patients on combination antimicrobial therapy converted to PCR negative compared to
those treated with placebo after 6 months of therapy.
CONCLUSION
In terms of chronic diseases, ReA is unique in that the
etiologic agents are known. This insight into disease
initiation has led to significant advances in the understanding of this condition but much remains to be
learned regarding its pathophysiology. In an almost
ironic fashion, the definitive nature of disease genesis is juxtaposed with convoluted evolution regarding disease terminology and the original overreliance
on the classic triad of symptoms; these issues have
now been clarified. However, there remains ambiguity
regarding a definitive therapeutic approach. Ongoing
studies will hopefully answer the latter.
KEY REFERENCES
25. Townes JM et al: Reactive arthritis following cultureconfirmed infections with bacterial enteric pathogens in
Minnesota and Oregon: A population-based study. Ann
Rheum Dis 67:1689, 2008
29. Carter JD et al: Chlamydiae as etiologic agents in
chronic undifferentiated spondylarthritis. Arthritis
Rheum 60:1311, 2009
30. Rich E et al: Reactive arthritis in patients attending
and urban sexually transmitted disease clinic. Arthritis
Rheum 39:1172, 1996
34. Gerard HC et al: Synovial chlamydia trachomatis in
patients with reactive arthritis/Reiters syndrome are
viable but show aberrant gene expression. J Rheumatol
25:734, 1998
38. Gerard HC et al: Patients with Chlamydia-associated
arthritis have ocular (trachoma), not genital, serovars of
C. trachomatis in synovial tissue. Microb Pathog 48:62,
2010
96. Wu BI, Schwartz RA: Reiters syndrome: The classic
triad and more. J Am Acad Dermatol 59:113, 2008
129. Carter JD et al: Combination antibiotics as a treatment
for chronic Chlamydia-induced reactive arthritis. Arthritis Rheum Feb 12, 2010. [Epub ahead of print]
Chapter 21 :: Pustular Eruptions of Palms and Soles

:: Ulrich Mrowietz
PALMOPLANTAR PUSTULOSIS
AT A GLANCE
Chronic inflammatory disorder with sterile
pustule formation.
Affects only palms and soles.
High rate of recurrence.

Often resistant to treatment.
PALMOPLANTAR PUSTULOSIS
PPP is a chronic pustular dermatosis localized on the
palms and soles only. High resistance to treatment and
a high recurrence rate are characteristic. Histologically,
it is characterized by intraepidermal vesicles filled
with neutrophils.
Although many textbooks describe PPP along with
psoriasis, it has an entity of its own.
The involvement of palms and soles has a great
impact on life quality and the ability to work.
EPIDEMIOLOGY AND GENETICS

PPP has a worldwide distribution. It is a rare condition, but the exact incidence is not known. Females
show a higher prevalence than males, with a ratio of
approximately 3:1. Onset of the disease occurs mostly
between the ages of 20 and 60 years; rarely, the condition occurs after the sixth decade of life, and in 10% of
the patients the onset is before the age of 20 years.
HLA typing of patients with PPP reveals no increased
frequency of any of the known psoriasis-linked alloantigens.1 In a direct comparison among chronic-plaque
psoriasis, guttate psoriasis, and PPP, the three major
candidate genes within the PSORS1 region [(1) HLACw*6, (2) HCR*WWCC, and (3) CDSN*5] showed a

The cause of PPP is not known. An imbalance of the
protease/antiprotease system in the skin consisting of
decreased antileukoprotease (elafin/SKALP) activity
in pustular psoriasis has been discussed as a possible
mechanism of pustule formation.7 Exacerbation of PPP
has been observed after patch testing with metals and
was accompanied by elevated leukotriene B4 levels in
plasma and pustules.8
In a long-term survey from Japan, the incidence of
PPP was found to be positively correlated to heavy
smoking (more than 20 cigarettes per day), tonsillitis,
and seasonal factors such as high humidity and high
temperature.9,10
The most striking association in PPP is smoking. In
two Swedish surveys, 95% of PPP patients were smokers at onset of disease and cessation of smoking was
the most important measure to treat the disease.11,12
There is evidence from immunohistochemical studies
that nicotinic acetylcholine receptors are modulated in
lesional skin from smoking PPP patients when compared to disease-free smokers and healthy controls
suggesting an abnormal response to nicotine in PPP.13
The possible involvement of neutrophils infiltrating
sweat glands and ducts expressing choline acetyltransferase and the -3 and -7 nicotinic acetylcholine
receptors as a target for nicotine/smoking was discussed as an important mechanism for manifestation
and/or maintenance of PPP.14
Investigating the tissue of tonsils of PPP-patients a
unique formation of lymphoid follicles surrounded
Pustular Eruptions of Palms and Soles
Pustular eruptions of the palms and soles include palmoplantar pustulosis (PPP), acrodermatitis continua
(Hallopeau disease), and infantile acropustulosis. The
entities present with chronic and persistent eruptions
of sterile, purulent vesicles.
A drug-induced rash clinically resembling PPP has
been described in patients treated with tumor necrosis
factor- (TNF-)-antagonists.
::
Can be part of SAPHO (synovitis, acne,

pustulosis, hyperostosis, osteitis) syndrome.
Chapter 21
Disabling in severe cases.
high association to guttate and chronic plaque psoriasis, not, however, to PPP.2 Investigation of the apolipoprotein E alleles e2, e3, and e4 in chronic plaque and
guttate psoriasis as well as in PPP in acitretin responders and nonresponders showed that the frequency of
the e4 allele was significantly higher in the psoriasis
groups but not in PPP patients as compared to healthy
controls.3 In chronic plaque psoriasis and psoriatic
arthritis an association with TNF--238 and -308 promoter polymorphisms have been found; however, the
association has not been found in PPP.4 Studies from
Japan provide evidence for phenotypic and genetic
heterogeneity of PPP according to its association/
provocation with tonsillitis. In patients in whom PPP
was not associated with tonsillitis, the phenotype frequency of the TNF-2 allele of the TNF- gene and of
the allele B of the TNF- gene was significantly higher
as compared to controls.5
Genetic association studies in a Caucasian cohort
revealed that genes encoding for cytokines of the IL-10
family, namely, IL-19, IL-20, and IL-24 show haplotypes
conferring increased risk for PPP.6
These findings further substantiate the notion that
PPP and psoriasis represent different entities.
253
Section 4
::
254
by reticular crypt epithelial cells was found which

was absent in tonsils of controls.15 Culturing crypt
epithelial cells it was shown that p53-related expression factors contributed to an upregulation of IL-6
gene expression. The possible importance of IL-6 for
PPP has been emphasized previously and it has been
shown that tonsillectomy leads to improvement of
lesions.16 In another study, the expression of inducible costimulator (ICOS), a costimulatory receptor on
activated T cells was higher in the tissue of tonsils of
PPP-patients as compared to controls.17 Tonsillectomy
or treatment of dental foci resulted in a marked and
sustained improvement of lesions suggesting a major
role of focal infections as a trigger for PPP. The role of
T cells in the tonsils for PPP is further substantiated by
the demonstration of an increased expression of cutaneous lymphocyte-associated antigen (CLA) on CD3+
T cells in tonsils and in diseased skin together with an
enhanced expression of the CLA-ligand E-selectin.18
Grafting involved PPP-skin onto SCID/CB-17 mice
injected with lymphocytes from tonsils of PPP patients
together with heat shock protein 60 induced high
antiheat shock protein 65-IgG levels together with
an increase of IL-6 and interferon .19 Recruitment of
lymphocytes seems to be mediated by the chemokine
CCL20/MIP3 the receptor of which, CCR6, is significantly expressed on tonsilar T cells of PPP patients as
compared to controls. Indeed, Tonsillectomy resulted
in a decreased CCR6 expression on peripheral PPP T
cells.20
The observation of either PPP or new onset psoriasis
in patients treated with anti-TNF- agents is not yet
understood21 but a shift from a TNF--driven immune
response toward an interferon-dominated inflammatory response is discussed.22 In an animal model, the
neutralization of TNF--induced skin inflammation
resulted in an increased expression of IL-1b, IL-6, IL-17,
IL-21, and IL-22 and a suppression of FoxP3-positive
regulatory T cells.23 In the light of the importance of
T cells and IL-6 for the development of PPP this shift
may at least in part explain this appears relevant.
CLINICAL FINDINGS
The primary lesions are pustules of nearly equal size
measuring two to four mm in diameter. Crops of pustules usually arise within a few hours on otherwise
normal-appearing palmar and plantar skin (Fig. 21-1).
Involvement is usually symmetric but unilateral location on palms and/or soles can be seen. Single lesions
then become surrounded by an erythematous ring.
Sometimes, the pustules extend to the dorsa of the fingers, the feet, or over the volar wrists (see Fig. 21-1C).
Episodes of new pustular eruptions occur at varying
intervals and remain strictly confined to the sites of
predilection.
As pustules become older, their yellow color changes
to dark brown, so that in untreated PPP, the lesions
show various shades of color (see Fig. 21-1). Dried pustules are shed within approximately 8 to 10 days.
Symptoms include itching or a burning sensation,
which may precede new crops of lesions. However, in
severe eruptions, pain and the inability to stand, walk, or

do manual work may greatly reduce the quality of life.
DISEASE ASSOCIATIONS. (Box 21-1.) An association of PPP and osteoarthritis of the anterior chest wall
was first described in Japan.24 As reported by Swedish authors, involvement of the manubriosternal joint
is present in 6% and of the sternoclavicular joints in
10% of patients.25 Scintigraphic investigations showed
sternocostoclavicular joint involvement to be present
in 16 of 73 (22%) patients.26 For this condition, the term
SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) has been established.27 Clinical manifestations of
SAPHO syndrome are similar when they occur either
with severe acne (mostly acne conglobata) or PPP (see
Chapter 80). The primary lesion consists of a sterile
abscess containing neutrophils. The site of predilection
is the anterior chest wall. Involvement of the sacroiliacal joints may occur.28
PPP is also seen in patients with chronic recurrent
multifocal osteomyelitis as well as with noninfectious
inflammatory bone lesions.
An association of PPP with gluten-sensitivity has
been suggested as far back as 1991.29 In a more recent
study of 123 patients with PPP IgA-antibodies against
gliadin were found in 18% of patients and against tissue transglutaminase in 10%, respectively.30 In these
patients CD3+ and CD8+ T cells were increased in
numbers in duodenal biospsies. In 6% of patients
diagnosis of celiac disease was made. Patients who
tested positive for any of the antibodies showed total
or nearly total clearance of skin lesions when they
adhered to a gluten-free diet.
HISTOPATHOLOGY. Histologically, there is an
intraepidermal cavity filled with polymorphonuclear
leukocytes associated with spongiform changes within
the surrounding epidermis (Fig. 21-2). Eosinophils and
mast cells are present in increased numbers in PPP
biopsies from lesional skin. Another hallmark is the
inability to visualize the epidermal part of the eccrine
duct in PPP specimens indicating an involvement of
the acrosyringium.31
LABORATORY FINDINGS. The lesions of PPP are
sterile; a moderately increased white blood cell count
may occasionally be observed, but all other laboratory
tests are usually normal. In patients with an infectious
trigger, infection-associated laboratory parameters,
such as C-reactive protein, may be increased. Increased
levels of antigliadin and/or tissue transglutaminase
antibodies may be found.
Box 21-1 Disease Associations
of PPP
SAPHO syndrome
Chronic recurrent multifocal osteomyelitis and
noninfectious inflammatory bone lesions
Gluten sensitivity
Chapter 21
::
Figure 21-1 Palmoplantar pustulosis. A and B. Groups of pustules measuring 2 to 4 mm in diameter occur on erythematous skin on palms and soles. Both feet and both hands are normally affected symmetrically but can also be found on one
side only. C and D. Lesions may occasionally spread beyond the predilection sites, and pustules may appear on the wrists.
Within several days after pustule formation, lesions dry, flatten, and acquire a brownish color. This may be followed by
eczematous changes with scaling and fissuring.

DIAGNOSIS
(Box 21-2)
PPP is a distinct entity. The course of the disease,
together with the characteristic morphology, permits
the proper diagnosis. The disease must be differentiated from dyshidrotic eczematous dermatitis (pom-
pholyx), especially when pustules due to secondary

infection are present (see Chapter 16). In that condition, the onset is also acute, but clear vesicles of various sizes are scattered on the palms, soles, and volar
and interdigital aspects of the fingers. These may
coalesce and secondarily become pustular because of
secondary bacterial infection.
Pustular variants of tinea of the palms and soles or
pustules developing in infected scabies may resemble
255
Section 4
Figure 21-2 Histologically, there is a spongiform pustule

and a moderate lymphohistiocytic infiltrate.
::
PPP. Bacterial cultures or demonstration of hyphae or

mites clearly separate these entities from PPP.
Rare clinical variants such as vesicopustular mycosis fungoides palmaris et plantaris,32 localized pustular
vasculitis,33 or palmoplantar involvement of generalized pustular psoriasis may also resemble PPP.
The clinical course of PPP is highly unpredictable. In
patients with active disease with ongoing development of fresh pustules at the beginning of treatment
relapse within a few days after cessation of any therapy or dose-reduction is highly likely. In phases of
remission fewer pustules are produced, but the skin
may remain erythematous and hyperkeratotic, sometimes resembling eczema. Cessation of smoking may
help to extend disease-free intervals and to decrease
activity of PPP.
TREATMENT
PPP is difficult to treat and all reported treatments
have a high recurrence rate. Treatment modalities of
PPP are summarized in Box 21-3.
In patients with limited disease or only focal lesions
topical therapy with corticosteroids (potent and super-

Most Likely
Dyshidrotic eczema with secondary bacterial infection
Pustular tinea of palms and soles
Consider
Keratoderma blenorrhagicum in Reiter disease
Involvement of palms and soles in generalized
pustular psoriasis
Infected scabies with pustulation
Vesicopustular mycosis fungoides of palms and soles
Localized pustular vasculitis
256
potent) is the treatment of choice. Increased efficacy

can be obtained by occlusive therapy. When PPP
involves larger parts of palms and/or soles systemic
treatment with or without additional topical therapy
should be initiated.
In a meta-analysis of several trials a modest efficacy
of retinoids (etretinate/acitretin) or PUVA (oral, topical, bath) was established when compared to placebo.
The addition of a retinoid to PUVA (re-PUVA) resulted
in increased efficacy. Cyclosporine showed good evidence of improvement up to clearance but no data support was given for long-term cyclosporine therapy.34
In a recent open trial in 52 patients with PPP 35%
could be controlled by topical therapy. In those patients
requiring systemic therapy acitretin was found most
efficacious followed by colchicine and methotrexate.35
Efficacy of fumaric acid ester therapy in PPP has been
described.36
In six female PPP-patients oral itraconazole (100 mg/
day for 4 weeks followed by 100 mg every other day for
4 weeks) lead to a complete clearance in three out of six
and in mild improvement in the other three patients.
All patients relapsed within 1 month after cessation of
therapy but therapeutic response could be regained in
two of the three former responders.37
In an open trial in 15 patients 15 mg alefacept i.m.
weekly for 16 weeks was found to be successful in
the majority of cases.38 However, in another series
of 15 PPP patients alefacept 1530 mg weekly was
found efficacious only in some cases with a maximum
response at week 10.39 There is debate as to whether
TNF- antagonists may be beneficial in PPP. Whereas
in chronic plaque type psoriasis and generalized pustular psoriasis the anti-TNF- monoclonal antibody
infliximab was found to be highly effective, this agent
was found to be both beneficial and to worsen PPP.40,41
In the SAPHO syndrome, infliximab led to a complete
remission of osteoarticular disease but PPP deteriorated during treatment.42 In a small placebo-controlled
trial in 15 PPP-patients etanercept given 2 50 mg
weekly s.c. for 6 months only few patients showed a
significant clinical response.43
MANAGEMENT AND PREVENTION

(See Box 21-4)
Cessation of smoking and, according to data mainly
generated in Asian countries, tonsillectomy may help
to prevent new eruptions of PPP. In patients tested
positive for antigliadin and/or tissue transglutaminase antibodies and/or with proven celiac disease a
gluten-free diet seems to be a preventive measure.
ACRODERMATITIS CONTINUA
(HALLOPEAU)
Acrodermatitis continua is a rare, sterile, pustular
eruption of the tips of the fingers or toes that slowly
extends proximally. Continuous pustulation leads to
nail destruction and atrophy of the distal phalanx.
Box 21-3 Treatments for Palmoplantar Pustulosis and

Acrodermatitis Continuaa
Topical
First line
Potent and
superpotent
steroids
Calcipotriol
bid, plastic
film
occlusion
bid
Second line
Anthralin
Tazarotene
Once daily
bid
Acitretin
0.5 mg/kg/bw/day
Methotrexate
Cyclosporine
1025 mg/wk
35 mg/kg/bw, when effective individual titration
of dose
Fumaric acid
estersb
According to dose-escalation scheme, corresponding to a maximum of 720

mg of dimethylfumarate/
day
12 mg/day
100 mg/day for 4 weeks
followed by 100 mg every
other day for 4 weeks
1530 mg/weekly
Dosing as recommended
for psoriasis
Third line
Colchicine
Itraconazole
Alefaceptc
TNF-antagonists
a
For treatment of acrodermatitis continua no data are available besides case-reports for some of the recommended treatments.
Registered in Germany only.
c
Registered in United States, Canada, and Switzerland only.
b
In 1888, Crocker described a relapsing bullous and

pustular eruption on hands and feet; this was further
delineated by Hallopeau.44,45 Acrodermatitis continua
is now classified as a form of acropustular psoriasis.
EPIDEMIOLOGY
There are no data on the prevalence or incidence of
acrodermatitis continua.
Box 21-4 Management of

Palmoplantar Pustulosis and
Prevention
I n the presence of anti-gliadin IgA- and/or tissue
transglutaminase-antibodies and/or celiac disease
Gluten-free diet
In smokers
Refer patients to antismoking programs
Also consider
Tonsillectomy
PUVA (Bath4/week
psoralen and
ultraviolet light
::
Systemic
Chapter 21
Physical

The etiology of acrodermatitis continua remains enigmatic. Even triggering factors have not been described
yet. Pustule formation may involve similar pathways
as discussed for PPP, but due to the rarity of the disease this has not been studied.
CLINICAL FINDINGS
Acrodermatitis continua most often begins at the tips of
one or two fingers (Fig. 21-3), less often on the toes. The
nail folds are affected very early, and trauma is thought
to play an initiating role. The first signs consist of small
pustules, which, on bursting, leave an erythematous,
shiny area in which new pustules develop. These then
tend to coalesce, forming polycyclic lakes of pus. As
the disease extends proximally, the affected area shows
either glossy erythema or a crusted, keratotic, and fissured surface with newly formed pustules underneath
(see Fig. 21-3). Pustulation of the nail bed and the nail
matrix almost always occurs and quite often leads to
loss of the nail plate or severe onychodystrophy (see
Fig. 21-3). Acrodermatitis continua of long duration
may show complete destruction of the nail matrix and
thus lead to anonychia. The skin becomes shiny and
257
to become confluent, forming denuded, erythematous,

or crusted lesions, distinguishes acrodermatitis continua from PPP or pustular dyshidrotic eczema. Atrophy and loss of nails do not occur in these conditions.
Contact dermatitis with secondary infection and pustulation has less clearly defined margins, runs a different clinical course, and lacks the persistence typical for
acrodermatitis continua.
Section 4
::
Figure 21-3 A. Acrodermatitis continua demonstrating

acral pustule formation and subungual lakes of pus with
destruction of the nail plate. B. Repeated eruptions lead to
nail loss and severe atrophy. Note micropustulation within
the atrophic epidermis of the distal phalanges.
severely atrophic, and there is atrophic thinning of the

distal part of the phalanx.
The disease may remain confined to the original
site, sometimes up to several years, but more often it
spreads proximally to cover the hand, dorsum of forearm, or foot. In such instances more than one extremity
is involved. Acrodermatitis continua may be associated with generalized pustular psoriasis of the Zumbusch type (see Chapter 18).
HISTOPATHOLOGY. The main histopathologic

feature of acrodermatitis continua is a subcorneal cavity filled with neutrophils. Epidermal cell necrosis and
spongiosis does not occur, but the roof and shoulder
zones adjacent to the pustule show aggregated leukocytes between the epidermal cells, forming spongiform pustules. There is a moderate lymphohistiocytic
infiltrate in the upper dermis, together with focal
edema.
Lesions of long duration show severe atrophy of the
papillary dermis and thinning of the epidermis.
LABORATORY FINDINGS. Systemic abnormalities are absent, and laboratory tests are usually within
normal ranges. The pustules are sterile. In advanced
cases, X-ray may reveal atrophy of the distal phalanx
and arthropathy of the interphalangeal joints.
258
Acrodermatitis continua at an early stage must be differentiated from acute paronychia caused by bacteria
or fungi and from herpetic lesions (see Chapter 193).
Cultures and smears help rule out infectious causes.
The distal localization and the tendency of the pustules
Acrodermatitis continua shows a chronic course with

a tendency of the lesions to spread proximally. Spontaneous improvement is rare, and episodes of acute
pustulation occur without apparent cause. The development of pustules at other sites, or even the eruption
of generalized pustular psoriasis, supports the idea
that acrodermatitis continua is a variant of psoriasis.
When uncontrolled, irreversible destruction of the
complete nail apparatus occurs.
TREATMENT
As in pustular psoriasis, no specific drug is able to
induce lasting remissions. Potent or superpotent
topical steroids, preferentially under occlusion, are
useful in blocking pustulation. Caution is advised
in cases already showing atrophy. PUVA suppresses
the eruption of new pustules and can be employed
for long periods as maintenance treatment (see
Chapter 238).
Treatment with a combination of systemic acitretin
and local calcipotriol/calcipotriene was successful
in one patient in a leftright comparison.46 In recalcitrant patients, dapsone may be tried.47 Recently, topical treatment with tacrolimus 0.1% ointment alone or
in sequential combination with calcipotriol was found
successful.48 Numerous case reports describe the successful use of anti-TNF- agents in acrodermatitis continua.49 With respect to the recalcitrant nature of the
diseases combination therapy of adalimumab, etanercept, or infliximab with either acitretin or methotrexate may be advisable in order to maintain treatment
response when stopping anti-TNF--therapy while
continuing acitretin or methotrexate.
In principle, regimens used for treatment of PPP
may also be used for therapy of acrodermatitis continua (see Box 21-3). The therapeutic result lasts as long
as the drugs are given, and relapses occur after withdrawal.
PREVENTION
There are no data on preventive measures for acrodermatitis continua.
INFANTILE ACROPUSTULOSIS
Infantile acropustulosis is discussed in Chapter 107.
KEY REFERENCES
2. Asumalahti K et al: Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis. J
Invest Dermatol 120:627, 2003
12. Michaelsson G et al: The psoriasis variant palmoplantar
pustulosis can be improved after cessation of smoking. J
Am Acad Dermatol 54:737, 2006
15. Koshiba S et al: Tonsillar crypt epithelium of palmoplantar pustulosis secretes interleukin-6 to support B-cell
development via p63/p73 transcription factors. J Pathol
214:75-84, 2008
21. Rallis E et al: Onset of palmoplantar pustular psoriasis
while on adalimumab for psoriatic arthritis: A class effect of TNF-alpha antagonists or simply an anti-psoriatic
treatment adverse reaction? J Dermatolog Treat 1:1-3, 2009
34. Chalmers R et al: Interventions for chronic palmoplantar
pustulosis. The Cochrane Library 4:1-49, 2009
49. Puig L et al: Treatment of acrodermatitis continua of
Hallopeau with TNF-blocking agents: Case report and
review. Dermatology 220:154-158, 2010
It is characterized by sharply demarcated,

yellow to red to brown, greasy or bran-like
scaling patches and plaques.
Lesions favor scalp, ears, face, presternal
chest, and intertriginous areas.
Flares occur when sebaceous glands are
most active (first few months of life, and post
puberty).
Generalized and erythrodermic forms rarely
occur.
The etiology is unclear but there are
associations with Malassezia yeasts, sebum
secretion and composition, and certain
drugs.
May be a cutaneous marker of HIV and
AIDS, especially when severe, atypical, and
therapy-resistant.
Seborrheic Dermatitis
Both infantile and adult forms exist.
include interscapular, umbilical, perineum, and the

anogenital crease.2 The dermatitis presents with pink
to erythematous, superficial patches and plaques
with a yellow, branny and sometimes greasy scale.
Excessive flaking on the face and scalp can lead to
social embarrassment which can have a negative
impact on ones quality of life, especially in women,
younger patients, and those with a higher educational level.3 Mild forms are most commonly encountered, but severe psoriatic and erythrodermic forms
can be seen as well.1 Seborrheic dermatitis is one of
the most common dermatoses seen in human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) patients along with certain
neurological disorders such as Parkinson disease.4,5
These patients tend to have widespread, erythrodermic, and treatment resistant forms. Severe forms
are also seen with immunosupression in premature infants and congestive heart failure patients.6,7
African-Americans and other darkly pigmented races
are susceptible to the annular or petaloid variant of
seborrheic dermatitis, which may be confused for discoid lupus, secondary syphilis, or sarcoidosis.8 A rare
pityriasiform variety of seborrheic dermatitis with
ovoid scaling patches can be seen on the trunk and
the neck, mimicking pityriasis rosea and secondary
syphilis. A higher incidence of seborrheic dermatitis
is also seen in patients with alcoholism and endocrinologic diseases that lead to obesity.9
::
SEBORRHEIC DERMATITIS
AT A GLANCE
Chapter 22
Chapter 22 :: Seborrheic Dermatitis

:: Chris D. Collins & Chad Hivnor
EPIDEMIOLOGY
INTRODUCTION
Seborrheic dermatitis is a common, chronic papulosquamous disorder affecting infants and adults alike.
It is characteristically found in regions of the body
with high concentrations of sebaceous follicles and
active sebaceous glands including the face, scalp,
ears, upper trunk, and flexures (inguinal, inframammary, and axillary).1 Less commonly involved sites
Seborrheic dermatitis is separated into two age

groups, an infantile self-limited form primarily during the first 3 months of life and an adult form that
is chronic. A male predominance is seen in all ages,
without any racial predilection, or horizontal transmission. The prevalence of seborrheic dermatitis is
3%5% of young adults, and 1%5% of the general
population, although its lifetime incidence is significantly higher.10
259
Section 4
::
The exact pathogenesis of seborrheic dermatitis is

yet to be fully elucidated, but this dermatosis is commonly linked with the yeast Malessezia, immunologic
abnormalities, sebaceous activity, and patient susceptibility.14,15 The amount of sebum produced is not an
essential factor, as not all patients with seborrheic dermatitis will have increased levels of sebum production.
On the other hand, some patients with elevated sebum
levels may not have seborrheic dermatitis either.16
Patients with seborrheic dermatitis show higher skin
surface lipid levels of triglycerides and cholesterol, but
lower levels of free fatty acids and squalenes. Both Malassezia species and the resident flora Propionobacterium
acnes have lipase activity resulting in transformation of
triglycerides into free fatty acids.17 All seven species of
Malassezia are lipophilic except the zoophilic species,
Malassezia pachydermatis. The free fatty acids and reactive oxygen radicals produced in turn have antibacterial
activity that alters the normal skin flora. Some authors
believe this disturbance in flora, lipase activity, and free
oxygen radicals may be more closely linked to seborrheic dermatitis than an altered immune response.18
IMMUNOLOGY
Many patients have normal levels of Malassezia species
on the skin, but have an abnormal immune response to
it resulting in a depressed helper T cell response and
less production of phytohemagglutinin and concanavalin when compared to control subjects.19,20 Levels of
antibodies are the same in both patients with and without seborrheic dermatitis. Malassezia species also play
a role in the inflammatory response with stimulation
of the alternative complement pathway.21 A disturbed
lymphocytic cellular immune response to Malassezia,
results in elevated levels of interleukin (IL)-10, with a
drop in IL-2 and interferon-.22 Both normal and elevated levels of antibodies to Malassezia furfur can be
seen in patients with seborrheic dermatitis. Malassezia
can lead to inflammation on the skin from metabolic
products produced and complement activation via the
direct and alternative pathways.
PHYSICAL FACTORS
Seasonal fluctuations in humidity and temperature
are noted to flare this disease, particularly with low
humidity and cold temperatures in the winter and
early spring, with some relief in the summer.23 Facial
PUVA (psoralen plus ultraviolet radiation) treatments
and facial trauma (i.e., scratching) are also reported to
trigger seborrheic dermatitis as well.24
MICROBIAL EFFECTS
260
The pathogenesis of seborrheic dermatitis has been

disputed since it was originally described over a hundred years ago. The presence or imbalance of microbial
flora likely plays a role in the disease. Although some

patients may have cultures showing Candida albicans,
Staphylococcus aureus, Propionobacterium acnes, and
other aerobic bacteria, none have been linked to the
pathogenesis of seborrheic dermatitis.25 Infants commonly have secondary contamination and infection
with Candida species. The pathogenic role of Malassezia furfur (previously known as Pityrosporum ovale) is
also controversial. The number of yeasts on the skin
does not directly correlate with the severity of seborrheic dermatitis also. Patients with both dandruff and
seborrheic dermatitis generally have abundant yeast
counts when compared to controls supporting the role
of yeast in the disease. A higher rate of seborrheic dermatitis is also seen in patients with Pityrosporum folliculitis and tinea versicolor.26 Clearance of seborrheic
dermatitis with antifungals and recurrence following
cessation of therapy also supports the premise that
Malassezia species is pathogenic.27
DRUGS
Several drugs are known to trigger seborrheic dermatitis like eruptions including griseofulvin, cimetidine,
lithium, methyldopa, arsenic, gold, auranofin, aurothioglucose, buspirone, chlorpromazine, ethionamide,
haloperidol, interferon-, phenothiazines, stanozolol,
thiothixene, psoralen, methoxsalen, and trioxsalen.
NEUROTRANSMITTER
ABNORMALITIES
Many neurologic disorders have been associated with
seborrheic dermatitis, with most of them resulting
in some facial immobility and sebum accumulation.
These include Parkinsons, Alzheimers, syringomyelia, epilepsy, cerebrovascular infarcts, postencephalitis, mental retardation, poliomyelitis, quadriplegia,
trigeminal nerve injury and other facial nerve palsies.28
The fact that administration of l-dopa improves seborrheic dermatitis in some Parkinson patients, and
some neuroleptic drugs that induce Parkinsonian
symptoms can induce seborrheic dermatitis suggests
that neurotransmitters may play a role in this dermatitis.29 Depression and emotional stress have also been
reported to trigger seborrheic dermatitis.30 A high rate
of this dermatitis is also seen among combat troops.31
In summary, these groups of patients do not have
increased rates of sebum, but rather excessive accumulation of sebum on the skin.
ABERRANT EPIDERMAL
PROLIFERATION
Patients with seborrheic dermatitis may have epidermal hyperproliferation or dyskeratinization related to
increased activity of calmodulin, which is also seen
in psoriasis.32 This explains why patients with seborrheic dermatitis improve while being treated with a
number of different cytostatic medications such as

azeleic acid.12
NUTRITIONAL DISORDERS
PSORIASIS AND SEBORRHEIC

DERMATITIS
SEBORRHEIC DERMATITIS IN
INFANTS COMPARED TO ADULTS
The infantile form occurs during the first few weeks to
3 months of life, is self-limited, and corresponds to the
time when the neonate produces sebum, which then
regresses until puberty.38 It is commonly concentrated
on the vertex of the scalp (i.e., cradle cap) with adherent, yellowbrown, greasy scale, which can sometimes spread to the entire scalp with inflammatory,
erythematous, and oozing crusts. Lesions can be seen
on the face, neck and can be disseminated to the trunk
and extremities with inflammatory glistening plaques
in intertriginous sites such as the axillae and groin
(Fig. 22-1). A differential diagnosis should be undertaken in any infant with a widespread form of seborrheic dermatitis (Box 22-1). Atopic dermatitis patients
tend to have lesions on the forearms and shins, while
sparing the axillae. Lesions isolated to the diaper
region suggest seborrheic dermatitis. Radioallergosorbent assay test screening to egg whites, milk antibodies,
A family history of seborrheic dermatitis is often

reported, but only recently has a mutation (ZNF750)
encoding a zinc finger protein (C2H2) been described
resulting in a seborrhea-like dermatitis. This Israeli
Jewish Moroccan family presented with an autosomal
dominant seborrhea-like dermatosis.35
Self-limited with a good prognosis in infants compared

to chronic and relapsing in adults. There is no evidence
to suggest infants with seborrheic dermatitis will have
disease as adults. Generalized flares and erythroderma
can sometimes occur.37
::
GENETIC FACTORS
Chapter 22
Seborrheic dermatitis has not been proven to be associated with any vitamin deficiency. Patients with zinc
deficiency (acrodermatitis enteropathica, and acrodermatitis enteropathica like conditions) may have
an eruption that appears similar to seborrheic dermatitis and improves with zinc supplementation, while
seborrheic dermatitis patients do not improve with
zinc supplementation.33 Infants with deficiency in biotin, holocarboxylase, biotinidase, and free fatty acids
may also have seborrheic-like dermatitis. But again,
biotin supplementation has not been substantiated to
improve seborrheic dermatitis.34

COURSE
The controversial term sebopsoriasis is often used in

patients when there appears to be an overlap of psoriasis and seborrheic dermatitis. It tends to localize to
the scalp, face, and presternal chest as seen with seborrheic dermatitis. However, the margins tend to be better defined, more erythematous and with thicker scales
than those seen with seborrheic dermatitis. The biopsy
can be indistinguishable from psoriasis, similar to the
chronic form of seborrheic dermatitis.36
CLINICAL FINDINGS
In all patients with seborrheic dermatitis, there is a socalled seborrheic stage, which is often combined with a
graywhite or yellowred skin discoloration, prominent
follicular openings, and mild to severe pityriasiform
scales. Several forms can be distinguished (Table 22-1).
TABLE 22-1
Clinical Patterns in Seborrheic Dermatitis

INFANTILE: Scalp (cradle cap), trunk (flexures and napkin
area), Leiners disease (nonfamilial and familial C3/C5
dysfunction).
ADULT: Scalp, face, eyelids (blepharitis), trunk (petaloid,
pityriasiform, flexural, eczematous, follicular, generalized,
erythrodermic).
Figure 22-1 Seborrheic dermatitis in an infant. Widespread pattern of seborrheic dermatitis with psoriasiform
lesions on the trunk and groin.
261

of Infantile Seborrheic Dermatitis
Most Likely
Atopic dermatitis
Consider
Scabies, psoriasis
Rule Out
Section 4
::
262
soybean, and total immunoglobulin E levels, may be

helpful in discerning infantile seborrheic dermatitis from atopic dermatitis. Some authors believe that
infantile seborrheic dermatitis is actually a variant of
atopic dermatitis rather than a separate entity. Extensive involvement plus lesions on the palms and soles
with severe pruritis suggests scabies. Infantile psoriasis
can also be extensive, with erythematous plaques and
scale, with less scale in intertriginous sites. Extensive
involvement with moist erythematous plaques and
petechial lesions of intertriginous sites and the scalp
suggests Langerhans cell histiocytosis (LettererSiwe)
and should be biopsied for confirmation and treated
appropriately.
The adult form on the other hand, tends to be chronic
and can persist from the fourth through the seventh
decades of life, with a peak at age 40. Lesions may also
Figure 22-3 Seborrheic dermatitis of the nasolabial fold.
Figure 22-2 Seborrheic dermatitis with involvement of

nasolabial folds, cheeks, eyebrows, and nose.
Figure 22-4 Seborrheic dermatitis of the ear: external

canal, concha bowl, and auricle.
be seen on the face with prominent symmetry (Fig. 22-2),

particularly medial eyebrows, forehead, upper eyelids,
nasolabial folds (Fig. 22-3), and lateral nares. Other sites
commonly involved include retroauricular regions,
external auditory canal, auricle, and conchae bowl
(Fig. 22-4), scalp (Fig. 22-5), occiput, and neck. The presternal region of the chest, upper back (Fig. 22-6), and
umbilicus can be involved as well, and can be petaloid or arcuate with fine pink scale. Intertriginous sites
such as axillary and inguinal regions show less scale
and mimic intertrigo. See Box 22-2 for site-specific differential diagnosis of seborrheic dermatitis. Erythema
and pruritis are common, as well as burning or tingling
sensitivity reported as well, particularly on the scalp.
Pityrosporum folliculitis can be seen as well with diffuse
monomorphic tiny pustules and papules with peripheral erythema on the trunk. Diagnosis can be confirmed
with a KOH (potassium hydroxide) preparation. Immunocompromised patients more commonly get this form
of folliculitis. The adult form typically begins during
puberty corresponding with androgen activity, which
Box 22-2 Site-Specific Differential

Diagnosis of Seborrheic Dermatitis
Scalp*
Face
Figure 22-5 Seborrheic dermatitis of the scalp, ear, sideburn area, beard, and face with diffuse scale and inflammation.
Chest, back
Leiner first described this controversial condition in

1908, dermatitis seborrhoides infantum, and is considered a severe, widespread, erythrodermic form
of infantile seborrheic dermatitis.39 These patients
have symptoms of fever, anemia, diarrhea, vomiting,
weight loss, and sometimes death if not treated properly with intense IV hydration, temperature regula-
Generalized*
Erythrodermic*
ERYTHRODERMA
DESQUAMATIVUM (LEINERS
DISEASE)
Intertriginous
::
Groin, buttock
results in an increase in size and activity of sebaceous
glands. Prepubertal patients tend to not get seborrheic
dermatitis because of this lack of androgen stimulation
of sebaceous glands, and have also not been shown to
have excessive colonization of Malessezia species.
Chapter 22
Ear canal
Eyelids
Psoriasis, atopic dermatitis, impetigo,

tinea capitis* (mimics dandruff in
children)
Psoriasis, rosacea, contact dermatitis, impetigo, discoid lupus,
sarcoid (petaloid type in AfricanAmericans), drug-induced photosensitivity
Psoriasis, contact dermatitis
Atopic dermatitis, psoriasis, Demodex folliculorum infestation
Pityriasis rosea, tinea versicolor,
subacute cutaneous lupus, psoriasis vulgaris
Intertrigo (fungal, candidal, erythrasma), glucagonoma, extramammary Pagets disease, zinc
deficiency
Inverse psoriasis, candidiasis, erythrasma, contact dermatitis, tinea
intertrigo, Langerhans cell histiocytosis (Letterer Siwe in infants)
Scabies, secondary syphilis, pemphigus foliaceous, pemphigus
erythematosus, Leiners (infants),
drug eruption
Psoriasis, contact dermatitis,
pityriasis rubra pilaris, drug eruption, mycosis fungoides (Sezary
syndrome), lichen planus, chronic
actinic dermatitis, HIV, Hodgkins
disease, paraneoplastic syndrome,
leukemia cutis
*Diffuse scalp dermatitis or inflammatory alopecia in children

warrants fungal culture, KOH prep. Widespread truncal types
warrant scabies prep and RPR to rule out syphilis. Erythrodermic
type should be biopsied.
tion, and antibiotics if they have secondary bacterial

infection. There is both a familial and nonfamilial
form of Leiners. The hereditary form has been associated with deficiencies of complement C3, C5, and
phagocyte malfunction therefore resulting in defective opsonization of bacteria. Patients with the hereditary form may necessitate treatment with fresh frozen
plasma and whole blood to supplement these complement deficiencies.40
PITYRIASIS AMIANTACEA
Figure 22-6 Seborrheic dermatitis of the upper back.
Pityriasis amiantacea was first described by Alibert in

1832, and is also known as asbestos scalp, tinea asbestina, keratosis follicularis amiantacea, and porrigo
263
plex chronicus can have patches of pityriasis amiantacea as well. Alopecia may result and is nonscarring
unless secondary scalp infection occurs with Streptococcus or Staphylococcus and should be treated appropriately. Staphylococcal isolates in the matted hairs
can be found in up to 96% of patients.42 Young females
commonly have concomitant postauricular scale and
fissures.
SEBORRHEIC DERMATITIS IN HIV

AND AIDS PATIENTS
Section 4
::
Figure 22-7 Pityriasis amiantacea. Masses of sticky silvery

scales adhere to the scalp and cause matting of hairs they
surround.
amiantacea.41 The use of the term tinea amiantacea
is discouraged since tinea capitis is rarely associated
with pityriasis amiantacea. This is a localized or diffuse condition, in which inflammation and massive silvery scaling of the scalp results in thick, matted, sticky
hair (Fig. 22-7). This condition can occur at any age,
especially adolescents and young females. It is most
commonly seen with psoriasis (35%), and eczematous
conditions like seborrheic dermatitis and atopic dermatitis (34%).42 Case reports of patients with lichen
planus and Dariers have had associated pityriasis
amiantacea.43 Middle-aged females with lichen sim-
264
Patients with HIV and AIDS have severe and extensive seborrheic dermatitis (Fig. 22-8) that tends to
be refractory to standard therapy.44 Treatment with
400 mg of oral ketoconazole daily for 2 weeks may
be necessary. The initial facial eruption may appear
as a butterfly rash, similar to the acute facial eruption
associated with systemic lupus erythematosus. The
histopathology also differs from seborrheic dermatitis
in HIV seronegative patients in that they have much
more parakeratosis, necrosis, lymphocytes, and focal
leukocytosis.45 Seborrheic dermatitis usually occurs
when CD4+ counts are between 200500 cells/mm3
and as one of the earliest skin manifestations of HIV
patients.46
HISTOPATHOLOGY
Depending on the stage of the lesion biopsied, the
changes seen include acute, subacute, and chronic
spongiotic dermatitis. In acute lesions there is folliculocentric scale crust composed of orthokeratosis and focal
parakeratosis with scattered neutrophils, mild focal
Figure 22-8 A and B. Widespread unusual distribution pattern of seborrheic dermatitis in a patient with AIDS. A. Moist
patches on the centrofacial region, beard and scalp. B. Moist lesions on the chest. In patients with AIDS, the disease
responds poorly to conventional therapy.
TABLE 22-2
Histopathologic Differences Between Classic

Seborrheic Dermatitis and AIDS-Associated
Classic Seborrheic
Dermatitis
Epidermis
Limited parakeratosis
Rare necrotic
keratinocytes
No interface obliteration
AIDS-Associated
Widespread parakeratosis
Many necrotic keratinocytes
Dermis
Thin-walled vessels
Rare plasma cells
No leukocytoclasis
Many thick-walled vessels

Increased plasma cells
Focal leukocytoclasis
TREATMENT
INFANTILE SEBORRHEIC DERMATITIS
This benign, self-limited form responds readily to
shampoos, emollients, and mild topical steroids.
Infants with prolonged inflammation on the scalp or
intertriginous areas can be treated with low potency
topical corticosteroids (hydrocortisone 1% cream or
lotion for a few days), followed by topical imidazoles (2% ketoconazole cream, lotion, or 1% shampoo). Aggressive removal of scale with keratolytics or
mechanical removal is discouraged to prevent further
inflammation. However, mild baby shampoos, with
Adults tend to have chronic and recurrent disease, and

as such, the patients should be informed that the aim
of treatment will be to control rather than cure the disease. Scalp seborrheic dermatitis can be treated with
shampoos containing zinc pyrithione, selenium sulfide
(1%2.5%), imidazoles (1%2% ketoconazole shampoo, creams, lotions, or foams), ciclopirox (cream, gel,
and shampoo), salicylic acid (shampoos, creams), coal
tar (creams, shampoos), or mild detergents. Dandruff
(pityriasis simplex capillitii) involves the face and scalp
as well with extensive scale, but shows minimal to no
inflammation and erythema. Dandruff responds to
more frequent shampooing or a longer period of lathering. Shampoos may be used on the scalp, beard and
chest, but may flare the disease if used on the face or
other intertriginous areas if left on for extended periods. Xanthotrichia or yellow hair has been reported
in patients using selenium sulfide shampoo. Severe
and thick scale on the scalp can respond to overnight
application of topical corticosteroids (low-, mid-, or
high-potency creams, lotions, or foams depending on
the severity) with shower cap occlusion as needed,
Bakers P&S solution, tar shampoo, or salicylic acid
(ointment or shampoo, especially for patients with
pityriasis amiantacea). Alternative effective treatments
include coconut oil compound (ointment combination
of coal tar, salicylic acid and sulfur). Patients should
avoid aggressive manipulation. Hair sprays and hair
pomades should be stopped. Treatment of any underlying secondary microbial infection should be treated
as well. Patients with severe inflammatory disease
that fail the above regimens may respond to a 1-week
course of systemic glucocorticoids (prednisolone 0.5
mg/kg body weight/day), while cautioning the patient
of side effects and informing them of potential rebound
flares following discontinuation of the medication.5257
Treatment of the face, trunk, and ears includes short
courses of low potency topical glucocorticoids (Class
IV or lower) to suppress the initial inflammation.
Excessive and long-term topical corticosteroid application should be discouraged as well to prevent steroid
acne, steroid rosacea, perioral dermatitis, and rebound
phenomenon. Topical calcineurin inhibitors (pimecrolimus and tacrolimus) have anti-inflammatory and
antifungal (tacrolimus) properties without the longterm side effects of topical corticosteroid use. Topical
antifungals such as ketoconazole, miconazole, fluconazole, itraconazole, econazole, bifonazole, climbazole,
ciclopirox, and ciclopiroxolamine have all been used
with varying success. Sulfur or sulfonamide combinations, or propylene glycol topical have also been
used. Benzoyl peroxide wash 5%10% can be used as
spongiosis, and a sparse superficial perivascular infiltrate of lymphocytes and histiocytes. Subacute lesions
show mild psoriasiform hyperplasia and numerous
yeast species in the stratum corneum in addition to the
above findings. Chronic lesions show even more psoriasiform hyperplasia and crusting scales in a folliculocentric distribution, superficial dilation of capillaries
and venules, and minimal spongiosis. The chronic form
may be difficult to distinguish from psoriasis clinically
and pathologically, but the folliculocentric distribution
supports seborrheic dermatitis.
HIV and AIDS patients with seborrheic dermatitis
show histopathologic findings consistent with severe,
chronic seborrheic dermatitis (Table 22-2). Patients with
pityriasis amiantacea show, spongiosis, mild exocytosis
of lymphocytes and acanthosis. The asbestos-like scale
seen is due to a thick layering of hyperkeratosis and
parakeratosis surrounding the outer hair shafts. Patients
with dandruff (pityriasis simplex capillitii, aka pityriasis
capitis) show minimal parakeratotic foci of scale, without any spongiosis or inflammatory infiltrates.47
ADULT SEBORRHEIC DERMATITIS
::
From Soeprono FF et al: Seborrheic-like dermatitis of acquired immunodeficiency syndrome: A clinicopathologic study. J Am Acad Dermatol 14:242, 1986, with permission.
Chapter 22
Prominent spongiosis
Focal interface obliteration with

clusters of lymphocytes
Sparse spongiosis
or without 3% salicylic acid applications, can help

remove thick, stubborn scale on the scalp. Secondary
infections with candidiasis or Staphylococcus should be
treated appropriately. Infants with seborrheic dermatitis do not respond to dietary alterations or restrictions
(milk-free, etc.) and vitamin supplementation that may
help patients with atopic dermatitis.38,4851
265
Section 4
::
well. Recommend patients to avoid alcohol-containing

solutions that flare the disease. Aluminum acetate solution can be used to maintain seborrheic otitis externa.
Patients with seborrheic blepharitis can be treated
with warm to hot compresses and washing with baby
shampoo followed by gentle cotton tip debridement of
thick scale. Avoid ocular glucocorticoids. Ophthalmic
sodium sulfacetamide ointment can be used for resistant seborrheic blepharitis.5868
There are many other alternative treatments. Oral
antifungals should be reserved for severe and refractory cases due to potential drug interactions and side
effects. Allylamines may also be effective including
topical butenafine and naftifine cream for mild cases
versus oral terbinafine for extensive involvement. Lithium succinate and lithium gluconate, both available in
some countries, have antifungal properties that can be
used for treatment as well. Vitamin D3 analogs (calcipotriol cream or lotion) have both anti-inflammatory
and antifungal properties and can be used in selected
patients as well. Other alternatives include topical
metronidazole cream or gel, once to twice daily. Oral
isotretinoin in low doses (2.55 mg daily; or 0.10.3
mg/kg/day) over 35 months can be used in refractory disease, of course while observing requirements
in child-bearing females. Phototherapy with narrowband ultraviolet B or psoralen plus ultraviolet A can
also be used in severe and refractory disease, but may
be ineffective if patients have thick hair.17,69,74
We would like to thank Gerd Plewig and Thomas Jansen for their previous editions of this chapter on seborrheic dermatitis and the use of their format, tables,
boxes, and photos while revising this chapter.
KEY REFERENCES
2. Johnson BA et al: Treatment of seborrheic dermatitis. Am
Fam Physician 61:2703-2714, 2000
15. DeAngelis YM et al: Three etiologic facets of dandruff and
seborrheic dermatitis: Malassezia fungi, sebaceous lipids,
and individual sensitivity. J Investig Dermatol 10:295-297,
2007
48. Arora V et al: Management of infantile seborrheic dermatitis. Am Fam Physician 75(6):807, 2007
53. Shin H et al: Clinical efficacies of topical agents for the
treatment of seborrheic dermatitis of the scalp: A comparative study. J Dermatol 36(3):131-137, 2009
56. Nowicki R: Modern management of dandruff. Pol Merkur
Lekarski 20(115):121-124, 2006
58. Bikowski J: Facial seborrheic dermatitis: A report on current status and therapeutic horizons. J Drugs Dermatol
8(2):125-133, 2009
67. Gupta AK et al: Etiology and management of seborrheic
dermatitis. Dermatology 208(2):89-93, 2004
Chapter 23 :: Exfoliative Dermatitis

:: Jane Margaret Grant-Kels, Flavia Fedeles, &
Marti J. Rothe
EXFOLIATIVE DERMATITIS AT A GLANCE
Exfoliative dermatitis (ED) is defined as
diffuse erythema and scaling of the skin
involving more than 90% of the total body
skin surface area.
Systemic and potentially life-threatening
complications include fluid and electrolyte
imbalance, thermoregulatory disturbance,
fever, tachycardia, high-output failure,
hypoalbuminemia, and septicemia.
266
ACKNOWLEDGMENTS
Common underlying etiologies are psoriasis,

atopic dermatitis, and other spongiotic
dermatoses, drug hypersensitivity reactions,
and cutaneous T-cell lymphoma (CTCL).
The cause of ED is unknown (idiopathic) in
approximately 20% of cases.
Diagnostic workup includes a complete

history and physical examination, with
careful analysis of pertinent clinical clues and
dermatohistopathology. Other laboratory
workup is often required and determined by
clinical clues.
Management of ED involves combining
symptomatic relief with addressing the
underlying etiology and potential systemic
complications. Inpatient hospitalization is
required in acute cases.
Prognosis is variable and depends primarily on
the underlying etiology. Drug-induced ED has the
best prognosis while malignancy-associated ED
has the highest mortality.
EPIDEMIOLOGY
Medications, such as lithium, terbinafine, and antimalarials

Topical irritants including tars
Systemic illness
Discontinuation of potent topical or oral corticosteroids, methotrexate, or biologics (efalizumab)22,23
Infection including human immunodeficiency
virus (HIV)
Pregnancy
Emotional stress
Phototherapy burns
Less common causes of ED in adults include immunobullous disease; connective tissue disease; infections, including scabies and dermatophytes; pityriasis
rubra pilaris (PRP) (4% of dermatoses); and underlying
malignancy. Even in patients with underlying dermatoses, it is critical to consider other possible etiologies.
In one case series, malignancy-related ED was identified in seven patients, five of whom had a preexisting
dermatosis.11 In about 5%10% of idiopathic ED cases,
erythrodermic CTCL was ultimately diagnosed.24 Solid
organ malignancies as well as hematologic and reticuloendothelial malignancies may manifest as ED.
Exfoliative Dermatitis
Establishing the etiology of ED can be challenging

since it can be caused by a variety of cutaneous and
systemic diseases (Table 23-1). A compilation of 18
published studies1,2,4,6,821 from various countries on
ED shows that a preexisting dermatosis is the most
frequent cause in adults (52% of ED cases; range,
27%68%) followed by drug hypersensitivity reactions (15%), and cutaneous T-cell lymphoma (CTCL)
or Szary syndrome (5%). No underlying etiology is
identified in approximately 20% of ED cases (range,
7%33%) and these cases are classified as idiopathic.
Psoriasis is the most common underlying skin disease to cause ED (23% of cases), followed by spongiotic dermatitis (20%). Possible triggers for psoriatic ED
include the following:
::
Chapter 23
Several large studies have reported a widely varied

incidence of exfoliative dermatitis (ED) ranging from
0.9 to 71.0 per 100,000 outpatients.14 A male predominance has been described, with a male-to-female ratio
of approximately 2:1 to 4:1. Any age group can be
affected, and with most studies excluding children, the
average age of disease onset varies from 41 to 61. ED is
a rare disease in children, and only little epidemiologic
data is available for pediatric populations. One study
found 17 patients, recorded over a 6-year period, with
a mean age of onset of 3.3 years and a male-to-female
ratio of 0.89:1.5 ED occurs in all races.6
A preexisting dermatosis plays a role in more than
one-half of the cases of ED. Psoriasis is the most common underlying skin disease (almost one-fourth of the
cases). In a recent study of severe psoriasis, ED was
reported in 87 of 160 cases.7
In neonates and infants, the differential diagnosis

includes dermatoses (such as psoriasis, atopic dermatitis, and seborrheic dermatitis), drugs, and infection
(particularly staphylococcal scalded-skin syndrome).
In addition, several congenital disorders including the ichthyoses, both bullous and nonbullous
congenital ichthyosiform erythroderma, Netherton
syndrome, and immunodeficiencies should be considered (Box 23-1).
Topical and systemic medications are implicated
in a significant percentage of ED cases (15%; range,
4%39%) and the introduction of new drugs is likely to
increase the incidence of ED. Both allopathic and naturopathic medications have been suggested to cause
ED and the list is constantly expanding (Table 23-2).
The most commonly implicated drugs include calcium
channel blockers, antiepileptics, antibiotics (penicillin
family, sulfonamides, vancomycin), allopurinol, gold,
lithium, quinidine, cimetidine, and dapsone. However,
most of the drugs are reported in single case reports.
In addition to drugs, the contrast medium iodixanol
(Visipaque) used during percutaneous coronary interventions has recently been reported to cause ED.25
Currently, the pathogenic mechanisms of ED have
not been elucidated. It is not well understood how a
preexisting dermatosis progresses to ED, an underlying disease manifests as ED, or the de novo ED
develops. While the clinical presentation is similar in
patients with diverse etiologies of ED, it is likely that
different pathways lead to the common end result of
skin-selective recruitment of inflammatory cells.
Cytokines, chemokines, and their receptors are
believed to play an important role in the pathogenesis of ED. A study of cytokine profile in dermal
infiltrates showed that there may be differences in
pathophysiologic mechanisms between benign ED
and Szary syndromea T helper 1 cytokine profile
was found in benign ED while a T helper 2 cytokine
profile was found in Szary syndrome.26 In a recent
report, an overexpression of both T helper 1- and T
helper 2-related chemokine receptors (CCR4, CCR5,
and CXCR3) was found in ED of inflammatory origin, while a selective overexpression of CCR4 was
found in Szary syndrome,27 suggesting that Szary
syndrome is a T helper 2 disorder and that different
pathways may contribute to skin homing of reactive
lymphocytes in different etiologies of ED. Another
study showed that Szary syndrome and inflammatory ED are characterized by different memory T-cell
subset expression, further suggesting different pathophysiologic mechanisms.28
The interaction between adhesion molecules and
their ligands is important during inflammatory and
immunological responses. Increased circulating levels
of adhesion molecules (intercellular adhesion molecule
1, vascular cell adhesion molecule 1, and E-selectin)
have been reported in benign reactive ED secondary to
psoriasis and atopic dermatitis compared to controls.29
In contrast, no differences in expression levels of these
molecules on endothelial cells were found in different
types of ED, leading to the hypothesis that there are
similarities in end-stage immunologic pathways in different types of ED.30
267
TABLE 23-1
Diseases Associated with Exfoliative Dermatitis

Dermatoses
Spongiotic dermatitis
Atopic dermatitisa
Seborrheic
dermatitis2
Contact dermatitis
Stasis dermatitis
Bullous
Pemphigus
foliaceus69
Paraneoplastic
pemphigus74
Bullous
pemphigoid
HaileyHailey77
Papulosquamous
Psoriasisa
Generalized
pustular psoriasis87
Pityriasis rubra
pilarisa
Impetigo
herpetiformis93
Photosensitive
Chronic actinic
dermatitis
Actinic reticuloid97
Adverse druga
Acute generalized
exanthematous
pustulosis
Toxic epidermal
necrolysis
Other
Pseudolymphoma103
Erythema gyratum
repens107
Perforating
folliculitis109
Radiation recall
dermatitis111
Senile erythroderma with
hyper-IgE115

Section 4
::
a
Most common diseases.
268
Systemic
ermatomyosiD
tis4348
Subacute cutaneous lupus4951
Acute graft-versushost disease56,a
Postoperative
transfusion induced59
Thyrotoxicosis60
Sarcoidosis6467
Hypercalcitonemia70
Idiopathic hypereosinophilic syndrome75
Monoclonal gammopathy of undetermined
significance76
Hemophagocytic
histiocytosis, viral
associated78,79

Infections
Bacterial
Tuberculosis52
Congenital
syphilis57
Viral
Hepatitis C61
Human immunodeficiency
virus
Human herpesvirus 671
Fungal
Dermatophyte14,18
Histoplasmosis8082
Congenital cutaneous
candidiasis84
Parasite
Norwegian scabies88
Toxoplasmosis90
Leishmaniasis94
Toxin-mediated
infections
Staphylococcal
scalded-skin
syndromea
Toxic shock
syndrome
Malignancy
Solid tumors
Lung14,17,18,53,54
Prostate14,18,58
Thyroid14
Liver14,62
Gallbladder68
Melanoma18,72
Breast18
Ovary18
Fallopian tube83
Esophagus85
Stomach17,86
Rectum18
Colon91
Thymus95
BuschkeLoewenstein tumor96
Lymphoproliferative
Cutaneous T-cell lymphomaa
Szary syndrome
Papuloerythroderma of Ofuji
Hodgkin lymphoma12,14,15,100
B-cell lymphoma102
(Cutaneous) anaplastic large
cell lymphoma104,105
Angioimmunoblastic T-cell
lymphoma108
Castleman disease110
Acute myeloid leukemia M6112
Acute myelomonocytic leukemia116
Adult T-cell leukemia117
T-cell prolymphocytic l
eukemia118
Chronic lymphocytic
leukemia12
Chronic myelogenous
leukemia119
Chronic eosinophilic
leukemia120
Myelodysplasia121
Premalignant myeloproliferative disorder122
Multiple myeloma34
Reticulum cell sarcoma8
Angioimmunoblastic
lymphadenopathy123
Cutaneous lymphoid
hyperplasia
Hypereosinophilic syndrome124126
Mastocytosis (type IIIV)127,128
Histiocytosis129
RosaiDorfman disease
Congenital
Immunodeficiency
Common variable hypogammaglobulinemia55
WiskottAldrich syndrome
Severe combined immunodeficiency
Omenn syndrome63
Leiner disease
Hyperimmunoglobulin E
(hyper-IgE) syndrome73
Secretory IgA deficiency
Metabolic
Maple syrup urine disease
Neutral lipid storage
disease
Essential fatty acid deficiency
Propionic acidemia89
Holocarboxylase synthetase deficiency92
Ichthyosis
Bullous congential ichthyosiform erythroderma
Nonbullous congenital
ichthyosiform
erythroderma
Netherton syndrome98
ConradiHnermann
syndrome99
Epidermolytic hyperkeratosis
Keratitis, ichthyosis, and
deafness101
Lamellar ichthyosis
Lethal congenital erythroderma106
SjgrenLarsson syndrome
Other
Ankyloblepharon
ectodermal
dysplasiaclefting
syndrome (AEC)113,114
BOX 23-1 Differential Diagnosis

Most Likely
Spongiotic dermatitis (20%24%) (atopic, 9%;
contact dermatitis, 6%; seborrheic dermatitis, 4%;
chronic actinic dermatitis, 3%)
Psoriasis (23%)
Drug hypersensitivity reaction (15%)
Cutaneous T-cell lymphoma (5%)
Idiopathic (approximately 20%)
::
Always Rule Out

Cutaneous T-cell lymphoma
Drug-induced hypersensitivity syndrome
Paraneoplastic
Chapter 23
Consider
Contact dermatitis
Immunobullous disease (superficial pemphigus,
bullous pemphigoid, paraneoplastic pemphigus)
Infection (scabies, dermatophytosis)
Toxin-mediated (toxic shock syndrome, staphylococcal scalded-skin syndrome)
Chronic actinic dermatitis
Collagen vascular disease
Paraneoplastic (solid tumors and hematologic)
Primary immunodeficiency
Congenital ichthyoses
ED cases, erythrodermic CTCL is ultimately diagnosed.24

A role for immunoglobulin (Ig) E in ED has been
proposed based on the observation of increased IgE
levels in many types of ED. For example, it has been
theorized that elevations in IgE in psoriatic ED may
point to a change from a T helper 1 cytokine profile
in psoriasis to a T helper 2 cytokine in psoriatic ED.38
This secondary mechanism is different than the primary overproduction of IgE in atopic dermatitis.
Hyper-IgE syndrome is an immune deficiency that has
been associated with ED, and has high IgE production
due to selective insufficient interferon- secretion.39
The mechanisms related to this elevation of IgE may
be related to the underlying disease process or to the
manifestation of the disease as ED. Again, the mechanisms of IgE elevation appear to be different in different types of ED.
Recently, it has been theorized that Staphylococcus
aureus colonization or another antigen, such as toxic
shock syndrome toxin-1, may play a role in the pathogenesis of ED.40,41 Research on the immunopathogenesis
of toxin-mediated infection demonstrates staphylococcal pathogenicity islands encoding superantigens
(see Chapter 177). These islands carry the genes for
the toxins of toxic shock syndrome and staphylococcal scalded-skin syndrome.42 83% of patients with ED
were noted to have S. aureus colonization in the nares,
while 17% had colonization in the skin; however, only
one in six patients was S. aureus enterotoxin positive.41
(See Tables 23-1 and 23-2.)
CLINICAL FINDINGS
The complex interaction between adhesion molecules and cytokines likely contributes to the significantly increased mitotic and epidermal turnover rate in
ED. The scaling of ED skin is a reflection of decreased
transit time through the epidermis and leads to significant loss of protein, amino acids, and nucleic acids.
Protein loss may increase by 25%30% via scaling in
psoriatic ED, and 10%15% in nonpsoriatic ED.31 Additionally, protein-losing enteropathy may contribute to
hypoalbuminemia.
Some patients with chronic idiopathic ED have
been reported to develop CTCL that has led to concern that patients with chronic idiopathic ED may be
at increased risk for progression to mycosis fungoides
or Szary syndrome.18,32 The chronic T-cell stimulation
in these patients has been suggested to promote the
development of CTCL.3337 Recently, a premalignant
or pre-Szary-like condition has been described in
elderly patients with chronic or relapsing ED without
progression to hematologic malignancy characterized
by a monoclonal expansion of CD4+CD7CD26 lymphocytes.34 The term monoclonal T-cell dyscrasia of
undetermined significance (MTUS), a T-cell equivalent
to monoclonal gammopathy of undetermined significance, has been proposed for this condition, which is
believed to be probably benign.34 However, chronic
idiopathic ED may also represent primary chronic,
undiagnosed CTCL. Indeed, in up to 10% of idiopathic
Figure 23-1 is an algorithm showing the approach to a

patient with ED.
HISTORY
A detailed history of a patient who presents with ED
is an important tool for diagnosing the underlying etiology. The patients may have a history of dermatoses
(psoriasis, atopic dermatitis) or a systemic medical
condition. A thorough medication history should be
elicited, including naturopathic and over the counter
therapies. Patients with history of psoriasis and atopic
dermatitis should be queried specifically regarding
use of topical and systemic corticosteroids, methotrexate, and other systemic medications; topical irritants; systemic illness; infection; phototherapy burns;
pregnancy; and emotional stress. ED patients commonly report thermoregulatory disturbances, malaise,
fatigue, and pruritus; these symptoms are not specific
to any etiology.
The onset of symptoms is important to assess different etiologies of ED. Primary skin diseases have
a slower course while drug reactions usually have a
rapid onset and resolution. One exception is ED associated with drug hypersensitivity reactions due to
anticonvulsants, antibiotics, and allopurinol. This reaction develops in 25 weeks after medication is started
269
TABLE 23-2
Drugs Implicated in Exfoliative Dermatitisa
Section 4
Antibiotics
Aztreonam
Cefoxitin130,131
Doxycycline123
Gentamicin136
Isoniazid2,12,15
Minocycline
Neomycin
Penicillin8,12,14,15
Ribostamycin145
Rifampin
Streptomycin2,14
Sulfasalazine153,154
Sulfonamides12,14
Teicoplanin158
Thiacetazone2
Tobramycin163
Trimethoprim1,164
Vancomycin166,167
Antivirals
Dideoxyinosine171
Indinavir173
Interferon 176
Zidovudine178
Antilepromatous
Clofazimine183
Dapsone185190
Antifungals
Nystatin197
Terbinafine201
Ketoconazole205
Griseofulvin207
Antiepileptics
Carbamazepine10,17,209,210
Lamotrigine214
Phenytoin12,17,215,216
Phenobarbital219
Aztreonam
::
a
270
Anti-inflammatory
Aspirin
Celecoxib132
Diflunisal135
Metamizole137
Phenylbutazone2
Piroxicam140
Cardiac drugs
Amiodarone143
Captopril146
Diltiazem148,149
Enalapril151
Isosorbide dinitrate12
Mexiletine
Nifedipine159
Nitroglycerin161
Practolol1
Quinidine8,17
Verapamil168
Chemotherapy
Bevacizumab172
Carboplatin174
Cisplatin177
Denileukin diftitox179
Doxorubicin182
Fluorouracil
Imatinib191193
Mitomycin C195
Pentostatin198
Vinca alkaloids202
Diabetic
Sulfonylureas
Chlorpropamide208
Psychiatric
Barbiturates
Bupropion217
Chlorpromazine1
Desipramine221
Escitalopram222
Etumine10
Fluoxetine224
Imipramine221
Lithium225
Phenothiazines
Methylphenidate226
Aspirin
Other
Allopurinol1,10,12,17
Antimalarials8,12,14,133,134
Arsenicals
Bacille Calmette-Gurin immunization138
Bromodeoxyuridine139
Cimetidine141
Clodronate142
Codeine14,144
Efalizumab147
Ephedrine150
Epoprostenol152
Erythropoietin155,156
Ethylenediamine157
Fluindione160
Furosemide162
Gold1,8,14,17
Homeopathic medicine (NatMur200)165
Hypericum (St. Johns wort)169
Interleukin 2170
Iodine14
Leflunomide175
Mercurials14,15
Omeprazole180,181
Phenolphthalein14
Propolis184
Pseudoephedrine194
Ranitidine196
Retinoids199,200
Rhus (lacquer)203,204
Roxatidine acetate hydrochloride206
Terbutaline12
Tetrachloroethylene14
Thalidomide211213
Thiazide12
Timolol eye drops218
Tocilizumab220
Tramadol
Tumor necrosis factor-170
Valiya narayana223
Allopurinol1,10,12,17
Most commonly implicated drugs are in italics.
and may remain ongoing after discontinuation of the

medication. Associated signs of a possible drug etiology include fever, lymphadenopathy, organomegaly,
edema, leukocytosis with eosinophilia, and liver and
renal dysfunction.153,215
History and clinical presentation alone may not be
sufficient to diagnose ED due to internal malignancy.
Important clues for this diagnosis are an absence of
prior skin disease, gradual onset, and a lack of response
to standard therapies. A history of transplant should
raise suspicion of CTCL, as it has been found that there
is a higher frequency of ED secondary to CTCL in posttransplant patients.227
CUTANEOUS LESIONS
The classic presentation of ED is erythematous patches
that increase in size and coalesce into generalized red
erythema with a shiny appearance. By definition, ED
involves more than 90% of the patients skin surface
(Fig. 23-2). A few days after the onset of erythema, fine
Approach to patient with exfoliative dermatitis
Look for clues to

etiology on
history and physical
examination
Perform multiple
punch biopsies;
consider multiple
repeat biopsies in 3-6
months for increased
diagnostic yield
Consider additional
tests such as:
biopsies for direct
immunofluorescence,
gene rearrangement,
CBC, CD4: CD8 ratio,
CXR, lymph node
biopsy
Refer to PCP to rule

out systemic disease
Figure 23-1 Approach to patient with exfoliative dermatitis. CBC = complete blood cell count; CXR = chest X-ray;
PCP = primary care physician.
Chapter 23
Likely diagnosis established and treatment initiated
::
Figure 23-2 Exfoliative dermatitis in psoriasis. There is universal erythema, thickening of the skin, and heavy scaling.
The patient had fatigue, malaise, and was shivering.
Some patients develop involvement of their hair and

nails. Scaling of the scalp, alopecia, and in some cases,
diffuse effluvium can be seen. Nail changes may include
onycholysis, subungual hyperkeratosis, splinter hemorrhages, paronychia, Beaus lines, and, occasionally, onychomadesis.2 Shore-line nails with alternating bands
of nail plate discontinuity represent drug-induced ED
reflecting the periods of time the drug was used.228
Sparing of the nose and paranasal areas (the nose
sign) has been described in some studies. Areolar
sparing has been noted in some cases of CTCL, drug
reactions, eczema, psoriasis, photosensitivity, and
PRP.229 Typically, there is not mucosal involvement.
Eruptive seborrheic keratoses may arise in patients
with ED.230232 The keratoses often resolve spontaneously as the ED subsides.
The cutaneous lesions may suggest the underlying
etiology of ED. For example, in early psoriatic ED, classic psoriatic plaques may be seen. Gottrons papules,
heliotrope rash, and muscle weakness may be present in ED caused by dermatomyositis. Papuloerythroderma of Ofuji typically spares the abdominal skin
folds (the deck chair sign).
Figure 23-3 Blepharitis, epiphora, and ectropion in atopic

exfoliative dermatitis.
white or yellow scaling begins, classically arising in

the flexures. Plate-like scaling may occur acutely and
on the palms and soles. The scaling progresses further,
giving the skin a dull red appearance. With chronicity, edema and lichenification lead to skin induration.
Ectropion and epiphora may develop secondary to
chronic periorbital involvement (Fig. 23-3). Palmoplantar keratoderma (Fig. 23-4) has been noted in up to
80% of patients with chronic ED.18
271
Section 4
::
Figure 23-4 Pityriasis rubra pilaris exfoliative dermatitis with keratoderma.

Note keratoderma with an orange hue and thickening of the thumbnails.
SPECIFIC FEATURES OF
UNDERLYING DISEASES
Features of underlying diseases may aid in diagnosis (see
Table 23-3 and eFigures 23-4.123-4.4 in online edition).

Related physical findings due to ED of any etiology
may include the following:

Tachycardia due to increased blood flow to the skin

and fluid loss due to disrupted epidermal barrier.
High-output cardiac failure has been infrequently
reported secondary to the high-flow state in ED.233
Thermoregulatory disturbances can result in hyperthermia or less commonly hypothermia; however,
most patients complain of feeling chilly.
Generalized lymphadenopathy occurs in more than
one-third of patients.2,12,15 The clinician must distinguish between dermatopathic lymphadenopathy
and lymphoma. If lymphadenopathy is prominent,
a lymph node biopsy may be required.
Hepatomegaly may occur in about one-third of
patients 2,12,15 and is more commonly seen in druginduced ED.
Splenomegaly has also been rarely reported12 and is
most commonly associated with lymphoma.
Peripheral pedal or pretibial edema may occur in
up to 54% of patients.15,32 Rarely, facial edema has
been reported in drug-induced ED.
LABORATORY TESTS
272
Laboratory tests are most often not diagnostic and not

specific. Common laboratory abnormalities found in
ED patients include anemia, leukocytosis, lympho-
cytosis, eosinophilia, increased IgE, decreased serum

albumin, and an elevated erythrocyte sedimentation
rate. Fluid loss may lead to electrolyte abnormalities and abnormal renal function (elevated creatinine
level). Elevated IgE levels have been noted in patients
with ED unrelated to atopic dermatitis,10,12,18 including
in 81.3% of psoriatic ED patients.38 Eosinophilia is nondiagnostic and has been found in 20% of ED patients.17
However, when highly elevated eosinophil counts are
noted, the possibility of associated Hodgkin disease
must be investigated.
It is very important to differentiate benign erythrodermic inflammatory diseases from Szary syndrome.
In cases where erythrodermic CTCL is suspected, a
thorough evaluation of skin, blood, and lymph node
samples is required for definitive diagnosis. Studies
have shown that a level of 20% or more circulating
Szary cells is a useful diagnostic criterion for Szary
syndrome, whereas less than 10% is nonspecific.17,32
Exceptions do occur, such as in certain severe druginduced reactions that can mimic Szary syndrome (as
hydantoin hypersensitivity).234 Several benign dermatoses, including psoriasis, atopic dermatitis, discoid
lupus, lichen planus, and parapsoriasis show the
presence of Szary cells in numbers less than 10%.235
Demonstration of a clonal T cell receptor gene rearrangement is recommended for a sensitive and specific
differentiation of Szary syndrome from other etiologies of ED.
In a recent study, quantitative real-time polymerase
chain reaction analysis of the expression values of five
genes [(1) STAT4, (2) GATA-3, (3) PLS3, (4) CD1D, and
(5) TRAIL] has proven useful for molecular diagnosis of Szary syndrome236 (see Chapter 145). Several
molecular markers of Szary cells have been recently
studied (Twist, EphA4, T-plastin). In one report,
CD158K/KIR3DL2, a killer immunoglobulin-like
receptor normally expressed by subsets of circulating
T CD8+ lymphocytes and natural killer cells, has been
TABLE 23-3
Specific Features of Underlying Disease Processa

Underlying Disease Process
Clinical Clues
Psoriasis (see Chapter 18)
History of localized disease

Personal or family history of psoriasis
Classic psoriasiform plaques on elbows, knees,
sacrum, etc.
Well-circumscribed plaques at margins of
erythroderma (eFig. 23-4.3 in online edition)
Large lamellar scales

Psoriatic nail changes: pits, oil drop sign,
onycholysis, subungual hyperkeratosis
Collarettes of scale suggestive of ruptured
pustules of pustular psoriasis
Psoriatic arthritis
Atopic dermatitis (see Chapter 14)
History of localized disease, most often

moderate to severe
Personal or family history of atopy (atopic
dermatitis, asthma, rhinoconjunctivitis)
Marked pruritus
Classic atopic lesions in antecubital and

popliteal fossae
Lichenification and prurigo nodularis
Excoriations
Focal skin atrophy from years of use of
potent topical steroids
Spongiotic dermatitis of other

etiologies, such as contact
dermatitis (see Chapter 13) (eFig.
23-4.1 in online edition) or stasis
dermatitis (see Chapter 174)
Distribution of original skin lesions

History of contactant
History of preexisting venous disease
Drug reaction (see Chapter 41)
Recent start of new drug, or use of frequently

implicated drug
Rapid onset of rash and progression to exfoliative
Dermatitis
Lymphadenopathy
Organomegaly
Fever
Cutaneous T-cell lymphoma (see

Chapter 145)
Severe debilitating pruritus

Fissured, painful keratoderma
Hepatosplenomegaly
Lymphadenopathy
Alopecia
Leonine facies
Immunobullous disease
Pemphigus foliaceus and fogo
selvagem (see Chapter 54)
Bullous pemphigoid
(see Chapter 56)
Paraneoplastic pemphigus
(see Chapter 55)
Flaccid blisters
Collarettes of scale at sites of previous blisters
Superficial erosions and crusts
Tense blisters (early lesions)
Deep erosions and superficial ulcers
Urticarial plaques
Mucosal erosions and crusting prominent
Rash resembles erythema multiforme
Failure to thrive (i.e., cachexia)
Pruritus
Elderly patient
Paraneoplastic ED
Failure to thrive (i.e., cachexia)
Pityriasis rubra pilaris (see Chapter 24)
Initial lesion: seborrheic dermatitis-like eruption

of the scalp
Worsening postsun exposure
Generalized salmon-colored slightly infiltrated
erythema (eFig. 23-4.4 in online edition)
Chronic actinic dermatitis (see

Chapter 91)
Photo-accentuation
Acute graft-versus-host disease

(see Chapter 28)
History of bone marrow transplantation or

blood transfusion
Initial lesion: palmar erythema

Progression to toxic epidermal necrolysis
Dermatomyositis (see Chapter 156)
Gottron papules
Heliotrope sign
Poikiloderma
Periungual telangiectasia
Muscle weakness
Sarcoidosis (see Chapter 152)
Apple jelly papules, plaques, and/or nodules
Norwegian scabies (see Chapter

208)
Down syndrome or nursing home patient

Burrows
ED = exfoliative dermatitis.
a
Features of underlying diseases may aid in diagnosis.
Pruritus
Palmoplantar keratoderma
::
Elderly men
Chronic and relapsing course
Dermatopathic lymphadenopathy
Chapter 23
Idiopathic erythroderma (red man

syndrome)
Islands of sparing (eFig. 23-4.4 in online

edition)
Palmoplantar keratoderma, often orange
(Fig. 23-4)
Follicular pink papules of elbows, wrists,
dorsal fingers or in skin spared from ED
Massively thickened nails

Keratoderma
273
Section 4
found to be useful as a molecular marker of Szary

syndrome in skin samples of patients with ED.237
Another study suggests that Szary syndrome may be
differentiated from inflammatory ED based on different memory T-cell subset expression and that CD27
expression may be helpful as an additional diagnostic
tool.28
Immunophenotyping of skin lymphocytes may be
a helpful adjunct study in differentiation of Szary
syndrome from actinic reticuloid. Szary patients
show a clonal CD4+ predominance while in patients
with underlying actinic reticuloid,238 there is a CD8+
lymphocyte predominance. More specifically, CD28+/
CD5+/NKa/CD4+ T cells with reduction of CD3, CD4,
CD7, CD2, and/or T-cell receptor / supports the
diagnosis of Szary syndrome in ED patients.239 The
nuclear contour index may also be a helpful investigation for the same differentiation.
::
HISTOPATHOLOGY
The histopathology findings differ depending on the
underlying etiology (Table 23-4). Multiple skin punch
biopsies over time are required in addition to clinical
evaluation to make a diagnosis. The biopsy specimens
often reveal a nonspecific picture that includes hyperkeratosis, parakeratosis, acanthosis, and a chronic
inflammatory infiltrate, which may mask features of
the underlying etiology. The histologic features may
vary depending upon the stage of the disease and the
severity of inflammation. One-third of biopsy specimens of erythroderma fail to reveal the underlying
diagnosis.240 The histologic features of the underlying disease may be more subtle than usually seen in
that disease entity when unassociated with ED.240
When dermatopathologists blinded to clinical information reviewed biopsies of erythroderma,241 an accurate
diagnosis was made only 50% of the time. Therefore,
multiple punch biopsies obtained simultaneously and
repeated over time are recommended to maximize
the possibility of histopathologic diagnosis. Direct
immunofluorescence, various special stains, immunoperoxidase studies, immunophenotyping, and gene
rearrangement studies may be required to determine
the underlying cause.
SPECIAL TESTS
274
Laboratory testing is driven by the patients medical history and clinical presentation. In addition to
multiple skin biopsies, lymph node biopsies may be
required to differentiate dermatopathic lymphadenopathy from lymphomatous involvement. Radiologic workup should be undertaken if the condition
is thought to be paraneoplastic. If a lymphoproliferative disease is considered as a possible cause of
the ED, a thorough evaluation should be done that
includes CD4:CD8 ratios, Szary cell counts, immunophenotyping of skin and blood, and analysis of
T-cell clonality by cytogenetics or T-cell receptor
gene analysis.
COMPLICATIONS
A variety of metabolic and physiological changes
occur in ED, including fluid and electrolyte imbalances, thermoregulatory disturbance, high-output
cardiac failure,233 cardiogenic shock,242 acute respiratory distress syndrome,243 decompensation of chronic
liver disease,244 and gynecomastia.245 Hypoalbuminemia is common since there is an increase of protein
loss via scaling (by 10%15% in nonpsoriatic ED and
up to 25%30% in psoriatic ED31) as well as increase in
metabolism and decrease in protein synthesis.246 These
processes lead to a negative nitrogen balance, muscle
wasting, and edema.
Another common complication in ED is body temperature dysregulation. Increased skin perfusion combined with increased transepithelial water loss and
loss of heat due to increased metabolic rate247 leads
to hypothermia. Furthermore, the capillaries cannot
respond appropriately to temperature changes via
vasoconstriction and vasodilation. Fluid and electrolytes loss from leaky capillaries leads to fluid and electrolyte imbalances. The shunting of blood to the skin
may lead to high-output cardiac failure, which is of
particular concern in patients with cardiac conditions
and the elderly.233
There is an increased susceptibility to bacterial colonization in ED due to inflammation, fissuring, and
excoriation of the skin. Sepsis may occur occasionally.
Staphylococcal sepsis in particular is especially a risk
for patients with CTCL and HIV-positive ED.40,243,248

COURSE
There are many factors affecting the clinical course
and prognosis of ED, such as the underlying etiology,
patients comorbidities, age, speed of onset, and early
therapy. In drug-induced ED, the course is usually
rapid and upon discontinuation of the offending drug
the ED clears readily and patients recover completely.1
An important exception to this is the severe systemic
hypersensitivity reactions that develop usually within
25 weeks after the medication is started and may persist for weeks after discontinuation of the drug. When
the underlying etiology is a primary skin disease as in
psoriatic and atopic ED, typically improvement takes
weeks to months; however, chronic and persistent
cases occur. Recurrence of psoriatic ED occurs in 15%
of patients after initial resolution.133
ED can prove fatal especially in the very young and
the elderly. Variable mortality rates (from 3.73% to
64%) have been reported in studies over the past 51
years.4,10,12,14,16,20 In early series of ED, high mortality
rates were reported in patients with severe drug reactions, lymphoproliferative malignancy, pemphigus
foliaceus, and idiopathic ED.8 The causes of death were
complications such as sepsis, pneumonia, and cardiac
failure.8,14,20 Lower mortality rates have been reported
in more recent studies with most deaths occurring in
TABLE 23-4
Histologic Clues of Underlying Disease
Actinic reticuloid
Atypical mononuclear cells admixed amongst

inflammatory cells
Superficial and deep perivascular, interstitial, and
lichenoid lymphocytic infiltrate
Overlying lichen simplex chronicus
With or without spongiosis
Immunophenotyping to differentiate
actinic reticuloid from Szary syndrome
Predominance of CD8+ lymphocytes in skin
and peripheral blood
Atopic dermatitis
Superficial perivascular lymphocytic infiltrate with

eosinophils
Spongiosis
Occasional eosinophilic spongiosis
Parakeratosis
With or without lichen simplex chronicus
Contact dermatitis
Same as atopic dermatitis
Patch testing, as appropriate

Patch testing may be attempted when
patient has partial clearing either
spontaneously or with treatment
CTCL/Szary
Atypical mononuclear cells singly and linearly along

the basal cell layer
Intraepidermal nests of atypical cells (Pautriers
microabscesses)
Spongiosis absent or minimal
Often lichenoid infiltrate
Immunophenotyping to detect clonal T-cell

population in skin (and blood)
Dermatomyositis/
erythematosus
Interface dermatitis with vacuolar alteration

Epidermal atrophy
Colloid bodies
Increased dermal mucin
Direct immunofluorescence
ANA
Muscle enzymes
Dermatophytosis
Hyphae within stratum corneum

Mounds of parakeratosis
Neutrophils in stratum corneum
Papillary dermal edema
KOH scraping
PAS stain
Culture
Drug eruption, morbilliform

type
Interface dermatitis
Vacuolar alteration
Necrotic keratinocytes at all levels of epidermis
Perivascular and interface inflammation with
eosinophils
Acute graft-versus-host
disease
Vacuolar alteration
Dyskeratosis in close proximity to epidermal
lymphocyties (satellite cell necrosis)
Subepidermal clefting possible
Idiopathic
Nonspecific
Usually subacute or chronic spongiotic dermatitis-like
changes
Lymphoprolifereative
disease
Nodular or diffuse infiltrate of monomorphous

mononuclear cells
Lower dermal cellular infiltrate usually denser than
that of the upper part
Neoplastic mononuclear cells often within adnexal
structures and walls of blood vessles
Paraneoplastic
Nonspecific and variable changes
Pemphigoid
Subepidermal bulla
Dermal eosinophils
Eosinophilic spongiosis
Pemphigus
Intraepidermal bulla
Acantholysis
Eosinophilic or neutrophilic spongiosis
Special Tests
::
Diagnostic Features
Chapter 23
Disease
Immunophenotyping
275
(continued)
TABLE 23-4
Histologic Clues of Underlying Disease (Continued)
Section 4
Diagnostic Features
Special Tests
Suprabasal acantholysis
Necrotic keratinocytes
Vacuolar alteration with lichenoid lymphotcytic
infiltrate
Epidermal hyperplasia
Horizontal and vertical alternating orthokeratosis and
parakeratosis
Dilated plugged follicular infundibulum
Psoriasis
Psoriasiform epidermal hyperplasia

Confluent parakeratosis layered with neutrophils
Spongiform pustules
Hypogranulosis
Dilated tortuous papillary blood vessels
Sarcoidosis
Naked tubercles (dermal granulomas with little or no

mantle of surrounding lymphocytes)
Chest X-ray
Scabies
Superficial and deep perivascular and interstitial

inflammation
Many eosinophils
Frequent spongiosis
Stratum corneum with mite or excreta and crusting
possible
Scraping of burrows to identify a mite or

excreta
Spongiotic psoriasiform dermatitis

Parakeratosis and neutrophils at lips of the follicular
ostia
Stasis with
autoeczematization
Spongiotic dermatisis
Often eosinophils
Lower leg biopsies demonstrate thick-walled
superficial blood vessels, extravasated red blood cells,
and siderophages
Infantile exfoliative
dermatitis ichthyoses
Nonbullous congenital
ichthyosiform erythroderma
(Lamellar ichthysosis)
Bullous congenital
ichthyosiform erythroderma
Changes of the specific type of inherited ichthyosis

(epidermolytic hyperkeratosis)
Can be nondiagnostic changes
Nondiagnostic
Orthohyperkeratosis and acanthosis
Epidermolytic hyperkeratosis
Massive orthohyperkeratosis
Acanthosis
Hypergranulosis
Electron microscopy
Genetic testing
Translgutaminase-1 deficiency in cultured
keratinocytes
Genetic testing to detect mutations in
TGM1
Electron microscopy: cholesterol clefts and
lipid droplets in the stratum corneum
Mutations in keratin genes KRT1 and KRT10
Netherton syndrome
Nondiagnostic
Parakeratotic hyperkeratosis
Diminished or absent granular layer
Acanthosis
PAS may stain stratum corneum strongly eosinophilic
Electron microscopy: premature lamellar

body secretion
Foci of electron-dense material in
intracellular spaces of stratum corneum
::
Disease
276
patients with malignancy-associated ED,1,12,17 usually

due to underlying disease progression, treatment complications, or sepsis.12 In a recent study, an average of
30-month follow-up of 80 ED patients demonstrated a
death rate of 3.75% (3 of 80 patients) with deaths due to
pneumonia in patients with pemphigus foliaceus and
Szary syndrome.16
ED secondary to malignancy including CTCL is
most often chronic and refractory. For mycosis fungoides and Szary syndrome-related ED, positive
prognostic factors include age younger than 65 years,
symptom duration greater than 10 years before diagnosis, absence of evidence of lymphoma involving a
lymph node, and the absence of circulating Szary cells
in mycosis fungoides.249 Mean survival ranges from 1.5
to 10.2 years based on these prognostic indicators.249
Idiopathic ED patients often have chronic symptoms and recurrences, which require long-term steroid
therapy. Complete remission occurs in one-third of
idiopathic ED patients and partial remission in onehalf of patients.18,32 Patients with chronic idiopathic
ED are at increased risk of evolution to the diagnosis
of CTCL.10,12,18,32 A proportion of patients with chronic

ED have been shown to have a monoclonal T-cell dyscrasia, which may indicate a possible premalignant or
pre-Szary-like condition (monoclonal T-cell dyscrasia
of undetermined significance).35
In pediatric patients presenting with fever and ED,
certain parameters (older age, vomiting, presence of
focal infection, specific laboratory values) can be used
to predict which patients are likely to develop hemodynamic deterioration.250 Predictors of developing
toxic shock syndrome in this population included age
3 years, ill appearance, elevated creatinine, and hypotension on arrival.250
The treatment of ED is summarized in Box 23-2.

Patients presenting acutely with ED may require
Chapter 23
TREATMENT
inpatient management due to significant fluid and

electrolyte imbalance and hemodynamic or respiratory compromise. However, most patients can be
managed on an outpatient basis. Regardless of etiology, the initial management involves fluid, electrolyte,
and nutritional replacement. Children presenting with
erythroderma and fever should be hospitalized and
managed aggressively since they are likely to develop
hemodynamic deterioration.250
The patient should be nursed in a warm (preferably 30C32C) and humid environment for comfort
and skin moisture, as well as to prevent hypothermia.
Gentle local skin care, including oatmeal baths and
wet dressings to weeping or crusted lesions, bland
emollients, and low-potency topical steroids should
be started. High-potency topical steroids251 and topical immunomodulators, such as tacrolimus,252 should
be avoided as systemic absorption may occur due to
the increased skin permeability and large surface area
::
First line
TOPICAL
SYSTEMIC
Oatmeal baths
Wet dressings
Sedating antihistamines
Systemic antibiotics if secondary
infection
Diuretics for peripheral edema
Fluid and electrolyte replacement
Bland emollients
Low-potency corticosteroids
Second line
(once etiology
established)
Single agent
Corticosteroids for drug hypersensitivity reactions, immunobullous disease, atopic dermatitis.

Cyclosporine for psoriasis, atopic
dermatitis
Methotrexate for psoriasis, atopic
dermatitis, pityriasis rubra pilaris
Acitretin for psoriasis, pityriasis
rubra pilaris
Mycophenolate mofetil for psoriasis, atopic dermatitis, immunobullous disease
Infliximab for psoriasis and pityriasis rubra pilaris
Etanercept for psoriasis and pytirasis rubra pilaris
Combination therapy
Methotrexate and infliximab for

psoriasis
Infliximab and acitretin for psoriasis and pityriasis rubra pilaris
Cyclosporine and etretinate for

psoriasis
DOSAGE
BOX 23-2 Therapy
12 mg/kg/day with taper
45 mg/kg/day
525 mg qwk depending on
renal function and response
to treatment
2550 mg qd
13 g qd
510 mg/kg
25 mg SC two times/week
2.74.4 mg/kg infliximab and
57.5 mg/week methotrexate
5 mg/kg infliximab and
0.30.6 mg/kg acitretin
(psoriasis)
5 mg/kg infliximab and
0.2 mg/kg/day acitretin
(pityriasis rubra pilaris)
3.54 mg/kg/day cyclosporine and 0.50.6 mg/kg/day
etretinate
277
Section 4
::
278
involved. Other topical irritants such as anthralin, tar,

hydroxyl acid moisturizers, and vitamin D analogs
should also be avoided.
Antihistamines can be administered for sedation and antipruritic effects. Systemic antibiotics are
required for patients with evidence of localized and
systemic secondary infection. Septicemia secondary
to Staphylococcus infection is often a complication of
ED and requires aggressive antibiotic and supportive
treatment. Even patients without evidence of secondary infection may benefit from systemic antibiotic
therapy as bacterial colonization may exacerbate ED.
Pedal and periorbital edema should be treated with
diuretics and adequate fluid intake should be maintained. All nonessential and possible offending medications should be discontinued, including drugs such
as lithium and antimalarials that may trigger a flare
in patients with underlying psoriasis. Folate supplementation and a diet of 130% of normal dietary
requirements for protein are recommended to replace
nutrient losses.31,253
Determining the underlying etiology early is essential for definitive treatment of ED as ED may be refractory to therapy until the cause is treated. Consensus
treatment recommendations for erythrodermic psoriasis have been recently put forth by the National
Psoriasis Foundation.254 Therapy should be based on
the severity of disease and underlying comorbidities.
Systemic agents such as methotrexate, cyclosporine,
acitretin, mycophenolate mofetil, and azathioprine can
be helpful as single agents or in combination.254 Experience with biologics, although limited so far, is very
promising. A number of small case series and reviews
suggest that infliximab alone or in combination with
methotrexate can lead to rapid and dramatic control
of psoriatic ED and high rates or remission.255259 There
are emerging data suggesting that etanercept may also
be effective260,261 as well as single case reports of adalimumab262 and alefacept263 being successfully used in
psoriatic ED. Currently, there is no data to support a
role of ustekimumab in the treatment of erythrodermic
psoriasis, although given its good efficacy for plaquetype psoriasis it may eventually prove to be useful.
Systemic steroids should be avoided given the danger
of rebound erythrodermic flare and exacerbation of the
disease. A recent case series supports the use of infliximab in patients with erythrodermic and recalcitrant
chronic plaque psoriasis who have failed multiple
therapies including biologics.264
Etanercept has also been used as a steroid-sparing
agent with relief of pruritus in Szary syndrome in
two patients.265 However, etanercept should be used
with caution in these patients because of risk of further immunosuppression. Options for treatment of
CTCL include topical corticosteroids, psoralen plus
ultraviolet A (UVA), total skin electron beam irradiation, systemic chemotherapy including CHOP-like
regimens (cyclophosphamide, hydroxydaunomycin,
vincristine, and prednisone), interferon-, extracorporeal photochemotherapy, and biologics such as
monoclonal antibodies (alemtuzumab),266,267 bexarotene (selective retinoic X receptor retinoid),268,269 and
denileukin diftitox.
Systemic corticosteroids are useful for drug hypersensitivity reactions. In severe and persistent cases,
intravenous Ig may be used. Cyclosporine, methotrexate, azathioprine, mycophenolate mofetil, and
systemic corticosteroids may be helpful for spongiotic
(eczematous) dermatitis. PRP usually responds to systemic retinoids or methotrexate. Recently, case reports
and case series have showed that tumor necrosis factor (TNF)- antagonists (infliximab, etanercept, adalimumab) alone or in combination therapy can be very
useful in the treatment of adult-onset PRP270277 and
juvenile PRP.278,279 Papuloerythroderma of Ofuji has
been treated with topical and systemic corticosteroids,
cyclosporine, interferon, etretinate, and most recently
with a combination of retinoid plus psoralen and UVA
light.280 Rituximab has proven useful in the treatment
of erythrodermic pemphigus foliaceus in a recent case
report.281
When the underlying cause of ED is unknown,
empiric therapy with systemic agents, including
methotrexate, cyclosporine, acitretin, mycophenolate mofetil, and systemic corticosteroids, has
been used. It should be emphasized that a strong
suspicion for psoriatic ED precludes systemic corticosteroid use due to risk for a rebound flare. Immunosuppressive drugs should not be used until CTCL
has been ruled out with the most current laboratory
testing.
PREVENTION
Prevention of ED depends on controlling the underlying cause. Medications and irritants that have
previously caused ED should be avoided. It is important that the patients maintain careful records of
allergies including potentially cross-reactive medications, such as topical agents (e.g., ED occurring
secondary to systemic gentamicin use in a patient
with known contact allergy to neomycin136 and ED
secondary to pseudoephedrine use in a patient with
a contact allergy to phenylephrine).194 Systemic steroids should be avoided in patients with psoriasis
to prevent rebound flares. Educating patients with
underlying diseases (e.g., psoriasis, atopic dermatitis) about possible triggers of ED (irritants, abrupt
discontinuation of certain therapies) may also be
helpful to prevent ED.
KEY REFERENCES
1. Hasan T, Jansen CT: Erythroderma: A follow-up of fifty
cases. J Am Acad Dermatol 8(6):836-840, 1983
2. Sehgal VN, Srivastava G: Exfoliative dermatitis. A
prospective study of 80 patients. Dermatologica 173(6):
278-284, 1986
3. Sigurdsson V, Steegmans PH, van Vloten WA: The incidence of erythroderma: A survey among all dermatologists in The Netherlands. J Am Acad Dermatol 45(5):675678, 2001
4. Wong KS et al: Generalised exfoliative dermatitisA

clinical study of 108 patients. Ann Acad Med Singapore
17(4):520-523, 1988
16. Rym BM et al: Erythroderma in adults: A report of 80
cases. Int J Dermatol 44(9):731-735, 2005
31. Kanthraj GR et al: Quantitative estimation and recommendations for supplementation of protein lost through scaling in exfoliative dermatitis. Int J Dermatol 38(2):91-95, 1999
35. Gniadecki R, Lukowsky A: Monoclonal T-cell dyscrasia of undetermined significance associated with
recalcitrant erythroderma. Arch Dermatol 141(3):361367, 2005

241. Walsh NM et al: Histopathology in erythroderma: Review of a series of cases by multiple observers. J Cutan
Pathol 21(5):419-423, 1994
254. Rosenbach M et al: Treatment of erythrodermic psoriasis:
From the medical board of the National Psoriasis Foundation. J Am Acad Dermatol 62(4):655-662, 2010 [Epub
Aug 8, 2009]
The disease is subclassified into six types

including both hereditary and acquired
forms.
The typical features of pityriasis rubra
pilaris include follicular hyperkeratosis and
a reddish orange, scaling dermatitis with
islands of normal skin.
Confusion with psoriasis presents the major
problem in diagnosis, particularly in early
phases of the disease.
Histopathological examination reveals
hyperkeratosis, alternating vertical and
horizontal parakeratosis, and a mild
superficial perivascular lymphocytic
infiltrate.
No single therapy is universally effective,
and some cases do not respond to multiple
therapies. The most successful treatment
options are retinoids, photochemotherapy
(PUVA), and antimetabolites
(methotrexate).
EPIDEMIOLOGY
Pityriasis rubra pilaris is a rare, chronic disorder with
an estimated incidence ranging from 1 in 5,000 to 1
in 50,000 dermatology patients. The age distribution
is bimodal with peak incidences in the first and fifth

Although an underlying dysfunction in vitamin A
metabolism has been suggested, the etiology and
pathogenesis of pityriasis rubra pilaris are still poorly
understood. Thus, the role of vitamin A deficiency
remains uncertain as attempts to produce keratotic
lesions by vitamin A deprivation have been unsuccessful. Moreover, the deficiency of retinol-binding protein
as an underlying pathogenic mechanism resulting in
inadequate transport of vitamin A to the skin has yet
to be ascertained. There are some cases in which pityriasis rubra pilaris may result from immune system
dysregulation and abnormal response to various antigenic triggers.2 A report of an exanthematous form of
juvenile pityriasis rubra pilaris that followed an upper
respiratory infection and initially resembled Kawasaki
disease supports the hypothesis of a superantigenmediated process. Finally, genetic factors with an
autosomal dominant pattern of inheritance have been
supposed to play a critical role for the induction of
pityriasis rubra pilaris. Nevertheless, affected relatives
are not observed in the classical acute-onset disease
and are infrequent in other variants.
Pityriasis Rubra Pilaris
A papulosquamous disorder of unknown

etiology that often progresses to
erythroderma and causes a disabling
keratoderma of the palms and soles.
decades of life. The disease occurs in all races and

affects the sexes equally.1
::
PITYRIASIS RUBRA PILARIS

AT A GLANCE
Chapter 24
Chapter 24 :: Pityriasis Rubra Pilaris

:: Daniela Bruch-Gerharz & Thomas Ruzicka
CLINICAL FINDINGS
CUTANEOUS LESIONS
Pityriasis rubra pilaris is generally believed to comprise more than a single entity and a classification
scheme based on clinical characteristics and course has
been proposed by Griffiths1 (Table 24-1).
Type I (classic adult) is the most common subtype
with over 50% of all cases. Characteristically, patients
present with an eruption of follicular hyperkeratotic papules that spread in cephalocaudal direction
(Fig. 24-1). As the disease further evolves, a reddish
279
TABLE 24-1
Classification Scheme of Pityriasis Rubra Pilaris (Types IV According to Griffiths1)
Section 4
Description
Clinical Characteristics
Distribution
Course
Classic adult
>50
Erythroderma with islands of

normal skin (nappes claires),
follicular hyperkeratosis, waxy diffuse
palmoplantar keratoderma
Generalized,
beginning on the
head and neck, then
spreading caudally
Often resolves within an

average period of 3 years
II
Atypical adult
Combination of follicular
hyperkeratosis and ichthyosiform
lesions on the legs, sparse scalp hair
Generalized
Long duration (>20 years)
III
Classic juvenile
10
Similar to type I but appears in years

1 or 2 of life
Generalized
Often resolves within an

average period of 12
years
IV
Circumscribed
juvenile
25
Prepubertal children; welldemarcated scaly, erythematous

plaques on the elbows and knees,
resembling localized psoriasis
Localized
Uncertain, some cases

clear in the late teens
Atypical juvenile
Begins in first few years, accounts

for most familial cases; follicular
hyperkeratosis, scleroderma-like
appearance of the hands and feet
Generalized
Chronic course,
improvement with
retinoids but relapses
when stopped
VI
HIV-associated
NAa
Similar to type I with variable

beginning; associated with acne
conglobata, hidradenitis suppurativa
and lichen spinulosus
Generalized
May respond to
antiretroviral triple
therapy
::
Type
Data not available.
280
Figure 24-1 Acuminate follicular papules of pityriasis rubra pilaris. Close-ups of discrete (A) and confluent (B) lesions.
Chapter 24
::
Figure 24-2 Generalized pityriasis rubra pilaris (A) with a reddish orange, scaling dermatitis, and islands of normal skin
(nappes claires), shown in more detail in (B).
orange, scaling dermatitis appears that often progresses to a generalized erythroderma over a period
of 23 months (Fig. 24-2). A diagnostic hallmark of
pityriasis rubra pilaris are sharply demarcated islands
of unaffected skin (nappes claires) in a random distribution (Fig. 24-2B). Many patients develop a waxy,
diffuse, yellowish keratoderma of the palms and soles
(Fig. 24-3).3 Nail changes are not uncommon and
include distal yellowbrown discoloration, nail plate
thickening, splinter hemorrhages, and subungual
hyperkeratosis. Eventually, the mucous membranes
may be affected with a diffuse whitish appearance of
the buccal mucosa as well as lacy white plaques and
erosions. Hair and teeth are normal.
Type II is an atypical variant with onset in adult age.
Areas of follicular hyperkeratosis as well as ichthyosiform scaling, especially on the legs, dominate the
clinical picture. This variant lacks the typical cephalocaudal progression observed in type I, and there is less
tendency for the patients to become erythrodermic.
Sparseness of the scalp hair is occasionally seen.
Type III (classic juvenile) typically begins in years 1
or 2 of life and shows all the morphological features of
type I (Fig. 24-4).
Type IV (circumscribed juvenile) affects approximately 25% of the patients. This type usually presents
several years after birth and is characterized by welldemarcated hyperkeratotic erythematous plaques on
the elbows and knees, resembling localized psoriasis.
According to Griffith,1 these lesions do not progress to
the widespread types I and III. Yet, some cases show

marked palmoplantar keratoderma.
Type V is an atypical variant of juvenile pityriasis rubra pilaris that usually presents in the first
few years of life and has a more chronic course. This
type is distinguished by follicular hyperkeratosis
with only minimal erythema and a scleroderma-like
appearance of the hands and feet. Most cases of familial pityriasis rubra pilaris belong to this type, which
may even represent a different clinical entity sharing
features with several poorly defined ichthyotic disorders such as follicular ichthyosis and the erythrokeratodermas.
Other reports have described a type VI variant associated with HIV infection. The clinical features of this
variant are similar to type I but with increased severity and additional manifestations of acne conglobata,
hidradenitis suppurativa, and lichen spinulosus.
RELATED FINDINGS
There have been rare cases of a pityriasis rubra pilarislike eruption, clinically and histologically, in patients
with dermatomyositis, often associated with internal neoplasia. Concomitant rheumatologic disorders,
mainly inflammatory polyarthritis, have also been
reported. In addition, numerous other noncutaneous
diseases were considered to be related to pityriasis
rubra pilaris, which are probably all fortuitous.
281
Section 4
::
Figure 24-3 Keratoderma in pityriasis rubra pilaris. Palmar (A) and plantar (B) erythema and waxy hyperkeratosis are frequent manifestations. Sometimes, there is an orangeyellow tint.
infundibula as well as perifollicular areas of parakeratosis may also be present. A prominent granular layer and dilated, but not tortuous capillaries are
features that help to distinguish pityriasis rubra pilaris from psoriasis, its most important differential
diagnosis.
PATHOLOGY
Pathological findings in pityriasis rubra pilaris vary
according to the duration of the disease. The findings
are most likely to be diagnostic in the acute phase,
when hyperkeratosis, acanthosis with broad short
rete ridges and alternating orthokeratosis and parakeratosis oriented in both horizontal and vertical
directions can be observed. Usually, there is a sparse
superficial, perivascular lymphocytic infiltrate in the
underlying dermis. Keratinous plugs of the follicular
282
See Box 24-1.
Figure 24-4 Juvenile pityriasis rubra pilaris. A. Confluence of lesions leads to extensive erythroderma. B. Characteristic
scattered islands of unaffected skin are evident. So is the plantar hyperkeratosis.

of Pityriasis Rubra Pilaris
BOX 24-2 Treatments for Pityriasis

Rubra Pilaris
Most Likely
Localized
Psoriasis
Ichthyosis
Generalized
Psoriasis
Erythrokeratoderma
FIRST LINE
Topical
Emollients (water-in-oil emulsion)
Keratolytics (salicylic acid, urea)
Vitamin D3 (calcipotriol)
Systemic symptoms are uncommon except when

generalized erythroderma occurs, and then they are
comparable to those seen in exfoliative dermatitis
(see Chapter 23). Occasionally, a mild ectropion may
develop when the face becomes uniformly erythematous. Even though rare, moderate to severe pruritus or
burning sensations may occur.
The classic adult disease (type I) usually remits
completely within an average of 3 years. However,
recurrences are recognized in up to 20% of patients,
sometimes after long periods of subclinical disease. In
the classic juvenile variant (type III) spontaneous clearing is commonly observed in 1 to 2 years. However, the
atypical variants (type II and IV) have a less favorable
prognosis for remission, some cases of type IV improve
in late teens. Moreover, there is little or no tendency of
type V to resolve spontaneously, improvements with
retinoids have been described but relapses occurred
when treatment was withdrawn. Clinical manifestations in the HIV-associated type VI are severe and
occasionally fatal, with death occurring due to complications of cutaneous sepsis.
TREATMENT
(Box 24-2)
SECOND LINE
Topical
Glucocorticoids (medium to high potency)
Vitamin A analogs (tazarotene)
Physical
UVA1 phototherapy
UVB (narrowband) phototherapy
UVB phototherapy
COMPLICATIONS
Systemic
Retinoids (0.50.75 mg/kg acitretin/day)
Methotrexate (1025 mg weekly)
Triple antiretroviral therapy7 (HIV-associated variant)
::
Always Rule Out

Generalized (therapy-resistant cases)
HIV infection
Physical
Photochemotherapy (topical or systemic PUVA)
Extracorporeal photopheresis
Chapter 24
Consider
Localized
Follicular eczema
Lichen planus acuminatus
Keratosis pilaris
Generalized
Pityriasis lichenoides chronica
Ichthyosiform erythroderma
Systemic
Azathioprine (100150 mg/day)
Cyclosporine A (5 mg/kg/day)
Fumaric acid esters4
TNF- antagonists6
Patients with pityriasis rubra pilaris are often irresponsive to multiple therapies, both topical and systemic.3 Because of the relative rarity of the disease
and its variable course, the chances for clinical trials
assessing treatment options have been limited. Previous treatment strategies, which relied on megadoses of
oral vitamin A or the anabolic steroid stanazol, proved
to be largely ineffective.
Currently, oral retinoids are the first line of therapy
in patients with pityriasis rubra pilaris. Isotretinoin
has been reported to be of some value, although a
comprehensive review suggests that acitretin may
be more effective in clearing patients. Accordingly,
most patients are treated first with acitretin. Alitretinoin, a novel panagonist retinoid (see Chapter 228),
might be an alternative option for systemic treatment in patients refractory to conventional therapy.
Treatment with methotrexate, using the guidelines
established for psoriasis, has shown variable rates
of success. Some cases respond well to photochemotherapy (PUVA), some may flare, and others require
combination treatment with retinoids or methotrexate. In patients with severe symptoms, effective amelioration of the disease may require extracorporeal
photopheresis but there are no evidence-based data.
283
Section 4
::
284
Immunosuppressive agents are of inconsistent benefit. Thus, controversy persists about the role of cyclosporine in the treatment of pityriasis rubra pilaris.
While most studies show lack of efficacy, several cases
of adult-type pityriasis rubra pilaris showed significant clearance in 24 weeks. Some patients are helped
by azathioprine, but this effect is also inconsistent.
The use of glucocorticosteroids in the management
of pityriasis rubra pilaris has been studied, but there
is no evidence to suggest a beneficial effect. Whether
phototherapy can be effective is controversial. Ultraviolet B (UVB) irradiation, which is efficiently used
for psoriasis, has not been helpful or even worsened
pityriasis rubra pilaris. UVA1 phototherapy may be a
satisfactory alternative.
When conventional treatment strategies fail, new
therapeutic approaches may include the use of immunomodulatory drugs. Fumaric acid esters were reported as
successful in inducing remission in a patient with juvenile pityriasis rubra pilaris unresponsive to the usual
treatment options.4 Kerr and Ferguson reported a patient
with type II adult-onset pityriasis rubra pilaris resistant
to multiple therapies whose condition improved markedly with high-dose human intravenous immunoglobulin (IVIg) infusions.5 Moreover, there is accumulating
evidence indicating that blockade of tumor necrosis factor (TNF-), which is beneficial in psoriasis and psoriasisarthritis, is effective in the adult- and juvenile-onset
types of pityriasis rubra pilaris as well.6
Topical treatment with keratolytics (where possible under an occlusive plastic dressing) has proved
a valuable mode of adjuvant therapy in pityriasis
rubra pilaris. For symptomatic relief, emollients and
antihistamines provide significant benefit. Topical
therapy with calcipotriol showed encouraging results.
Its disadvantage is that total body treatment for the
erythrodermic patient could be toxic. Success has been
reported with topical aminonicotinamide 1%, although
it is not commonly used.3
Pityriasis rubra pilaris associated with HIV infection

has responded to triple antiretroviral therapy.7
Present therapeutic options (including drug doses)
for pityriasis rubra pilaris used in adults and children
are listed in Box 24-2.
PREVENTION
Pityriasis rubra pilaris is a rare, but socially and psychologically disabling condition, occurring in children
and adults of both sexes. Suicide remains a risk in
patients with generalized disease. Therefore, knowledge of the clinical pattern and cutaneous findings is
crucial for an early therapeutic intervention, and may
prevent protracted illness and serious complications in
this clinically challenging condition.
KEY REFERENCES
DVD contains additional content
1. Griffiths WAD: Pityriasis rubra pilaris. Clin Exp Dermatol
5:105, 1980
2. Batinac T et al: Pityriasis rubra pilaris in association with
laryngeal carcinoma. Clin Exp Dermatol 34:e917, 2009
3. Clayton BD et al: Adult pityriasis rubra pilaris: A 10-year
case series. J Am Acad Dermatol 36:959, 1997
4. Coras B et al: Fumaric acid esters therapy: A new treatment
modality in pityriasis rubra pilaris? Br J Dermatol 152:388,
2005
5. Kerr AC, Ferguson J: Type II adult-onset pityriasis rubra pilaris successfully treated with intravenous immunoglobulin. Br J Dermatol 156:1055-1056, 2007
6. Mller H et al: Infliximab monotherapy as first-line treatment for adult-onset pityriasis rubra pilaris: Case report
and review of the literature on biologic therapy. J Am Acad
Dermatol 59:S65, 2009
7. Gonzlez-Lpez A et al: HIV-associated pityriasis rubra pilaris responsive to triple antiretroviral therapy. Br J Dermatol 140:931, 1999
Chapter 25 :: P
arapsoriasis and Pityriasis
Lichenoides

:: Gary S. Wood, Chung-Hong Hu, &
Rosemarie Liu
PARAPSORIASIS
PARAPSORIASIS AT A GLANCE
Parapsoriasis occurs worldwide and affects

mainly adults.
Lesions are chronic and favor nonsunexposed skin; LPP may be poikilodermatous.
Pathology consists of superficial, mostly
CD4+ T-cell infiltrate; dominant clonality is
more common in LPP than in SPP.
LPP appears to exist on a continuum
with patch-stage mycosis fungoides (MF)
and progresses to overt MF at a rate of
approximately 10% per decade.
SPP has minimal risk of progression to overt
MF in the experience of most experts.
Treatment options include topical
corticosteroids; ultraviolet B (UVB)
irradiation, and psoralen and ultraviolet A
(UVA) irradiation; excimer laser; and topical
cytotoxic drugs.
HISTORICAL ASPECTS
The term parapsoriasis was coined originally by Brocq
in 1902.1 As shown in Table 25-1, the currently accepted
classification of parapsoriasis includes large- and
small-plaque forms of parapsoriasis en plaques (often
referred to simply as parapsoriasis) as well as acute and
chronic forms of pityriasis lichenoides [known today
as pityriasis lichenoides et varioliformis acuta (PLEVA)
and pityriasis lichenoides chronica (PLC), respectively].2
Pityriasis lichenoides was first described in 1894 by
Neisser3 and Jadassohn.4 In 1899, Juliusberg delineated
EPIDEMIOLOGY
Large-plaque parapsoriasis (LPP) and small-plaque
parapsoriasis (SPP) are, in general, diseases of middleaged and older people, with a peak incidence in the
fifth decade. Occasionally, lesions arise in childhood
and may be associated with pityriasis lichenoides. SPP
shows a definite male predominance of approximately
3:1. LPP is probably more common in males, but the
difference is not as striking as in SPP. Both occur in all
racial groups and geographic regions.

It is likely that a complete understanding of the
pathogenesis of parapsoriasis will develop with our
understanding of the pathogenesis of both chronic
dermatitis and mycosis fungoides (MF), because parapsoriasis appears to bridge these disorders. The T cells
that mediate most inflammatory skin diseases belong
to the skin-associated lymphoid tissue (SALT).11 These
T cells express the cutaneous lymphocyte-associated
antigen and traffic between the skin and the T-cell
domains of peripheral lymph nodes via the lymphatics and bloodstream. MF (see Chapter 145) has been
shown to be a neoplasm of SALT T cells. Sensitive
polymerase chain reaction (PCR)-based tumor clonality assays have underscored the SALT nature of MF
tumor clones by showing that they can continue to
traffic after neoplastic transformation12 and can even
participate in delayed-type hypersensitivity reactions
to contact allergens.13 This implies that rather than
being a skin lymphoma per se, MF is actually a SALT
lymphoma, i.e., a malignancy of a T-cell circuit rather
than of one particular tissue. Trafficking of MF tumor
cells has been detected even in patients with very early
stage disease whose lesions were consistent clinicopathologically with LPP.12,14 Therefore, it can be said
that at least in some cases LPP is a monoclonal proliferation of SALT T cells that have the capacity to traffic
between the skin and extracutaneous sites.
Parapsoriasis and Pityriasis Lichenoides
Large and small plaque lesions actually

present as flat patches rather than infiltrated
plaques.
::
Large-plaque parapsoriasis (LPP) and smallplaque parapsoriasis (SPP) are recognized.
Chapter 25
Also known as parapsoriasis en plaques.
the chronic form and named it PLC.5 Mucha redescribed the acute form in 1916 and distinguished it
from the chronic form.6 Habermann named the acute
variant PLEVA in 1925.7 MuchaHabermann disease
is synonymous with PLEVA. Some authors regard
lymphomatoid papulosis as a variant of pityriasis
lichenoides, whereas others consider it to be a separate
disease.2,810 Lymphomatoid papulosis is discussed in
Chapter 145 as part of the spectrum of CD30+ cutaneous lymphoproliferative disorders.
285
Relationship of clonal dermatitis

to mycosis fungoides (MF)
TABLE 25-1
Classification of Parapsoriasis
1. Parapsoriasis en plaques
A.Large-plaque parapsoriasis variants: poikilodermatous,
retiform
B. Small-plaque parapsoriasis variant: digitate dermatosis
2. Pityriasis lichenoides
A. Pityriasis lichenoides chronica (Juliusberg)
B.Pityriasis lichenoides et varioliformis acuta (Mucha
Habermann)
Section 4
::
286
This view is also supported by the presence of structural and numerical chromosomal abnormalities in the
peripheral blood mononuclear cells of patients with
LPP.15 In this context, LPP can be regarded as the clinically benign end of the MF disease spectrum, which
eventuates in transformed large cell lymphoma at its
malignant extreme. To say that these diseases belong
to the same disease spectrum is not to say that they
are biologically equivalent disorders. To lump them all
together simply as MF would be to ignore their distinctive clinicopathologic features, which are likely due
to genetic and/or epigenetic differences, such as the
p53 gene somatic mutations observed in some cases of
large cell transformation of MF.1618 It is likely that several such differences separate these clinicopathologically defined disorders in a stepwise fashion analogous
to the sequential acquisition of somatic mutations that
occurs in the colon cancer disease spectrum as colonic
epithelial cells progress through normal, hyperplastic,
in situ carcinoma, invasive carcinoma, and metastatic
carcinoma stages.19,20
A unifying feature of the parapsoriasis group of diseases is that all of them appear to be cutaneous T-cell
lymphoproliferative disorders: LPP,12,2128 SPP,23,28,29
pityriasis lichenoides,28,3032 and lymphomatoid papulosis23,3335 have all been shown to be monoclonal disorders in many cases.36 These relationships suggest that
progression from LPP through the various stages of the
MF disease spectrum is accompanied by an increasing
gradient of dominant T-cell clonal density resulting
from mutations that confer increasing growth autonomy to the neoplastic T-cell clone.37 Interestingly, analysis of peripheral blood has demonstrated that clonal
T cells are often detectable in patients with LPP/early
MF27,28 or SPP,28,38 which again supports the systemic
SALT nature of these primary skin disorders.
Dominant clonality as seen in the parapsoriasis disease group, follicular mucinosis, pagetoid reticulosis,
and certain other disorders does not equate to clinical
malignancy. In fact, most patients with these diseases
experience a benign clinical course, and in some cases
the disease resolves completely. In addition, other
types of chronic cutaneous T-cell infiltrates sometimes
exhibit dominant clonality, including primary (idiopathic) erythroderma and nonspecific chronic spongiotic dermatitis. This has given rise to the concept of
clonal dermatitis,14,39 originally described in the context of clonal nonspecific chronic spongiotic dermatitis
but later expanded to include other nonlymphomatous
cutaneous T-cell infiltrates that harbor occult monoclo-
NCSD
al Dermatit
on
is
l
C
LPP
MF
PE
FM
Figure 25-1 The relationship of clonal dermatitis to

mycosis fungoides (MF) and various types of chronic
dermatitis. The proportions of each entity that represent
clonal dermatitis and mycosis fungoides vary with each
disease and are not drawn to scale. FM = follicular mucinosis; LPP = large-plaque parapsoriasis; NCSD = nonspecific
chronic spongiotic dermatitis; PE = primary erythroderma.
nal T-cell populations. Several cases of clonal dermatitis, some of which have progressed to MF, have been
identified.14,21,39 We suspect that for each disease with a
potential for progression to MF, the principal risk may
reside in the subset showing clonal dermatitis, because
this is the subset in which dysregulation has begun to
occur.
The postulated relationships among MF, clonal dermatitis, and selected types of chronic dermatitis are
depicted in Fig. 25-1. Each of the entities shown is postulated to be at risk for MF through a clonal dermatitis intermediate. In this model, MF becomes the final
common pathway for the clonal evolution of neoplastic T cells emerging from the polyclonal SALT T-cell
populations present in each of the various precursor
diseases.
Various viruses have been proposed to play a role in
the pathogenesis of MF. None has been substantiated
thus far. The most recent virus implicated in both LPP
and MF is HHV-8; however, conflicting reports await
resolution.4042
CLINICAL FINDINGS
CUTANEOUS LESIONS. LPP lesions are either
oval or irregularly shaped patches or very thin plaques
that are asymptomatic or mildly pruritic. They are usually well marginated but may also blend imperceptibly
into the surrounding skin. The size is variable, but typically most lesions are larger than 5 cm, often measuring

of Poikiloderma
Figure 25-2 Large-plaque parapsoriasis. Irregularly

shaped patches of variable size on the arm of a 16-yearold girl.
Figure 25-4 Large-plaque parapsoriasis. Retiform variant.
and papules in a net-like or zebra-stripe pattern that

eventually becomes poikilodermatous (Fig. 25-4).
SPP characteristically occurs as round or oval discrete patches or very thin plaques, mainly on the trunk
(Fig. 25-5). The lesions measure less than 5 cm in diameter; they are asymptomatic and covered with fine,
moderately adherent scales. The general health of the
patient is unaffected. A distinctive variant with lesions
of a finger shape, known as digitate dermatosis,43 has
yellowish or fawn-colored lesions (Fig. 25-6). It follows
lines of cleavage of the skin and gives the appearance
of a hug that left fingerprints on the trunk. The long
axis of these lesions often measures greater than 5 cm.
Chronic superficial dermatitis is a synonym for SPP.44
Digitate lesions with a yellow hue were referred to in
the past as xanthoerythrodermia perstans.2
::
Figure 25-3 Large-plaque parapsoriasis. Poikilodermatous variant.
Large-plaque parapsoriasis
Dermatomyositis
Lupus erythematosus
Chronic radiation dermatitis
Bloom syndrome
RothmundThomson syndrome
Dyskeratosis congenita
Chapter 25
more than 10 cm in diameter. Lesions are stable in size

and may increase in number gradually. They are found
mainly on the bathing trunk and flexural areas (Fig.
25-2). Extremities and the upper trunk, especially the
breasts in women, also may be involved. They are
light redbrown or salmon pink, and their surface is
covered with small and scanty scales. Lesions may
appear finely wrinkledcigarette paper wrinkling.
Such lesions exhibit varying degrees of epidermal atrophy. Telangiectasia and mottled pigmentation also are
observed when the atrophy becomes prominent (Fig.
25-3). This triad of atrophy, mottled pigmentation, and
telangiectasia defines the term poikiloderma or poikiloderma atrophicans vasculare, which also may be seen in
other conditions (Box 25-1).
Retiform parapsoriasis refers to a rare variant of LPP
that presents as an extensive eruption of scaly macules
287
Section 4
Figure 25-7 Large-plaque parapsoriasis. Mildly hyperkeratotic and focally parakeratotic epidermis with moderately
dense superficial perivascular infiltrate. Lymphoid cells are
mostly small, cytologically normal lymphocytes, and there
is focal single-cell epidermotropism. (Used with permission from Helmut Kerl, MD.)
::
288
Figure 25-5 Small-plaque parapsoriasis. Small, discrete

patches less than 5 cm in diameter.
LABORATORY TESTS
HISTOPATHOLOGY. In early LPP lesions, the
epidermis is mildly acanthotic and slightly hyperkeratotic with spotty parakeratosis. The dermal lymphocytic infiltrate tends to be perivascular and scattered
(Fig. 25-7). In the more advanced lesions one observes
an interface infiltrate with definite epidermotropism.

These invading lymphocytes may be scattered singly
or in groups, sometimes associated with mild spongiosis. In addition, the poikilodermatous lesions show
atrophic epidermis, dilated blood vessels, and melanophages (Fig. 25-8). Immunohistologic studies have
revealed similar features in LPP and early MF, including a predominance of CD4+ T-cell subsets, frequent
CD7 antigen deficiency, and widespread epidermal
expression of Class II HLA (HLA-DR).2224,4548
SPP exhibits mild spongiotic dermatitis with focal areas
of hyperkeratosis, parakeratosis, scale crust, and exocytosis. In the dermis, there is a mild superficial perivascular lymphohistiocytic infiltrate and dermal edema (Fig.
25-9). There is no progression of the histologic features
with time. Immunohistologic studies reveal a predominantly CD4+ T-cell infiltrate with nonspecific features
resembling those seen in various types of dermatitides.47

DIAGNOSIS
LPP is distinguished from SPP by the larger size,
asymmetric distribution, and irregular shape of its
Figure 25-6 Small-plaque parapsoriasis. Digitate dermatosis variant. Typical fingerprint patches on the flank.
Note that their length often exceeds 5 cm.
Figure 25-8 Large-plaque parapsoriasis. Atrophic variant.

Sparse superficial lymphoid infiltrate with mild epidermotropism and epidermal atrophy.
::
lesions, which are less discrete and often poikilodermatous. LPP may be clinically and histopathologically indistinguishable from the patch stage of MF.
Both LPP and SPP are readily distinguished from
more advanced infiltrated plaques of MF because
parapsoriasis lesions are, by definition, not thicker
than patches or at most very thin plaques. This is so
because the English equivalent of the French term
plaques is patches, i.e., lesions that are essentially flat
and devoid of induration or palpable infiltration.49
Failure to appreciate this important distinction has
led to considerable confusion and misuse of the terms
large-plaque parapsoriasis and small-plaque parapsoriasis
by some individuals. These designations more appro-
Chapter 25
Figure 25-9 Small-plaque parapsoriasis. Superficial perivascular lymphoid infiltrate, mild spongiosis, parakeratosis, and focal scale crust.
priately might be thought of as large-patch parapsoriasis

and small-patch parapsoriasis.
The degree to which LPP is differentiated from early
MF depends primarily on the histopathologic criteria
used to diagnose the latter disorder. Unfortunately,
there are no universally accepted minimal criteria for
the diagnosis of MF; however, one set proposed by
the International Society for Cutaneous Lymphoma is
presented in Table 25-2.50 This algorithm is based on a
holistic integration of clinical, histopathologic, immunopathologic, and clonality data. It differs significantly
from many prior approaches because it does not rely
solely on histopathologic features.51 Assuming that
histopathologic examination does not disclose features
diagnostic of some other dermatosis, these criteria
allow lesions to be classified as either patch-stage MF
or not. For the practical purposes of clinical management, patients presenting clinically with patch lesions
whose features result in a score of four points or more
are considered to have unequivocal MF. Obviously,
the more liberal the criteria, the more cases could be
considered to be MF. However, there will always be
some cases that fail to meet any specific set of criteria,
and the designation LPP is a useful term to apply to
them because it guides treatment and follow-up and
conveys an understanding that the risk of dying from
lymphoma is small.
The clinical and/or histopathologic differential
diagnosis of LPP also includes those collagen vascular
diseases and genodermatoses exhibiting poikilodermatous features, lichenoid drug eruptions, secondary
syphilis, chronic radiodermatitis, and occasionally
several other diseases tabulated in Box 25-2. These
TABLE 25-2
Algorithm for the Diagnosis of Patch-Stage Mycosis Fungoides (Four Points are Required)
Parameter
2 Points
1 Point
Clinical:
Persistent, progressive patches and plaques
Nonsun-exposed distribution
Variation in size and shape
Poikiloderma
Any two
Any one
Histopathologic:
Superficial dermal T-cell infiltrate
Epidermotropism
Nuclear atypia
Both
Either
Immunopathologic:
CD2, CD3, or CD5 <50%
CD7 <10%
Epidermaldermal discordance
Not applicable
Any one
Molecular biologic:
Dominant T-cell clonality
Not applicable
Present
Note: Epidermotropism implies the lack of significant spongiosis (intraepidermal lymphoid cells associated with spongiosis is termed exocytosis
rather than epidermotropism). Discordance refers to differential antigen expression between the epidermis and dermis, as opposed to the biopsy
specimen as a whole.
From Pimpinelli N et al: Defining early mycosis fungoides. J Am Acad Dermatol 53:1053, 2005, with permission.
289
Section 4
::
290

of Large-Plaque Parapsoriasis
(LPP) and Small-Plaque
Parapsoriasis (SPP)
Most Likely
LPP
Tinea corporis
Plaque-type psoriasis
Contact dermatitis
Subacute cutaneous lupus erythematosus
SPP
Nummular dermatitis
Pityriasis rosea
Plaque and guttate psoriasis
Pigmented purpuric dermatoses
Consider
LPP
Xerotic dermatitis
Atopic dermatitis
Dermatomyositis
Drug eruption
Erythema dyschromicum perstans
Pigmented purpuric dermatoses
Early inflammatory morphea
Atrophoderma of PasiniPierini
Erythema annulare centrifugum
Genodermatoses with poikiloderma
Chronic radiodermatitis
SPP
Tinea versicolor
Drug eruption
Always Rule Out
LPP
Mycosis fungoides
SPP
Mycosis fungoides
Secondary syphilis
generally can be distinguished by their associated clinical findings. Histopathologic differentiation among
these diseases is covered largely in the discussion of
pseudo-MF in Chapter 146.
SPP, when it presents with its distinctive digitate
dermatosis lesions parallel to skin lines in a truncal
distribution, stands out from other types of parapsoriasis. Individual SPP lesions may show some superficial resemblance to PLC. SPP is distinguished from
psoriasis by the absence of the Auspitz sign (see
Chapter 18), micaceous scale, nail pits, and typical
psoriatic lesions involving the scalp, elbows, and

knees. Histologically, its mild spongiotic dermatitis and absence of other characteristic features distinguish it from PLC, psoriasis, and several of the
other entities listed in Box 25-2. Clinical features are
also important, such as the herald patch of pityriasis
rosea and the papulovesicular coin-shaped patches
favoring the lower extremities in nummular dermatitis.
Sometimes patients with MF may exhibit small
patches of disease at presentation; however, these
lesions typically have histopathologic features at
least consistent with MF and generally are associated
with larger, more classic lesions of MF elsewhere on
the skin. They also may show poikilodermatous features not seen in SPP. Furthermore, the presence of
well-developed, moderate to thick small plaques, as
seen in some MF patients, is incompatible with the
diagnosis of SPP because the latter disorder includes
only lesions that are no more than patches or very
thin plaques. It is also important to recognize that
partially treated or early relapsing lesions of MF may
show only nonspecific features that should not be
taken as evidence of a pathogenetic link to SPP or any
other dermatosis.
COMPLICATIONS
LPP can be associated with other forms of parapsoriasis and overt cutaneous lymphomas as detailed elsewhere in this chapter. Both LPP and SPP occasionally
can develop areas of impetiginization secondary to
excoriation.
PROGNOSIS AND CLINICAL COURSE

Both LPP and SPP may persist for years to decades
with little change in appearance clinically or histopathologically. Approximately 10%30% of cases of
LPP progress to overt MF.2,5254 In this context, LPP
represents the clinically benign end of the MF disease
spectrum, with transformation to large cell lymphoma
at the opposite extreme. The rare retiform variant is
said to progress to overt MF in virtually all cases.2
In contrast to LPP with its malignant potential, SPP
is a clinically benign disorder in the experience of most
experts. Patients with this disease as defined in this
chapter rarely develop overt MF.11,44,55,56 Despite this fact
and what most observers consider to be its nonspecific
histopathologic features, some authors favor lumping
SPP within the MF disease spectrum as a very early,
nonprogressive variant.55,57 This issue has been debated
at length.31,57,58 A few studies report progression from
SPP to MF in about 10% of cases but may have used different criteria than described in this chapter.53,54
TREATMENT
Patients with SPP should be reassured and may forego
treatment. The disease may be treated with emollients,
BOX 25-3 Treatment of LargePlaque Parapsoriasis and

Small-Plaque Parapsoriasis
FIRST LINE
Emollients
Topical corticosteroids
Topical tar products
Sunbathing
Broadband UVB phototherapy
Narrowband UVB phototherapy
(Mainly for large-plaque parapsoriasis cases considered
to be early mycosis fungoides)
PITYRIASIS LICHENOIDES
AT A GLANCE
Pityriasis lichenoides et varioliformis acuta
(PLEVA) and pityriasis lichenoides chronica
(PLC) represent two ends of a disease
spectrum; both entities and intermediate
forms can coexist.
All forms are characterized by spontaneously
resolving, temporally overlapping crops of
papules.
PLEVA papules last for weeks and may
develop crusts, vesicles, pustules, or ulcers.
::
PLC papules persist for months and develop

scales.
All forms contain interface, cytolytic
T-cell infiltrates with variable epidermal
destruction.
In PLEVA, CD8+ cells predominate.
topical tar preparations, topical corticosteroids, and/

or broadband or narrowband UVB phototherapy
(Box 25-3).59 Response to therapy is variable. Patients
should initially be examined every 36 months and
subsequently every year to ensure that the character of
the process is stable.
LPP requires more aggressive therapy: highpotency topical corticosteroids with phototherapy
such as broadband UVB, narrowband UVB, or psoralen and UVA (PUVA). The goal of treatment is to
suppress the disorder to prevent possible progression to overt MF. Other methods of treatment, such
as topical nitrogen mustard, have been used, particularly for the poikilodermatous type. Localized lesions
may respond to excimer laser (308 nm).60,61 The
patient should be examined carefully every 3 months
initially and every 6 months to 1 year subsequently
for evidence of progression. Repeated multiple biopsies of suspicious lesions should be performed. Cases
that satisfy the clinicopathologic criteria for early
MF can be treated with broadband UVB, narrowband UVB, PUVA, topical nitrogen mustard, topical
bexarotene gel, topical imiquimod, or topical carmustine (BCNU).62 Electron-beam radiation therapy
generally is reserved for more advanced, infiltrated
lesions of MF.
PREVENTION
Because LPP and SPP are uncommon diseases that
appear to affect patients randomly, there are no known
preventive measures.
In PLC, CD8+ or CD4+ cells predominate.

Dominant T-cell clonality can be detected in
all forms, more often in PLEVA than in PLC.
Treatment depends on severity and ranges
from topical steroids, systemic antibiotics,
UV irradiation, and psoralen and UVA to
systemic immunosuppressants.
Topical bexarotene
Topical imiquimod
Psoralen and UVA phototherapy
Topical mechlorethamine
Topical carmustine (BCNU)
Excimer laser (308 nm)
Chapter 25
SECOND LINE
PITYRIASIS LICHENOIDES
EPIDEMIOLOGY
Pityriasis lichenoides affects all racial and ethnic
groups in all geographic regions.6368 It is more common in children and young adults but can affect all
ages with seasonal variation in onset favoring fall and
winter. There is a male predominance of 1.5:1 to 3:1.
PLC is three to six times more common than PLEVA.

The etiology of pityriasis lichenoides is unknown.
Some cases have been associated with infectious
agents such as Toxoplasma gondii,69,70 Epstein-Barr
virus,70,71 cytomegalovirus,70,71 parvovirus B19,70,72,73
and human immunodeficiency virus.74,75 At least one
case was linked repeatedly with estrogenprogesterone therapy, another with chemotherapy drugs, and
a third with radiocontrast iodide.7678 It is uncertain
291
Section 4
::
whether these agents are actively involved in disease

pathogenesis or merely coincidental bystanders; however, several cases associated with toxoplasmosis have
cleared fairly quickly in response to specific therapy.69
A tenfold higher level of maternal keratinocytes have
been reported in the epidermis of children with PL
compared to controls.79
Immunohistologic studies have shown a reduction in
CD1a+ antigen-presenting dendritic (Langerhans) cells
within the central epidermis of pityriasis lichenoides
lesions.80 Keratinocytes and endothelial cells are HLADR+, which suggests activation by T-cell cytokines.80
CD8+ T cells predominate in PLEVA, whereas either
CD8+ or CD4+ T cells predominate in PLC.8082 Many
of these T cells express memory proteins (CD45RO)
and cytolytic proteins (TIA-1 and granzyme B).72,73
Dominant T-cell clonality has been demonstrated
in about half of PLEVA cases and a minority of PLC
cases.32,83,84 In aggregate, these findings raise the possibility that pityriasis lichenoides is a variably clonal
cytolytic memory T-cell lymphoproliferative response
to one or more foreign antigens. Deposition of immunoglobulin M, C3, and fibrin in and around blood vessels and along the dermalepidermal junction in early
acute lesions suggests a possible concomitant humoral
immune response, although this could be a secondary
phenomenon.
The relationship of pityriasis lichenoides to lymphomatoid papulosis remains controversial10,51,80 (see
also Chapters 145 and 146). Common features include
dominant T-cell clonality and spontaneous resolution
of papular, predominantly lymphoid lesions. Furthermore, individual lesions with the clinicopathologic
characteristics of either pityriasis lichenoides or lymphomatoid papulosis can coexist in the same patient,
either concurrently or serially. It remains to be determined whether this can be explained as an artifact of
sampling lymphomatoid papulosis lesions at various
stages of their evolution. The presence of large CD30+
atypical lymphoid cells is the hallmark of lymphomatoid papulosis (at least types A and C).84 Furthermore,
these cells are typically CD4+ and often lack one or
more mature T-cell antigens such as CD2, CD3, and
CD5. These features serve to distinguish lymphomatoid papulosis from pityriasis lichenoides. Although
occasional CD30+ cells can be seen in a wide variety of
dermatoses, the presence of any appreciable number
should favor lymphomatoid papulosis over pityriasis
lichenoides as a matter of definition. It may be that
the PLC-PLEVA and lymphomatoid papulosis
CD30+ anaplastic large cell lymphoma disease spectra
are intersecting rather than overlapping entities, i.e.,
although pityriasis lichenoides is a distinct cutaneous
T-cell disorder, it is possible that it may sometimes
serve as fertile soil for the development of the CD30+
T-cell clone characteristic of lymphomatoid papulosis.
CLINICAL FINDINGS
292
CUTANEOUS LESIONS. PLC and PLEVA exist

on a clinicopathologic continuum.2,51 Therefore, individual patients may exhibit a mixture of acute and
Figure 25-10 Pityriasis lichenoides chronica. Polymorphous appearance ranging from early erythematous
papules to scaling brownred lesions and tan-brown involuting, flat papules, and macules.
chronic lesions sequentially or concurrently. In addition, lesions representing clinical or histopathologic
intergrades between the extremes may also occur at
any time.
Lesions are often asymptomatic but can be pruritic
or burning, especially in the more acute cases. PLC
typically presents as recurrent crops of erythematous scaly papules that spontaneously regress over
several weeks to months (Fig. 25-10). PLEVA manifests as recurrent crops of erythematous papules that
develop crusts, vesicles, pustules, or erosions before
spontaneously regressing within a matter of weeks
(Fig. 25-11). The more severe ulcerative variant is
known as pityriasis lichenoides with ulceronecrosis and
hyperthermia (PLUH) or febrile ulceronecrotic Mucha
Habermann disease (FUMHD).85 It presents as purpuric
papulonodules with central ulcers up to a few centimeters in diameter (Fig. 25-12). Some have proposed
that this severe variant is actually an overt T-cell lymphoma.31 Pityriasis lichenoides lesions tend to concentrate on the trunk and proximal extremities, but
any region of the skin and even mucous membranes
can be involved. Rare regional or segmental lesion
distributions have been described,10,86 as has rare
conjunctival nodular inflammation.87 Although there
are usually numerous coexistent lesions, occasionally only a small number of lesions will be present at
any one time. All forms of pityriasis lichenoides can
result in postinflammatory hypopigmentation or
hyperpigmentation.63 Chronic lesions can resolve with
Chapter 25
::
postinflammatory hypopigmentation, sometimes presenting as idiopathic guttate hypomelanosis. Chronic

lesions rarely lead to scars. In contrast, acute lesions
result in deeper dermal injury and consequently often
resolve leaving varioliform (smallpox-like) scars. The

presence of lesions in various stages of evolution
imparts a polymorphous appearance that is characteristic of pityriasis lichenoides.
Figure 25-11 Pityriasis lichenoides et varioliformis acuta.

A. Adolescent with multiple erythematous papules and
crusted lesions in various stages of evolution. B. Larger
papulovesicular and hemorrhagic, crusted lesions in an
adult. Note varioliform scars adjacent to active lesions on
posterior thigh and leg. C. Pustules, crusts, and necroticcentered papules with erythematous, indurated base.
LABORATORY TESTS
Miscellaneous nonspecific abnormalities in blood test
results occur but are of little practical value. Leukocytosis and a decreased CD4/CD8 ratio can occur.
Figure 25-12 Pityriasis lichenoides, ulceronecrotic, hyperacute variant. Large necrotic eschar with halo erythema
developing in febrile patient with antecedent pityriasis
lichenoides et varioliformis acuta.
HISTOPATHOLOGY. As with the morphology of

the clinical lesions, pityriasis lichenoides can exhibit a
range of histopathologic features encompassing acute,
chronic, and intermediate lesional variants (Figs. 25-13
and 25-14). All cases of pityriasis lichenoides contain
an interface dermatitis that is denser and more wedge
shaped in the acute lesions. The infiltrate is composed
mainly of lymphocytes with a variable admixture of
neutrophils and histiocytes. There is exocytosis, parakeratosis, and extravasation of erythrocytes. Epidermal damage ranges from intercellular and extracellular
edema in less severe cases to extensive keratinocyte
necrosis, vesicles, pustules, and ulcers. The acute variants can exhibit lymphocytic vasculitis with fibrinoid
degeneration of blood vessel walls.
Occasional CD30+ lymphoid cells and occasional
atypical lymphoid cells may be seen as a nonspecific
finding in many cutaneous lymphoid infiltrates. The
293
Section 4
Figure 25-13 Pityriasis lichenoides et varioliformis acuta. A. Ulcerated papule with epidermal necrosis, hemorrhage, and
superficial and deep perivascular lymphocytic infiltrate. Hematoxylin and eosin (H&E) stain. B. Parakeratosis and crust with
marked spongiosis and epidermal necrosis. Lymphocyte exocytosis and basal hydropic changes. H&E stain.
::
presence of an appreciable numbers of these cells is

not consistent with classic pityriasis lichenoides of any
type and should raise concern for the lymphomatoid
papulosisCD30+ anaplastic large cell lymphoma disease spectrum.30 Other immunohistologic features and
the clonality of pityriasis lichenoides are discussed in
Section Etiology and Pathogenesis under Section
Pityriasis Lichenoides.
The differential diagnosis of pityriasis lichenoides
includes many papular eruptions (Box 25-4). Those
that develop crusts, vesicles, pustules, or ulcers are
grouped with PLEVA, whereas those that form predominantly scaly papules are grouped with PLC.
Most of them can be excluded based on history and
typical clinicopathologic features. A few, such as
secondary syphilis and virus-associated lesions, can
also be excluded based on serologic tests. Among the
most challenging diseases to distinguish from pityriasis lichenoides are lymphomatoid papulosis and
294
macular or papular variants of MF.8891 As detailed

earlier, the presence of large atypical lymphoid cells
(often CD30+) differentiates lymphomatoid papulosis from pityriasis lichenoides.84 Macular or papular
variants of MF are rare. They exhibit classic histopathological features of MF, including small atypical epidermotropic lymphoid cells with convoluted
nuclei and a band-like superficial dermal lymphoid
infiltrate.90
COMPLICATIONS
Secondary infection is the most common complication
of pityriasis lichenoides. PLEVA may be associated
with low-grade fever, malaise, headache, and arthralgia. Patients with PLUH/FUMHD can develop high
fever, malaise, myalgia, arthralgia, and gastrointestinal
and central nervous system symptoms. Occasionally,
debilitated patients may die.85,92 PLC has been associated uncommonly with LPP in children.44 Despite
their sometimes dominant T-cell clonal nature, PLC
and PLEVA are considered clinically benign disorders
Figure 25-14 Pityriasis lichenoides chronica. A. Compact parakeratosis, lymphocytic exocytosis, occasional eosinophilic
necrotic keratinocytes, edema, and diffuse lymphocytic infiltrate localizing to epidermaldermal interface and perivascular sites within the dermis. Hematoxylin and eosin (H&E) stain. B. Parakeratosis, spongiosis, and a predominant mononuclear cell infiltrate in the epidermis and dermis with papillary edema. H&E stain.

of Pityriasis Lichenoides et
Varioliformis Acuta (PLEVA)
and Pityriasis Lichenoides
Chronica (PLC)
without significant linkage to lymphomas or other

malignancies.

Pityriasis lichenoides has a variable clinical course
characterized by recurrent crops of lesions that spontaneously resolve. The disorder may resolve spontaneously within a few months or, less commonly,
persist for years. PLEVA usually has a shorter duration than PLC. Although the conclusion was not
confirmed by subsequent investigation, one report
suggested that the duration of pityriasis lichenoides
in children correlated better with its clinical distribution than with the relative abundance of acute and
chronic lesions, which often coexisted.67 From longest to shortest duration, the distribution of lesions
SECOND LINE
Topical tacrolimus100,101
Prednisone (60/40/20 mg PO taper, 5 days each)102
Methotrexate (1025 mg PO weekly)103,104
Phototherapy (UVAI, psoralen + UVA)
Cyclosporine (2.54 mg/kg/day total dose divided
into twice-daily PO doses; use the minimum)75
Retinoids (e.g., acitretin 2550 mg PO daily)105
Photodynamic therapy94
Bromelain (pineapple extract)95
ranged from peripheral (distal extremities) to central

(trunk) to diffuse.
TREATMENT
Always Rule Out

PLEVA
Lymphomatoid papulosis
Secondary syphilis
PLC
Mycosis fungoides (papular variant)
Secondary syphilis
Antibiotics (erythromycin 500 mg PO 24 daily96;
tetracycline 500 mg PO 24 daily,97 minocycline
100 mg PO twice daily; azithromycin 500 mg PO on
day 1 and 250 mg PO on days 25 bimonthly93)
Phototherapy (sunbathing, UVB,90 UVA + UVB,98
narrowband UVB99)
::
Consider
PLEVA
Folliculitis
Rickettsiosis
Erythema multiforme
PLC
Spongiotic dermatitis, papular variant
Small-plaque parapsoriasis
Lichen planus
GianottiCrosti syndrome
FIRST LINE
Chapter 25
Most Likely
PLEVA
Arthropod bites, stings, infestations
Leukocytoclastic vasculitis
Viral exanthem (e.g., varicella-zoster, herpes
simplex)
PLC
Pityriasis rosea
Drug eruption
Guttate psoriasis
BOX 25-5 Treatment of Pityriasis

Lichenoides et Varioliformis Acuta
and Pityriasis Lichenoides Chronica
The mainstay of traditional therapy has been a combination of topical corticosteroids and phototherapy
(Box 25-5). Systemic antibiotics in the tetracycline and
erythromycin families are used primarily for their antiinflammatory rather than antibiotic effects. One newer
option is azithromycin.93 Cases with minimal disease
activity may not require any treatment. Photodynamic
therapy has been used successfully for PLC.94 The more
acute the clinical course and the more severe the individual lesions, the more systemic therapy is indicated.
Methotrexate is often effective in relatively low doses.
Calcineurin inhibitors and retinoids may also be beneficial. Severe cases of PLEVA and PLUH often require
systemic corticosteroids or similar drugs to gain control of systemic symptoms. Topical and systemic antibiotics may be needed to treat secondary infections
complicating ulcerated skin lesions. These agents are
often selected initially to cover Gram-positive pathogens, but subsequent use should be guided by culture
results. Bromelain, a pineapple extract, cleared PLC
lesions in 8/8 cases.95
PREVENTION
There are no known preventive measures.
295
KEY REFERENCES
Section 4
2. Lambert WC, Everett MA: The nosology of parapsoriasis.

J Am Acad Dermatol 5(4):373-395, 1981
39. Wood GS et al: Detection of clonal T-cell receptor gamma
gene rearrangements in early mycosis fungoides/Sezary
syndrome by polymerase chain reaction and denaturing
gradient gel electrophoresis (PCR/DGGE). J Invest Dermatol 103(1):34-41, 1994
43. Hu CH, Winkelmann RK: Digitate dermatosis. A new look
at symmetrical, small plaque parapsoriasis. Arch Dermatol
107(1):65-69, 1973
44. Samman PD: The natural history of parapsoriasis en
plaques (chronic superficial dermatitis) and prereticulotic
poikiloderma. Br J Dermatol 87(5):405-411, 1972
50. Pimpinelli N et al: Defining early mycosis fungoides. J Am

Acad Dermatol 53(6):1053-1063, 2005
53. Vakeva L et al: A retrospective study of the probability
of the evolution of parapsoriasis en plaques into mycosis
fungoides. Acta Derm Venereol 85(4):318-323, 2005
64. Bowers S, Warshaw EM: Pityriasis lichenoides and its
subtypes. J Am Acad Dermatol 55(4):557-572, 2006; quiz
573-556
65. Ersoy-Evans S et al: Pityriasis lichenoides in childhood: A
retrospective review of 124 patients. J Am Acad Dermatol
56(2):205-210, 2007
66. Khachemoune A, Blyumin ML: Pityriasis lichenoides:
pathophysiology, classification, and treatment. Am J Clin
Dermatol 8(1):29-36, 2007
85. Sotiriou E et al: Febrile ulceronecrotic Mucha-Habermann
disease: A case report and review of the literature. Acta
Derm Venereol 88(4):350-355, 2008
::
296
Chapter 26 :: Lichen Planus

:: Mazen S. Daoud & Mark R. Pittelkow
LICHEN PLANUS AT A GLANCE
Worldwide occurrence: Less than 1%.
Lesions: Symmetric, grouped, erythematous
to violaceous, flat-topped, polygonal
papules.
Distribution: Widespread, predilection for
flexural aspects of arms and legs.
Variants: Based on configuration,
morphology of lesion, and site of
involvement.
Pathology: Basal epidermal keratinocyte
damage and lichenoid interface lymphocytic
reaction.
Lichen planus (Greek leichen, tree moss; Latin planus,

flat) is a unique, common inflammatory disorder
that affects the skin, mucous membranes, nails, and
hair. The appearance of lichen planus-like lichenoid
dermatoses has been likened to the scurfy, finely furrowed, dry excrescences of the symbiotic vegetation
known as lichen. Although this morphologic comparison may be antiquated, lichen planus is a distinctive
entity with prototypic lichenoid papules that show
distinctive color and morphology, develop in typical locations, and manifest characteristic patterns of
evolution. Microscopic features are also distinctive,
although the microscopic pattern of inflammation and
skin response is shared by several dermatoses. The

term lichenoid reaction1 is the histologic description
used to capsulize the pathologic characteristics of skin
diseases resembling lichen planus.
The four Ps(1) purple, (2) polygonal, (3) pruritic,
and (4) papuleis the mnemonic device often used to
recall the constellation of symptoms and skin findings
that characterize lichen planus.
HISTORICAL ASPECTS
EPIDEMIOLOGY
The exact incidence and prevalence of lichen planus
are unknown, but the overall prevalence is believed
to be somewhat around 1% of the general population. Estimates between 0.14% and 1.27% have been
reported worldwide and approximately 0.44% in
the United States. No racial predilection has been
observed.2,3
At least two-thirds of cases occur between the ages
of 30 and 60 years of age. No sexual predilection is
evident. Females are usually affected in their 50s and
60s, whereas males develop lichen planus at a somewhat earlier age. The disease is less common in the
very young and the elderly. The development of lichen
planus may be affected by seasonal or environmental
factors.2
Fewer than 100 cases of familial lichen planus have
been reported. The familial form tends to be more
protracted and severe and presents in erosive, linear,
or ulcerative patterns or with atypical features affecting young adults and children.4 Some believe that the
familial form represents a separate, unique dermatosis.
Different HLA haplotypes were reported in familial

lichen planus, including HLA-B7, -Aw19, -B18, and
-Cw8. In nonfamilial lichen planus, HLA-A3, -A5,
-A28, -B8, -B16, and -Bw35 are more common.5 HLAB8 is more common in patients with oral lichen planus as a sole manifestation, and HLA-Bw35 is more
strongly associated with cutaneous lichen planus.
Lichen Planus
It is evident that the majority of T cells in the infiltrate of lichen planus, both within the epithelium and
adjacent to damaged basal keratinocytes, are activated
CD8+ cytotoxic lymphocytes. Evidence from oral lichen
planus suggests that CD8+ lesional T cells recognize a
lichen planus-specific antigen associated with major
histocompatibility complex (MHC) class I on lesional
keratinocytes. The nature of this antigen is unknown.
Theoretically, the antigen may be an autoreactive peptide, thus classifying lichen planus as an autoimmune
disease. Alternatively, it may represent an exogenous
antigen such as an altered protein, drug, contact
allergen, viral or infectious agent, or an unidentified
immunogenic target. Innate immune responses that
become activated by exogenous stimuli in a genetically susceptible individual may trigger the development of lichen planus and, further, involves a small
but significant lesional population of CD56+CD16 NK
lymphocytes that secrete interferon-, tumor necrosis
factor (TNF)-, and only minimal amounts of IL-22,
IL-17, or IL-4.
::
LICHEN PLANUS-SPECIFIC
ANTIGEN RECOGNITION
Chapter 26
It is evident that specific immunologic mechanisms

control the development of lichen planus. T-cell mediated pathologic alterations involving proinflammatory
and counterregulatory mechanisms function in the
pathogenesis of lichen planus.6 No consistent alterations in immunoglobulins (Igs) have been shown in
lichen planus, and humoral immunity most likely is a
secondary response in immunopathogenesis.
Cell-mediated immunity, on the other hand, plays
the major role in triggering the clinical expression of
the disease. Both CD4+ and CD8+ T cells are found in
lesional skin of lichen planus. Progression of disease
may lead to preferential accumulation of CD8+ cells.
The majority of lymphocytes in the infiltrate of lichen
planus are CD8+ and CD45RO (memory) positive cells
and express the T-cell receptor (TCR), and in a
minority, the receptor. This later cell subtype is not
normally found in healthy skin. These cells are considered responsible for the development of the most
characteristic change observed in the lichenoid reaction, namely, apoptosis.7 The inflammatory process
that leads to apoptosis is complex and not fully understood. The epitheliumlymphocyte interaction can be
divided into three major stages: (1) antigen recognition, (2) lymphocyte activation, and (3) keratinocyte
apoptosis.
The role of T-helper (CD4) cells in the pathogenesis of lichen planus is not fully defined. T cells may
become activated via professional antigen-presenting cells such as Langerhans cells, dendritic cells, or
accessory cells such as epidermal keratinocytes in
association with members of the MHC II and specific
cytokines. T-helper lymphocytes may also propagate
CD8+ cytotoxic lymphocytes through cellular cooperation and release of cytokines.
The nature of antigenic stimulation is not known.
Contact sensitizers such as metals could act as haptens
and elicit an immunologic response. Enhanced lymphocyte reactivity to inorganic mercury, a component
of dental amalgam, has been found in patients with
oral lichenoid reactions. Low-grade chronic exposure to mercury, and possibly to other metals such as
gold, may stimulate a lymphocytic reaction that manifests as lichen planus. A list of contact chemicals and
drugs that can elicit lichenoid reactions is discussed
in Section Drug-Induced Lichen Planus. With more
widespread use of biologics for various chronic inflammatory diseases, cases of lichenoid, interface dermatitis are being recognized and implicate dysregulated
cytokine production, including upregulation of type-I
interferon expression in the setting of tumor necrosis
factor (TNF)- blockage.8 The role of infection in the
development of lichen planus has been repeatedly
raised over the years. Though provocative, no conclusive evidence has molecularly linked lichen planus
to any of the following infections or microorganisms:
syphilis, herpes simplex virus 2, human immunodeficiency virus (HIV), amebiasis, chronic bladder infections, hepatitis C virus (HCV), Helicobacter pylori, or
human papillomavirus.
CYTOTOXIC LYMPHOCYTE
ACTIVATION
Following antigen recognition, CD8+ T cells are activated. Activated cytotoxic lymphocytes undergo
lesional tissue clonal expansion, leading to oligoclonal and occasionally to monoclonal proliferation as
detected by analysis of the TCR- chain gene products.
Activated lymphocytes, both by helper subsets
(Th1 and Th2) and cytotoxic-suppressor cells, release
soluble mediators (cytokines and chemokines), such
as interleukin (IL)-2, IL-4, IL-10, interferon (IFN)-,
tumor necrosis factor (TNF)-, and transforming
growth factor-1, that attract lymphocytes and regulate their biologic activities within and adjacent to the
epithelium. Both pro- and anti-inflammatory cytokines, i.e., mixed Th1 and Th2 cytokine products, are
generated simultaneously. The balance between lymphocytic activation and down regulation determines
the clinical behavior of the disease. IFN-, produced
by T-helper cells during the antigen recognition stage,
induces keratinocytes to produce lymphotoxin- and
TNF-, and to upregulate MHC class II, thus increasing interactions with T-helper cells. Furthermore, IFN upregulates the expression of intercellular adhesion
molecule-1 and vascular cell adhesion molecule-1
by basal keratinocytes, Langerhans cells, and other
297
Section 4
::
298
macrophage-dendritic cells. IFN- and IL-4 are elevated in saliva from oral lichen planus. Intercellular
adhesion molecule-1 is a ligand for the 2-integrin,
leukocyte function-associated antigen-1, on the surface of lymphocytes, which further enhances the
interaction of these lymphocytes with the antigenpresenting cells. Laminin-5 and collagen types IV and
VII are increased in lesional lichen planus and serve as
ligands for 1-integrin on the surface of lymphocytes,
thus allowing for enhanced association of lymphocytes
with the basement membrane. Integrin 3 is present
on activated, skin-homing T cells and may localize
these effector cells to the epidermaldermal interface
and basement membrane, which contain epiligrin/
laminin-5, a ligand for this integrin. This close interaction between lymphocytes and basement membrane
targets metalloproteinases produced by lymphocytes
to alter extracellular matrix proteins and integrins,
and the process eventuates in apoptosis, basement
membrane disruption, reduplication, and subepidermal cleft formation (see Section Pathology). TNF-
upregulates the expression of matrix metalloproteinase (MMP)-9 mRNA in lesional T lymphocytes, thus
further enhancing basement membrane disruption
(see Section Keratinocyte Apoptosis).9
Keratinocytes also participate in the response by
producing IL-1, IL-4, IL-6, granulocytemacrophage
colony-stimulating factor, and TNF-. These cytokines
further activate tissue macrophages and peripheral
blood mononuclear cells and upregulate expression of
cell surface adhesion molecules and migration activity. Keratinocyte-produced cytokines also upregulate
expression of specific keratin genes. Keratin (K)17,
usually restricted to adnexal structures, is variably
expressed in the basal and suprabasal layers of the
interfollicular epithelium of affected epidermis. K6
and K16 also become detectable in the basal and suprabasal layers. K4 and K13 are reduced in the suprabasal
compartment in areas with orthokeratosis, associated
with increased production of K1 and K10.
KERATINOCYTE APOPTOSIS
The exact mechanisms used by activated cytotoxic T
cells to trigger apoptosis of keratinocytes are not completely known. Possible mechanisms include: (1) T-cell
secreted TNF- binding to the TNF- R1 receptor on
the keratinocyte surface, (2) T-cell surface CD95L (Fas
ligand) binding CD95 (Fas) on the keratinocyte, and (3)
T-cell secreted granzyme B entering the keratinocyte
via perforin-induced membrane pores. In lichen planus, granzyme B predominates in lesional epidermis
versus perforin in graft-versus-host disease.10 All these
mechanisms may activate the keratinocyte caspase
cascade, resulting in keratinocyte apoptosis. Caspase
3 is frequently found to be elevated in both cutaneous
and oral lichen planus lesional skin.11
Recruited lymphocytes may further contribute
to apoptosis via a different mechanism, the loss of a
basement membrane-derived cell survival signal that
normally prevents the onset of apoptosis. Hence, basement membrane disruption may trigger apoptosis.
Principle mediators are the MMPs, a family of zinccontaining endoproteinases that primarily function to
degrade connective tissue matrix proteins. The action
of these enzymes is also regulated by inhibitors such
as tissue inhibitors of metalloproteinases (TIMPs) (see
Chapter 63). It has been shown that lesional T cells in
lichen planus have higher MMP-9 levels than peripheral blood T cells. Lesional T-cell MMP-9 activity
increases following stimulation with TNF-, but not
TIMP-1, an inhibitor for MMP-9. These observations
suggest that T-cell secreted MMP-9 disrupts epithelial
basement membranes, blocking cell survival signals to
keratinocytes and inducing apoptosis.
Various other environmental, behavioral, or infectious factors have been observed on occasion to be
associated with the development or exacerbation of
lichen planus. However, no well-established association has been documented between emotional stress,
tobacco use, or oral or gastrointestinal candidiasis and
development of lichen planus.
SPECIFIC AND GLOBAL GENE RESPONSES.
Recent studies using microarray technologies to examine and characterize in greater detail various inflammatory and immune-mediated skin diseases have
provided considerable new insights into mechanisms
mediating-specific inflammatory responses, including
lichen planus, oral lichen planus, lichen planopilaris as
well as lichenoid eruptions, and interface dermatitis.
Lichen planus was distinguished from atopic dermatitis, psoriasis, and healthy skin by elevated expression of type I interferon-induced genes and a specific
cytokine expression pattern.12 CXCL9, the ligand for
CXCR3 was the most significant marker for lichen
planus. In the scarring alopecias, specifically lichen
planopilaris, microarray analysis implicates the loss
of peroxisome proliferator-activated receptor (PPAR)
expression in contributing to proinflammatory lipid
accumulation and inflammatory cell infiltration leading to pilosebaceous destruction.13 Recently, Brn2, a
transcription factor expressed by keratinocytes as well
as lymphocytes, when overexpressed in epidermis,
has been found to not only cause epidermal changes
characteristic of lichen planus but also inflammatory,
interface cellular reactivity.14
CLINICAL FINDINGS
CUTANEOUS LESIONS
The classic cutaneous lesion of lichen planus is a faintly
erythematous to violaceous, flat-topped, polygonal
papule, sometimes showing a small central umbilication (Fig. 26-1). Papules are grouped and tend to
coalesce. A thin, transparent, and adherent scale may
be discerned atop the lesion. Fine, whitish puncta or
reticulated networks referred to as Wick-ham striae
are present over the surface of many well-developed
papules (see Fig. 26-1). These are considered to be
highly characteristic and are more easily observed
after applying oil, xylene, or water and visualizing the
Figure 26-2 Generalized lichen planus. Small, flat-topped

violaceous papules, some grouped, some disseminated,
becoming confluent on the trunk.
unusual. Inverse lichen planus usually affects the axillae, groin, and inframammary areas.
Lichen planus tends to be quite pruritic, although
some patients are completely asymptomatic. The
degree of pruritus is generally related to the extent
of involvement, with more intense pruritus in generalized form. An exception is hypertrophic lichen planus, which is more localized but extremely pruritic.
Oral involvement is generally asymptomatic unless
erosions or ulcers developed, after which it becomes
extremely painful. In the acute, evolving stages of the
disease, scratching, injury, or trauma may induce an
isomorphic (Koebner) response (Fig. 26-5). Lichen planus usually heals with hyperpigmentation (see Fig.
26-1), which is more prominent among patients with
darker skin color. Hypopigmentation uncommonly
develops after resolution of lesions.
Most reports of lichen planus in children have come
from the Indian subcontinent, suggesting that children
Lichen Planus
::
lesions with a magnifying lens or a handheld dermatoscope. The surface alteration may result from localized
thickening of the keratohyalin-containing cell layers of
the stratum granulosum, although a focal increase in
the activity of lichen planus may account for the morphologic alteration of Wickham striae.
Lichen planus usually develops over several weeks.
Sometimes multiple lesions develop rapidly with dissemination following the initial appearance. In generalized disease (Fig. 26-2), the eruption often spreads
within 14 months from onset. The initial lesions
almost always appear on the extremities, especially
the legs.
The lesions are usually distributed symmetrically
and bilaterally over the extremities. Lichen planus
tends to involve the flexural areas of the wrists, arms,
and legs (see Fig. 26-1). The thighs, lower back, trunk,
and neck may also be affected. Oral mucous membranes (Fig. 26-3) and the genitalia (Fig. 26-4) are additional sites of involvement. The face is usually spared
in classical cases, and palmoplantar involvement is
Chapter 26
Figure 26-1 Flat-topped, polygonal, sharply defined

papules of violaceous color, grouped and confluent.
Surface is shiny and reveals fine white lines (Wickham
striae). Note pigmentation of resolving lesions.
Figure 26-3 Mucosal lichen planus. A. A typical lace-like whitish reticulated pattern of oral lesions is seen on the buccal
mucosa. B. Erosive gingivitis. Here lichen planus manifests as painful erosions on the gingiva.
299
common. Mucous membrane involvement, thought to

be rare, may occur in up to one-third of patients. The
hypertrophic variant occurs in one-fourth of children
with lichen planus.
CLINICAL VARIANTS
Section 4
Many variations in the clinical presentation have been

described and are generally categorized according to (1)
the configuration of lesions, (2) the morphologic appearance, or (3) the site of involvement. These variations are
patterned by subtle or unknown properties of the disease. The prototypic papule can be altered or modified
in configuration, morphology, or anatomic distribution.
::
CONFIGURATION OF LESIONS
Annular Lichen Planus. Annular lesions occur in
Figure 26-4 Lichen planus on the penis. Agminate

pattern of lesions involving the glans, sulcus, and meatus
(not seen) of the penis.
of South Asian origin are more susceptible to developing lichen planus.15 Although the clinical and pathologic features of childhood lichen planus are similar to
those in adults, scalp, nail, and hair involvement are not
approximately 10% of cases and commonly develop as

arcuate groupings of individual papules that develop
rings or peripheral extension of clustered papules with
central clearing. They tend to occur in blacks and are
more common on the penis and scrotum (see Chapter 75). It occurs also when larger lesions on trunk
and extremities reach 23 cm in diameter and become
hyperpigmented with a raised outer rim. Actinic lichen
planus (see below), seen in subtropical zones on sunexposed, dark-skinned young adults and children, is
frequently annular in shape.
Linear Lichen Planus. Papules of lichen planus

may develop a linear pattern secondary to trauma
(koebnerization) (see Fig. 26-5) or, rarely, in less than
0.2% of cases as a spontaneous, isolated eruption, usually on the extremities following Blaschko lines. The
segmental formation is thought to be due to a postzygotic mutation that affects one of the genes predisposing its development that lead to the formation of
a keratinocyte clone that is more susceptible to development of lichen planus.16 Drug-induced linear lichen
planus has also been reported.17,18
It is important to differentiate linear lichen planus
from nevus unius lateris, lichen striatus, inflammatory
linear verrucous epidermal nevus, linear psoriasis, and
linear DarierWhite disease, which have different presentations clinically and histopathologically.
MORPHOLOGY OF LESIONS
Hypertrophic Lichen Planus.
Hypertrophic
lichen planus (lichen planus verrucosus) usually occurs
on the extremities, especially the shins and interphalangeal joints, and tends to be the most pruritic variant
(Fig. 26-6).19 Lesions are thickened and elevated, purplish or reddish-brown in color, and hyperkeratotic.
Occasionally, verrucous plaques develop. Lesions
may show accentuated and elevated follicular induration and chalk-like scale. This variant usually heals
with scar formation and hyper- or hypopigmentation.
Chronic venous insufficiency is frequently present.
300
Figure 26-5 Lichen planus. Linear pattern with Koebner

response adjacent to clustered papules on the flexural wrist.
Atrophic Lichen Planus. The atrophic variant

is rare and is characterized by the presence of a few
Vesiculobullous Lichen Planus. The development of vesicles and bullae in lichen planus is rare. (Fig.
26-7). The bullae, which appear most commonly on the
extremities, arise from existing papules of lichen planus and rarely from normal-appearing skin. They may
appear suddenly during an acute flare of disease and
are usually associated with mild constitutional symptoms. These lesions usually resolve in a few months.
Figure 26-7 Vesiculo-bullous lichen planus. Vesicles

and bullae with violaceous-erythematous papules and
plaques on the foot.
Lichen Planus
well-demarcated, white-bluish papules or plaques,

sometimes more erythematous, with central superficial atrophy.2 The lesions are a few millimeters wide
but may coalesce to form larger plaques. They are most
common on the lower extremities or trunk. The lesions
often resemble lichen sclerosus et atrophicus. However,
the histologic features are diagnostic.
::
Figure 26-6 Hypertrophic lichen planus in the pretibial

region of a dark-skinned individual. Lesions are almost
nodular and very dark with the violaceous sheen of lichen
planus. Lesions may later become hyperkeratotic.
Bulla arising in oral lichen planus can lead to painful

erosions. Histologically, subepidermal separation is
present in addition to typical features. Bullae formation does not necessarily indicate a longer duration of
the disease. Bullae arising from normal skin are more
characteristic of lichen planus pemphigoides and should
be differentiated by direct and indirect immunofluorescence (see below).
Chapter 26
Figure 26-8 Erosiveulcerative lichen planus showing

erosions, ulcers, and granulation tissue and scarring of
toes, interdigital web spaces, and soles.
Erosive and Ulcerative Lichen Planus.
A
rare variant presents with chronic, painful bullae and
ulcerations of the feet with often, cicatricial sequelae
(Fig. 26-8). Patients typically have nails, and mucosal
involvement in addition to classical skin lesions, which
often aids in establishing the diagnosis. Permanent loss
of toenails and cicatricial alopecia of the scalp are common. Squamous cell carcinoma (SCC) may develop in
lesions of ulcerative lichen planus.20
Erosions and ulcerations may also develop in more
severe cases of oral lichen planus.
Follicular Lichen Planus. Follicular lichen planus
may occur alone or in association with other forms of
cutaneous or mucosal lichen planus.16 The term lichen
planopilaris has been used to describe this distinctive
variant, but other terms include lichen planus follicularis, peripilaris, and acuminatus. Individual keratotic
follicular papules and studded plaques are seen. Sites
of predilection include the trunk and medial aspects
of the proximal extremities.21 Follicular lichen planus
may affect the scalp with the development of cicatricial alopecia (see Section Lichen Planus of the Scalp;
Fig. 26-9). The triad of follicular lichen planus of skin
(lichen planus spinulosus) and/or scalp, multifocal
cicatricial alopecia of the scalp, and nonscarring alopecia of the axillary and pubic areas, has been described
as GrahamLittlePiccardiLassueur (or Graham
LittleFeldman) syndrome. Sometimes more typical
lesions of the skin and nails are seen. Other variants
of follicular lichen planus include the lichen planus follicularis tumidus with oval pseudotumoral plaques of
the mastoid area, postmenopausal frontal fibrosing
alopecia,22 and lichen planoporitis, with the lichenoid
301
Section 4
::
302
reaction centered over the acrosyringium and eccrine

ducts entering the epidermis.
Lichen Planus Pigmentosus.
This variant is
characterized by hyperpigmented, dark-brown macules
in sun-exposed areas and flexural folds. This entity
tends to occur in patients with darker pigmented
skin. Histologically, an atrophic epidermis, a vacuolar
alteration of the basal cell layer with a scarce
lymphohistiocytic lichenoid infiltrate, and pigment
incontinence are seen. This variant bears significant
similarity to ashy dermatosis or erythema dyschromicum
perstans. It may represent an overlap in the phenotypic
spectrum of lichenoid inflammation in darkly pigmented
skin, with ethnic and genetic factors influencing the
expression of disease (see Chapter 75).23 In cases where
the inflammatory phase was minimal, such as lichen
planus invisible de Gougerot, the pigmentation may
be the only sign of the disease.
Actinic Lichen Planus. Also known as lichen planus

subtropicus, lichen planus tropicus, summertime actinic
lichenoid eruption, lichen planus actinicus, lichen planus
atrophicus annularis, and lichenoid melanodermatosis.
Actinic lichen planus affects young people of the
Middle East in spring and summer, where sunlight
appears to have a precipitating effect. Exposed areas
of the face, dorsal hands and arms, and the nape of the
neck are usually affected. Papules are hyperpigmented
Figure 26-9 Lichen planus. A. Irregular patches of alopecia with violaceous papules and coalescing plaque of
lichen planus within scalp. B. Lichen planopilaris resulting in atrophic, scarred, porcelain-colored area centrally
with bordering follicular involvement consisting of dusky
erythema, perifollicular hyperkeratosis and scale, and follicular convergence resulting in dolls hair formation. C. Extensive hair loss leading to pseudopelade of Brocq appearance. Several remaining tufts of hair showing violaceous
erythema and disease activity.
with violaceous-brown color and a thready, rolled

edge showing well-defined borders. Annular lesions
are common, but pigmented and linear forms were
seen.24,25 Typical lichen planus lesions may be present
over the extremities. Pruritus and scaling are minimal.
Other Variants.
A perforating variant has been

described in which transepidermal elimination of
lichen planus-like inflammatory tissue is observed.
Guttate lichen planus is another variant that resembles
guttate psoriasis but with the characteristic lichenoid histology. Exfoliative and exanthematous forms
are very rare and may represent manifestations of
lichenoid drug reactions (Fig. 26-10). The rare entity
of invisible lichen planus describes lesions that are not
perceptible with visible light illumination but become
apparent with Woods lamp examination. Pruritus is
present and biopsy evaluation shows lichenoid histology. This entity may be a minimal variant of lichen planus invisible de Gougerot.
SITE OF INVOLVEMENT
Lichen Planus of the Scalp. Lichen planopilaris
(LPP) or follicular lichen planus may affect the scalp in

a distinctive clinical and histologic pattern that affect
women more than men.2630 LPP can be subdivided
into three variants: (1) classic LPP, (2) frontal fibrosing
alopecia, and (3) LassueurGrahamLittlePiccardi
Figure 26-11 Lichen planus. Perianal leuko- and hyperkeratosis with hypertrophic, folded violaceous epithelium,
fissures, and healing biopsy site.
Lichen Planus
Mucosal Lichen Planus. Lichen planus can

affect the mucosal surfaces of mouth, vagina,
esophagus, conjunctiva, urethra, anus, nose, and
larynx. Its prevalence is estimated at approximately
1% of the adult population. Oral involvement occurs
in approximately 60%70% of patients with lichen
planus. It may be the only manifestation in 20%30%
of patients.
::
syndrome. In classic LPP, individual keratotic follicular

papules that coalesce and merge over the scalp to form
patches are typically seen. Perifollicular erythema and
acuminate keratotic plugs are characteristic features.
Follicular-centered lesions are usually observed under
close inspection of the scalp and orifices, particularly at
the margins of the alopecic area or within patches still
bearing hair. Cutaneous, nail, or mucous membrane
involvement with lichen planus may also be present.
Patients present with uni- or multifocal hair loss that
may be extensive and sometimes involve the entire
scalp (see Fig. 26-9). The condition can have major psychological impact on affected individuals.
End-stage disease is characterized by a nondescript
scarring alopecia that has led to the use of several
clinical terms describing the entity: lichen planopilaris,
folliculitis decalvans et atrophicus, lichen spinulosus at folliculitis decalvans, and GrahamLittle syndrome.
Frontal fibrosing alopecia is an uncommon condition
characterized by progressive frontotemporal recession
due to inflammatory destruction of hair follicles. It is
more common in postmenopausal women, but it can
occur in younger women. It may be associated with
mucocutaneous lichen planus. Recession of the hairline may progress inexorably over many years, but this
is not inevitable.22,31
Pseudopelade of Brocq is a rare clinical syndrome of
scarring alopecia and fibrosis, in which distinct pathologic features are absent. It is generally accepted that
pseudopelade of Brocq is the end stage of follicular
fibrosis caused by a primary inflammatory dermatosis such as lichen planus, lupus erythematosus, pustular-scarring forms of folliculitis, or fungal infections,
including favus, scleroderma, and sarcoidosis.
Chapter 26
Figure 26-10 Lichen planus-like eruption. Generalized

violaceous papules with superficial scale coalescing to
form erythematous variant. History of associated drug exposure leading to lichenoid reaction.
In oral lichen planus, different types have been

described, including reticular, plaque-like, atrophic,
papular, erosive/ulcerative, and bullous forms (see
Fig. 26-3).32,33 The reticular pattern is considered the
most common, but patients with erosive form are more
likely to seek medical help due to the symptomatology (pain and burning sensation) and chronicity. Most
patients have more than one type. The buccal, gingival,
and glossal mucosae are the most commonly affected
areas. The palate, floor of the mouth, retromolar pads,
and lips may also be affected. Gingival involvement
may take the form of gingival stomatitis or desquamative gingivitis, and could be the sole presentation in 8%
of oral lichen planus. On the other hand, lichen planus
is the most common cause for desquamative gingivitis.34
Oral lichenoid reaction is similar clinically and histologically to oral lichen planus, however, with identifiable etiology. Differentiating these two entities is
often difficult. It is usually seen on the buccal mucosa
adjacent to amalgam dental fillings.35,36 Patch tests frequently show positive reactions to mercury, gold, and
other metals.37,38
Bilateral reticular keratotic or atrophic changes of
the buccal mucosa and lichenoid atrophic patches over
the dorsal tongue have been described in patients with
HIV infection. The eruptions usually follow zidovudine or ketoconazole intake.
Esophageal Lichen planus is rare and affects the proximal esophagus. It manifests as progressive dysphagia
and odynophagia. Endoscopic findings can include
lacy white papules, pinpoint erosions, desquamation, pseudomembranes, and stenosis. Histologically,
it shows parakeratosis, epithelial atrophy, and lack of
hypergranulosis. Squamous cell carcinoma of esophagus may develop after longstanding disease.39,40
Male genitalia are involved in 25% of cases, and the
glans penis is most commonly affected, with annular
lesions frequently present (see Fig. 26-4). Anal lesions
of mucosal lichen planus present with leukokeratosis,
hyperkeratosis, fissuring, and erosions (Fig. 26-11).
Vulvar and vaginal lichen planus is present in over half
of patients with oral lichen planus.41 Clinically, the condition is often asymptomatic unless erosions develop.
303
Section 4
Burning, itching, pain and abnormal discharge then

become common.42 Examination reveal patches of leukoplakia or erythroplakia, sometimes with erosions,
and, occasionally, as a more generalized desquamative
vaginitis. Vaginal adhesions and labial agglutination
may result.
The vulvo-vaginal gingival syndrome is characterized
by involvement of vulvar and gingival tissues. Erythema and erosions of the gingivae and tongue and,
occasionally, white reticulated plaques, is associated
with desquamation and erosions of vulva and vagina.43
Conjunctival lichen planus may manifest as cicatricial conjunctivitis. Histologically, irregular thickening
with reduplication of the basement membrane is seen.
Direct immunofluorescence distinguishes ophthalmic
lichen planus from cicatricial pemphigoid.
Lichen Planus of the Nails.
::
(See also Chapter

89.) Nail involvement occurs in 10%15% of patients.44
Lichen planus limited to the nails is uncommon, and
the initial involvement is followed, in many cases, by
the development of typical lesions elsewhere. Lichen
planus of nails is infrequent in children. Thinning, longitudinal ridging, and distal splitting of the nail plate
(onychoschizia) are the most common findings. Onycholysis, longitudinal striation (onychorrhexis), subungual hyperkeratosis, or even absence (anonychia) of
the nail plate can also be seen. Twenty-nail dystrophy
(trachyonychia) may represent an isolated nail finding
of lichen planus. Psoriasis and alopecia areata can also
lead to these distinctive nail changes. Nail loss may
result from ulcerative lichen planus involving the nail
unit. Pterygium or forward growth of the eponychium
with adherence to the proximal nail plate is a classic
finding of lichen planus of the nail (Fig. 26-12). An
atrophic cicatrizing form of lichen planus with random
and progressive nail loss in Asians and blacks has also
been reported. The tenting or pup-tent sign is observed
as a result of nail bed involvement that elevates the
nail plate and may cause longitudinal splitting.2
Inverse Lichen Planus. The inverse pattern

occurs only rarely and is characterized by red-brownish, discrete papules, and nodules. The eruption occurs
mainly in the flexural areas such as axillae, inframammary, groin, and, less likely, the popliteal and antecubital areas. Koebnerized lesions are occasionally present.
Palmoplantar Lichen Planus. This is a rare

variant that is difficult to diagnose if present as an isolated finding. Very pruriginous, erythematous, scaly
plaques with or without hyperkeratosis are characteristic. Lesions are often seen on the internal plantar
arch. Yellowish, compact keratotic papules or papulonodules are seen on the lateral margins of the fingers and hand surfaces; however, they are less likely
to affect the fingertips. They appear like callosities
with an inflammatory, erythematous halo. The lesions
resemble psoriasis vulgaris, warts, calluses, porokeratosis, hyperkeratotic eczema, tinea, or secondary syphilis.45 Palmoplantar lichen planus may also present
as erosiveulcerative type (see Section Erosive and
Ulcerative Lichen Planus).
SPECIAL FORMS OF LICHEN PLANUS OR
LICHENOID ERUPTIONS
Drug-Induced Lichen Planus. Lichen planus-
like or lichenoid eruptions describe a group of cutaneous reactions identical or similar to lichen planus
(see Fig. 26-10).46 Lichenoid drug eruptions have been
reported after ingestion, contact, or inhalation of certain chemicals (Table 26-1). They may be localized or
generalized with eczematous papules and plaques
and variable desquamation. They typically manifest
postinflammatory hyperpigmentation and alopecia,
and do not exhibit classic Wickham striae. The eruptions usually appear symmetrically on the trunk and
extremities, unlike the flexural distribution of classic
lichen planus. Mucous membrane involvement is less
common and is often associated with specific drugs
and chemicals. A photodistributed pattern is often found
in sun exposed areas, and several drugs frequently
induce this reaction (see Table 26-1).
The latency period for development of a lichenoid
drug eruption by these agents varies from months to
a year or more based on the dosage, host response,
previous exposure, and concomitant drug administration. Resolution of the eruptions is quite variable, but
most disappear in 34 months, except in gold-induced
lichenoid eruption that may require up to 2 years after
discontinuation. For many inciting drugs, the severity
and extent of the eruption influences the rate of clearance. Occasionally, the lichenoid drug eruption disappears or may recur intermittently despite continuation
of treatment.
Lichenoid contact dermatitis may result from contact
with compounds such as color film developers, dental
restoration materials, metals (e.g., mercury, silver, and
gold), and aminoglycoside antibiotics.46 Oral lichenoid
drug eruptions are mostly related to dental restoration
metals such as mercury, silver, and gold.
Lichen PlanusLupus
Overlap Syndrome. This
304
Figure 26-12 Lichen planus. Classic pterygium formation

and tenting of several fingers with loss of nail plates.
Erythematosus
is a rare variant characterized by lesions that share features of lichen planus and lupus erythematosus. Atrophic plaques and
patches with hypopigmentation and a livid red to
blueviolet color with telangiectasia and minimal scaling are characteristic. Transient bullae may develop.
Classic lesions of lichen planus, photosensitivity,
TABLE 26-1
Agents Inducing Lichen Planus and Lichenoid

Reactions
Common inducers
Gold salts
blockers
Antimalarials
Diuretics; Thiazide, Furosemide, Spironolactone
Penicillamine
Inducers of oral lichen planus and lichenoid eruption

Allopurinol (Zyloprim)
ACE inhibitors
Cyanamide
Dental restorative materials, Mercury, Silver, Gold
Gold salts
Ketoconazole (Ketoconazole)
Nonsteroidal anti-inflammatory drugs
Penicillamines (Cuprimine)
Sulphonylurea
Interferon- and Ribavirin
ACE = angiotensin-converting enzyme.
Figure 26-13 Lichen planuslupus erythematosus

overlap syndrome. Lichenoid lesions involving dorsal
hand and forearm with direct immunofluorescence evidence of lupus erythematous.
Lichen Planus
Inducers of photodistributed lichenoid eruption

5-Fluorouracil (Efudex)
Carbamazepine (Tegretol)
Chlorpromazine (Compazine, Thorazine)
Diazoxide (Proglycem)
Ethambutol
Pyritinol
Quinine
Quinidine (Quinaglute)
Tetracycline
Thiazide
Furosemide (Lasix)
::
Inducers of lichen planus by contact

Color film developers
Dental restorative materials
Musk ambrette
Nickel
Gold
Chapter 26
Less common
ACE inhibitors
Calcium channel blockers
Sulfonylurea
Nonsteroidal anti-inflammatory drugs
Ketoconazole
Tetracycline
Phenothiazine
Sulfasalazine
Carbamazepine
Lithium
Antituberculosis
Iodides
Radiocontrast media
Radiotherapy
Antipsoriatic therapy: Etanercept, Infliximab, Adalimumab
Omalizumab
pruritus, and follicular plugging are also not common.

Lesions may develop anywhere, but are most common
on the extremities (Fig. 26-13). Some patients with this
overlap syndrome may progress to systemic lupus erythematosus. In other instances, laboratory evaluation
may reveal only a weak-positive antinuclear antibody.
This disease variant is characterized by a prolonged
course and lack of response to treatment. Histologically, a lichenoid reaction typical for lichen planus
and histologic features of lupus erythematosus are
usually present in the same biopsy.47 By direct immunofluorescence, cytoid bodies staining with IgG, IgM,
and C3 intraepidermally or at the dermalepidermal
junction, as seen in classic lichen planus, are most common. Linear to granular deposition of IgM and C3 (as
seen in lupus erythematosus, but not in lichen planus)
and shaggy deposition of fibrinogen at the basement
membrane zone, typical of lichen planus have been
observed occasionally.47
Lichen Planus Pemphigoides. Lichen Planus

Pemphigoides is characterized by the development of
tense blisters atop lesions of lichen planus or the development of vesicles de novo on uninvolved skin or oral
mucosa (Fig. 26-14). It is important to differentiate this
entity from bullous lichen planus, in which blisters
develop in lesions of long-standing lichen planus as a
result of intense lichenoid inflammation and extensive
liquefaction degeneration of basal keratinocytes. The
etiology of this variant is not clear. It was proposed
that basal cell keratinocyte damage by lymphocytes
in lichen planus may unmask hidden antigenic
305
CD4:CD8 ratio were not different. Langerhans cells are

often increased in both conditions.
Lichenoid Keratosis.
Lichenoid keratoses are

brown to red, scaling maculopapules found on sunexposed skin of extremities. Histologic features of
lichen planus are present, with the additional finding
of focal parakeratosis. They frequently occur with solar
lentigo, seborrheic keratosis, and actinic keratosis and
likely represent an involuting lichenoid plaque.53
RELATED FINDINGS
Section 4
::
Figure 26-14 Lichen planus pemphigoides. Lichenoid

maculopapular erythema, erosions, and bullae with direct
immunofluorescence showing features of bullous pemphigoid. Indirect immunofluorescence also was positive.
determinants and lead to autoantibody formation and

induction of bullous lesions. Captopril was described
to induce this entity also.48 Histologic findings resemble those of lichen planus. Direct immunofluorescence
shows linear deposition of IgG and C3 at the dermal
epidermal junction.49 Sera from these patients react
with the epidermal side of NaCl-split human skin.
Circulating IgG autoantibodies react to the major noncollagenous extracellular domain (NC16A) of the 180kDa bullous pemphigoid antigen within the basement
membrane zone. Further mapping showed that lichen
planus pemphigoides serum reacts with amino acids
4659 of domain NC16A, a protein segment that was
previously shown to be unreactive with bullous pemphigoid sera. This newly described epitope is designated MCW-4.50
Lichenoid Reaction of Graft-Versus-Host

Disease. (See Chapter 28.) Chronic graft-versus-host
306
disease (GVHD) (occurring 100 days after transplant)

may present as a lichenoid eruption indistinguishable
clinically and histologically from lichen planus. Lichenoid GVHD favors the trunk, buttocks, hips, thighs,
palms, and soles. In oral mucosa, xerostomia and oral
ulcerations are occasionally seen. Histologically, the
findings in lichen planus and oral GVHD are similar,
although more infiltrating CD3+ T lymphocytes are
present in oral lichen planus than in GVHD.52 Natural killer cells, Leu-8-positive T cells (homing receptor:
CD62L, LECAM), CD25-positive lymphocytes, and the
Lichen planus is seen with increased frequency in

association with liver diseases such as autoimmune
chronic active hepatitis, primary biliary cirrhosis, and
postviral chronic active hepatitis.55 The association
with primary biliary cirrhosis is observed regardless of
treatment with d-penicillamine, a drug that may cause
an exacerbation of lichen planus.
Hepatitis C infection has been implicated in triggering lichen planus. The prevalence of HCV infection
varied between 16% and 29% in southern European
patients with lichen planus.56,57 On the other hand,
many studies from northern Europe and the United
States did not substantiate any link.58,59 Genetic factors controlling disease susceptibility and prevalence
of certain HCV genotypes in certain geographic areas
may have significantly influenced these results. No
strong link between hepatitis B infection and lichen
planus is shown.60 Lichen sclerosus is seen in 16% of
cases of erosive vaginal lichen planus.41
There is no evidence to link lichen planus to diabetes
mellitus, autoimmune diseases, or internal malignancies. Cases of severe erosive gingivitis and stomatitis
with histologic appearance of lichen planus in association with internal malignancies may represent cases
of paraneoplastic autoimmune multiorgan syndrome
(PAMS) or paraneoplastic pemphigus (see Chapter 55).
LICHEN PLANUS AND MALIGNANT

TRANSFORMATION
There has been considerable controversy as to whether
oral lichen planus inherently harbors malignant potential.61,62 It is currently believed that the risk of malignant transformation is fairly low (Fig. 26-15). Risk
factors that increase the likelihood of developing oral
cancer are long-standing disease, erosive or atrophic
types, tobacco use, and possibly esophageal involvement. It is generally accepted that about 2% of patients
with oral lichen planus develop SCC.32 The majority
of these cases are in situ carcinoma or with microinvasive pattern. The most common site for cancer is
the tongue, followed by buccal mucosa, gingiva, and,
rarely, the lip. Clinically, the lesions appear as indurated, nonhealing ulcers, or exophytic lesions with a
keratotic surface. Red atrophic plaques could also be
seen and often correlate with SCC in situ. Advanced
cases could result in nodal metastases and occasionally death.
LABORATORY TESTS
No specific abnormalities of laboratory analyses are
seen in lichen planus. The total white blood cell count
and lymphocytes may be decreased. This could be
related to cytokine activation and local trafficking of
cells to skin or other tissue compartments.
Patch tests in patients with oral or cutaneous lichen
planus usually reveal positive results in a majority
of patients.63 Sensitivity to mercury and gold is often
positive in one-half of the cases. Chromate, flavoring
agents, acrylate, and thimerosal are common sensitizers. Avoidance of these clinically relevant sensitizers
results in amelioration of disease. Dyslipidemia is more
common in patients with lichen planus than controls.64
Lichen Planus
The risk of skin malignancy in cutaneous lichen planus is extremely low. Most patients developing SCC in
cutaneous lichen planus had a history of either arsenic
or X-ray exposure.
older, waning lesions, in dark-skinned individuals and

lichen planus pigmentosus. Separation of the epidermis in small clefts (Max Joseph cleft formation) is occasionally seen (Fig. 26-17).
Direct immunofluorescence shows numerous apoptotic cells at the dermalepidermal junction (60%)
staining with IgM and, occasionally, with IgG and IgA.
Shaggy deposition of fibrinogen at the dermalepidermal junction (55%) is characteristic of lichen planus (Fig.
26-18).65 Immunocytochemical studies show that the
majority of the cells in the infiltrate are T lymphocytes,
with scattered B lymphocytes. An increased density of
Langerhans cells, dermal dendritic cells, and histiocytes
have also been seen, especially in early active lesions.
The presence of abundant plasma cells and eosinophils in the infiltrate, focal parakeratosis and hypogranulosis, and the presence of cytoid bodies high in
the stratum corneum favor lichenoid tissue eruptions.
Furthermore, lymphocytic infiltration is less dense.
The differential diagnosis of lichen planus is shown in
Boxes 26-1 and 26-2.
::
Figure 26-15 Lichen planus and squamous cell carcinoma. Long-standing oral lichen planus with scarring
changes of tongue. Circumscribed erythroplakia and erosions of the right lateral tongue was biopsied and confirmed squamous cell carcinoma.
Chapter 26
Figure 26-16 Lichen planus. Typical hyperkeratosis,

hypergranulosis, early sawtooth changes, and lichenoid
interface reaction of classic lichen planus.

Lichen planus is an unpredictable disease that typically
persists for 12 years, but which may follow a chronic,
relapsing course over many years.66 The duration
PATHOLOGY
The two major pathologic findings in lichen planus
are (1) basal epidermal keratinocyte damage and (2)
lichenoid-interface lymphocytic reaction. The epidermal changes include hyperkeratosis, wedge-shaped
areas of hypergranulosis, and elongation of rete ridges
that resemble a sawtooth pattern (Fig. 26-16). Multiple
apoptotic cells or colloid-hyaline (Civatte) bodies are
seen at the dermalepidermal junction. Eosinophilic
colloid bodies are present in the papillary dermis. A
band-like lymphocytic infiltrate is seen in the papillary dermis that abuts the epidermis. Plasma cells are
more prominent in mucous membrane specimens.
Few eosinophils are seen in drug-induced lichen planus or lichenoid drug eruptions. Melanin pigmentation is invariably present and is more pronounced in
Figure 26-17 Lichen planus. More extensive epidermal

alterations with hydropic changes, thinned epidermis,
focal wedge-shaped hypergranulosis, compact orthokeratosis, and pronounced lichenoid inflammation with focal
hemorrhage.
307
Section 4
::
Figure 26-18 Lichen planus. Direct immunofluorescence examination of involved skin. A. Numerous immunoglobulin Mpositive cytoids at the dermalepidermal junction. B. Fibrinogen/fibrin, shaggy pattern at the dermalepidermal junction.
varies according to the extent and site of involvement
and morphology of lesions. Generalized eruptions
tend to have a rapid course and heal spontaneously
faster than limited cutaneous disease. Lichen planopilaris is one of the most chronic and often progressive
disease variants with little potential for hair regrowth

after follicular inflammation and destruction. Hypertrophic lichen planus typically follows a protracted,
unremitting course. Spontaneous regression is also an
uncommon feature of oral lichen planus. The mean

of Lichen Planus

of Site-Specific Lichen Planus
Classic
Nail
Annular
Linear
Hypertrophic
Atrophic
Follicular
Childhood
308
Psoriasis
Drug eruption
Granuloma annulare
Tinea
Nevus unius lateris
Lichen striatus
Linear epidermal nevus
Prurigo nodularis
Lichenoid cutaneous amyloidosis
Kaposi sarcoma
Lichen sclerosus
Lichen nitidus
Lichen spinulosus
Lichen nitidus
Lichen striatus
Papular acrodermatitis of childhood
Genital
Palms and soles
Lichen planopilaris
Mucosal
Psoriasis
Onychomycosis
Alopecia areata
Psoriasis
Secondary syphilis
Cicatricial alopecia
Lupus erythematosus
Inflammatory folliculitis
Alopecia areata
Cicatricial pemphigoid
Keratosis follicularis spinulosa
decalvans
Candidiasis
Lupus erythematosus
Leukokeratosis
Secondary syphilis
Traumatic patches
duration for oral lichen planus is 5 years. The reticular

variant has a better prognosis than erosive disease that
does not heal spontaneously. Generally, the duration of
disease conforms to the following order, from shortest
duration to longest duration: (1) generalized, (2) cutaneous, (3) cutaneous + mucous membrane, (4) mucous
membrane, (5) hypertrophic, and (6) lichen planopilaris.
Relapse of disease occurs in 15%20% of cases and
tends to occur in the same area as the initial episode.
Recurrences are more common in generalized lichen
planus and are usually of shorter duration.
TREATMENT
Lichen Planus
(Box 26-3)
Topical Steroids. Topical steroids are the first-line

therapy in mucosal lichen planus.6769 Use of occlusive
materials suitable for mucous membranes, such as
Orabase, may provide protection, sustained tissue contact with the medication, and alleviate the discomfort
associated with erosive lesions. Triamcinolone acetonide (0.1%), Fluocinonide gel, 0.1% fluocinolone acetonide, and 0.025% clobetasol propionate in Orabase
showed good results.70 Application four to six times a
day is recommended. Treatment is often complicated
by oral candidiasis. The use of chlorhexidine gluconate
mouthwashes and topical anticandidal medications is
recommended during therapy.71
Topical corticosteroids are sometimes compounded
with anesthetics to provide symptomatic benefit
for patients with difficulty eating and chewing, for
::
MUCOSAL LICHEN PLANUS
For oral lichen planus,

good oral hygiene and regular personal and
professional dental care need to be encouraged.
Replacement of amalgam or gold dental restorations
with composite material is frequently of considerable
benefit in patients with oral lichenoid reactions, even
in the apparent absence of relevant patch test results.
Chronic lesions on the buccal mucosa in contact with
metal or other contact sensitizers frequently heal
promptly after replacement. Occasionally, lesions at
sites distant to oral lesions may also clear after removal
of metal restorations. Gingival lesions may respond
less favorably. The decision to undergo removal and
restoration is often difficult and usually depends on
the chronicity, severity, and clinical and patch-test
evidence for involvement by the metal/prosthesis as
well as the level of frustration of the patient.
Chapter 26
Management of lichen planus can be challenging and

discouraging for both the patient and physician. Lichen
planus may be associated with only minor symptoms
or may cause considerable discomfort and disability.
Hence, treatment options should be assessed for attendant risks and benefits and tailored to the extent and
severity of disease. Avoidance of exacerbating drugs,
unless necessary, and minimizing trauma to skin and
mucosal tissues are routinely recommended.
Various drugs have been proposed for the treatment of mucosal and cutaneous lichen planus and the
majority of these consist of small series of patients or
anecdotes.67 Many of the advocated treatments lack
conclusive evidence for efficacy.
GENERAL MEASURES.
BOX 26-3 Treatment for Oral Lichen Planus

Topical
First line
Second line
Physical
Topical steroids
Tacrolimus (Protopic)
Pimecrolimus (Elidel)
Tretinoin gel
Isotretinoin gel
Lidocaine
Intralesional steroids
Foursix times daily

14 per day
14 per day
2 per day
2 per day
PRN
540 mg/mL
Cyclosporine mouthwash
Topical Rapamycina
24 daily
(1 mg/mL)
Extracorporeal photopheresisa
Systemic
Anticandidal systemic steroids
Etretinate
Acitretin
Isotretinoin
3080 mg/day
Hydroxychloroquine
Alefacepta and
Efalizumab*
Cyclosporine
Thalidomide
Azathioprine,
Methotrexate, cyclophosphamide,
mycophenolate
mofetil
50200 mg/day
Antipsoriatic
dose
75 mg/day
2550 mg/day
2040 mg/day
310 mg/kg/day
Variable
Variable
Experimental.
*No longer on market
309
Section 4
::
310
example, Intralesional Triamcinolone acetonide 10 mg/

mL or at diluted concentrations, if effective and safe.72
Glucocorticoids containing vaginal and rectal suppositories are usually helpful for mucosal involvement
in these areas. Topical ultrapotent corticosteroid is an
effective treatment for erosive lichen planus of the
vulva, giving relief of symptoms in 71%.73
Systemic Glucocorticoids. Systemic glucocorticoids
provide effectiveness in erosive oral and vulvovaginal
lichen planus to achieve rapid relief during periods of
exacerbations.74 Systemic dosing can be used alone, or,
more commonly, in conjunction with topical glucocorticoids. Prednisone dose range from 30 to 80 mg/day,
tapered over 36 weeks, and Betamethasone 5 mg on
two consecutive days per week show benefit. Relapses
are common after dose reduction or discontinuation.
Higher doses are often needed for esophageal lichen
planus in addition to intralesional steroid injection and
mechanical dilatation.75 Oral candidiasis is a common
complication.
Retinoids. Topical retinoic acid (tretinoin gel) has been
shown to be effective in erosive as well as plaque-like
oral lesions, however, site irritation often makes it less
attractive. Isotretinoin gel is also effective, especially in
nonerosive oral lesions. However, recurrence is common after discontinuation of therapy.76 Topical retinoids are often used in conjunction with topical glucocorticoids. Although not proven in clinical trials, this
may improve the efficacy and lessen the side effects.
Etretinate orally has been used at 75 mg/day (0.6
1.0 mg/kg/day) in erosive oral lichen planus with
significant improvement in the majority of patients.
Relapses are common after discontinuation of medication.77 Two-thirds of patients showed marked
improvement or complete remission within 8 weeks
of instituting acitretin, 30 mg/day.78 The topical use of
isotretinoin gel is effective also in oral disease.79
Tacrolimus and Pimecrolimus. Tacrolimus, effective
in erosive mucosal disease, provides rapid relief from
pain and burning with minimal side effects.80,81 It is at
least equally effective to clobetasol propionate 0.05%
ointment and triamcinolone acetonide 0.1% paste in
the treatment of oral lichen planus.8284
Pimecrolimus 1% cream was shown to be as effective as triamcinolone acetonide 0.1% paste in treating
oral lichen planus, and proved to be effective in treating vulvar disease.8587
Cyclosporine. Topical application of cyclosporine,
100 mg/mL, 5 mL three times daily has shown benefit
for oral lichen planus. Application modalities include
mouthwashes and manual administration with local
massage. Topical cyclosporine washes seem to be
effective in oral lichen planus, especially the severe
erosive forms,88,89 but they do not appear to be better
than local glucocorticoid therapy.90 Lack of effectiveness
in a few cases, high cost of this medication, and lack of
proper commercial formulation for topical application
limit its use. Oral cyclosporine at dose regimens of
310 mg/kg/day has been used for severe ulcerative
disease and in cases with esophageal involvement.91
Miscellaneous. Antifungal agents (e.g., fluconazole,

itraconazole) are useful in reducing candidal overgrowth associated with glucocorticoids use.
Hydroxychloroquine at 200400 mg/day for at least
6 months is also used cautiously because antimalarials
are implicated as possible inducers of lichen planus.92
Thalidomide should be reserved for cases recalcitrant
to other remedies. The dose could be started at 50 mg/
day and increased gradually to 200 mg/day.93
Dapsone can be used orally at 100200 mg daily and
has proved effective in two-thirds of patients with
cutaneous and oral disease.
Extracorporeal photochemotherapy twice a week for
3 weeks and then tapered has had favorable results.94,95
Alefacept at 15 mg every week for 12 weeks and Efalizumab (no longer on market) 0.7 mg/kg subcutaneously at week 0 followed by 1.0 mg/kg weekly from
week 1 to week 11 exhibited therapeutic response in
erosive lichen planus.9698 Frequent topical hyaluronic
acid gel preparation (0.2%) appears to be of some benefit.99 Aloe vera gel is also effective in improving the
symptoms.100 Topical rapamycin (1 mg/mL) twice a
day for 3 months may be effective in some refractory
erosive cases.101
Successful treatment of severe long-standing erosive
vulvovaginal lichen planus using 1015 mg of oral
methotrexate once weekly in conjunction with topical
clobetasol dipropionate 0.05% ointment and tacrolimus 0.03%0.10% ointment within 48 weeks.102
CUTANEOUS LICHEN PLANUS

(Box 26-4)
TOPICAL GLUCOCORTICOIDS. A large variety

of topical and systemic therapies are available for the
treatment of cutaneous lichen planus, and this range of
options may be attributed to the chronicity, symptomatology, and variable responsiveness of the dermatosis. Topical glucocorticoids are typically used for limited
cutaneous disease. Potent topical glucocorticoids with
occlusion, are often needed.
Intralesional triamcinolone acetonide (510 mg/mL)
is effective in treating oral and cutaneous lichen planus. This may also be used in lichen planus of the nails
with injection of the proximal nail fold every 4 weeks.
Regression of lesions occurs within 34 months. For
hypertrophic lichen planus, higher concentrations of
intralesional glucocorticoid (1020 mg/mL) may be
required. Regular and close observation should be performed to monitor for any signs of atrophy or localized hypopigmentation that should prompt cessation
of therapy. Intralesional injection is of special value in
lichen planopilaris.27
Systemic glucocorticoids are often useful and effective
in doses greater than 20 mg/day (e.g., 3080 mg prednisone) for 46 weeks with subsequent taper over 4
6 weeks. Symptoms are often alleviated, and patients in
the early stages of evolution or experiencing a flare have
marked benefit and attenuation or aborted progression
of disease. In lichen planopilaris, potent topical glucocorticoids in conjunction with oral glucocorticoids,
BOX 26-4 Treatment for Cutaneous Lichen Planus

TOPICAL
SYSTEMIC
Cyclosporine
Dapsone
Hydroxychloroquine
Azathioprine
310 mg/kg/day
100200 mg/day
200400 mg/day
75150 mg/day
1,000 mg bid
Special
forms
Doxycycline, tetracycline, and nicotinamide

Interferon- 2b
Metronidazole
Cyclophosphamide
Lichen planus pemphigoides
Methotrexate
3040 mg/day, for at least 3 months, seems to be successful. Relapse typically occurs following discontinuation. Long-term, chronic continuation of oral or injected
glucocorticoids is contraindicated in most cases because
of the high risk of complications.
RETINOIDS. The systemic retinoids demonstrate

anti-inflammatory activity and have been used in the
treatment of lichen planus. Remission and marked
improvement was achieved with 30 mg/day of
acitretin for 8 weeks.78 Oral tretinoin is used at 10
30 mg/day with marked improvement and mild side
effects.103 Low-dose etretinate (1020 mg/day) use has
been associated with complete remission of cutaneous,
oral, and nail lichen planus after 46 months of treatment. Prompt beneficial response was noted with the
use of 75 mg/day of etretinate,104 but side effects of
retinoids are dose related and may limit use of higher
dose therapeutic regimens.
PHOTOCHEMOTHERAPY.
Psoralen and ultraviolet A (PUVA) light photochemotherapy is usually successful in generalized cutaneous lichen planus.105 It has
been used in conjunction with oral glucocorticoids to
hasten the response. Trioxsalen, 50 mg added to 150 L of
water, then exposing the patients to UVA after 10 minutes of bathing gave good results.106 UVA-1 phototherapy may also benefit more protracted lichen planus.
UVB, both broad and narrow band, are safe and efficient
treatment options for generalized disease.107109
IMMUNOSUPPRESIVE AGENTS. Systemic cyclosporine has been used successfully in recalcitrant lichen
Generalized
Generalized
Refractory lichen
planus
Refractory lichen
planus
Lichen Planus
Second
line
Variable
Variable
Psoralen and
ultraviolet A
light
Broad band UVB
Narrow band UVB
::
3080 mg/day
1075 mg/day
2550 mg/day
2040 mg/day
12 per day
520 mg/mL
Chapter 26
Systemic steroids
Etretinate
Acitretin
Isotretinoin
First line
Topical steroids
Intralesional
steroids
Tacrolimus
Pimecrolimus
PHYSICAL
planus.110 The administered dose can range from 3 to

10 mg/kg/day. Pruritus usually disappears after 1
2 weeks. Clearance of the rash is seen in 46 weeks.
Low doses (1.02.5 mg/kg/day) are probably sufficient to achieve remission. Adverse effects as well as
relapse after discontinuation of the drug, limit its use
to severe cases.111
Azathioprine is useful in recalcitrant, generalized
cutaneous lichen planus and in lichen planus pemphigoides.112 Methotrexate is of value in generalized and
erosive vulvar lichen planus.113 Mycophenolate mofetil
was effective at reducing the signs and symptoms of
active lichen planopilaris in 83% of patients who had
failed multiple prior treatments after at least 6 months
of treatment.114 Similar results are seen with mycophenolate mofetil at a dose of 1500 mg twice daily.115
Cyclophosphamide should be reserved for refractory
cases due to its toxicity.
MISCELLANEOUS. Hydroxychloroquine is effective

in decreasing symptoms and signs in Lichen planopilaris and its variant frontal fibrosing alopecia in 69%
and 83% of patients after 6 and 12 months of treatment,
respectively.116 It is also the main treatment in actinic
lichen planus at 200400 mg/day in addition to sun
protection.24
Thalidomide can be used in lichen planus unresponsive to other therapies.117,118 Oral metronidazole 500 mg
twice daily for 12 months also reportedly clears the
majority of cases of generalized lichen planus.119
Based on the benefit in bullous pemphigoid, combination therapy with tetracycline or doxycycline and nicotinamide has been reported as useful in the treatment of
311
Section 4
::
lichen planus pemphigoides.120 Tetracycline should be

considered in lichen planopilaris.27
A case of generalized Lichen planus with oral
involvement was treated with adalimumab, a tumor
necrosis factor (TNF) antagonist with good results121
and Alefacept.122
Low-molecular-weight heparin in low doses has lymphoid antiproliferative and immunomodulatory properties.123,124 At a dose of 3 mg weekly, heparin injections
have been reported to significantly improve the symptoms of pruritus and activity of the disease. Four to
six injections of heparin induced complete regression
of lesions within 410 weeks. Cutaneous involvement
and reticulated oral lesions had the best response. Oral
erosive lichen planus showed minimal improvement
with this regimen.
Skin grafting has been beneficial in the management
of ulcerative lichen planus of the feet that is recalcitrant to other treatments.
KEY REFERENCES
2. Boyd AS, Nelder KH: Lichen planus. J Am Acad Dermatol
25:593, 1991
7. Wenzel J, Tuting T: An IFN-associated cytotoxic cellular
immune response against viral, self-, or tumor antigens is
a common pathogenetic feature in interface dermatitis.
J Invest Dermatol 128:2392, 2008
Chapter 27 :: Lichen Nitidus

:: Mazen S. Daoud & Mark R. Pittelkow
LICHEN NITIDUS AT A GLANCE
Small, glistening, flesh-colored to pink or
reddish-brown papules of unknown etiology.
Distinctive, circumscribed infiltrate of
lymphocytes and histiocytes in papillary
dermis situated directly beneath thinned
epidermis.
There is no associated systemic disease.
Prognosis is good.
312
12. Wenzel J et al: Gene expression profiling of lichen planus

reflects CXCL9+-mediated inflammation and distinguishes this disease from atopic dermatitis and psoriasis. J Invest Dermatol 128:67, 2008
15. Balasubramaniam P, Ogboli M, Moss C: Lichen planus in
children: Review of 26 cases. Clin Exp Dermatol 33:457, 2008
19. Lehman JS, Tollefson MM, Gibson LE: Lichen planus. Int J
Dermatol 48:682, 2009
26. Kang H et al: Lichen planopilaris. Dermatol Ther 21:249,
2008
29. Mehregan DA et al: Lichen planopilaris: Clinical and
pathologic study of forty-five patients. J Am Acad Dermatol
27:935, 1992
35. Cobos-Fuentes MJ et al: Oral lichenoid lesions related to
contact with dental materials: A literature review. Med
Oral Patol Oral Cir Bucal 14:e514, 2009
42. Kennedy CM, Galask RP: Erosive vulvar lichen planus:
Retrospective review of characteristics and outcomes in
113 patients seen in a vulvar specialty clinic. J Reprod Med
52:43, 2007
46. Ellgehausen P et al: Drug-induced lichen planus. Clin Dermatol 16:325, 1998
54. Oliver GF et al: Lichenoid dermatitis: A clinicopathologic
and immunopathologic review of sixty-two cases. J Am
Acad Dermatol 21:284, 1989
62. Eisen D: The clinical features, malignant potential, and
systemic associations of oral lichen planus: A study of 723
patients. J Am Acad Dermatol 46:207, 2002
66. Carbone M et al: Course of oral lichen planus: A retrospective study of 808 northern Italian patients. Oral Dis 15:235,
2009
67. Zakrzewska JM et al: A systematic review of placebocontrolled randomized clinical trials of treatments used in
oral lichen planus. Br J Dermatol 153:336, 2005
75. Wedgeworth EK et al: Management of symptomatic
esophageal involvement with lichen planus. J Clin Gastroenterol 43:915, 2009
Lichen nitidus (Latin nitidus, shiny or glistening)

is an uncommon, usually asymptomatic cutaneous
eruption first described by Felix Pinkus in 1901 and
further characterized by him in 1907.1,2 Lichen nitidus consists of small, glistening, flesh-colored to pink
or reddish-brown papules that may be limited to the

penis, genitalia, abdomen, and extremities or, less frequently, may occur as a generalized condition. The
histopathologic findings are characteristic. Although
the condition is often chronic, the prognosis is good,
and no clearly associated systemic illnesses have been
documented.
EPIDEMIOLOGY
Epidemiologic characteristics of lichen nitidus have
not yet been defined completely. Lichen nitidus occurs
infrequently and has been reported to affect blacks
more than Caucasians; children and young adults
more than the elderly; and males more than females.
The incidence is estimated to be approximately 3.4
cases/10,000 population, based on a 25-year survey of
skin diseases in African-Americans.3 The crude ratio
of lichen nitidus to lichen planus is 1.7:100, based on
pathologic diagnosis of cases evaluated over several
decades at the Mayo Clinic.
CLINICAL FINDINGS
::
Lichen Nitidus
Lichen nitidus is composed of multiple, discrete,

smooth, and flat, round papules. Individual papules
are 12 mm in size, flesh-colored to slightly pink or,
in blacks, hypopigmented, with a glistening appearance (Fig. 27-1). Sometimes, minimal scale is present or
can be elicited by rubbing the surface of the papules.
Occasionally, the papules are grouped and the isomorphic or Koebner phenomenon is observed. Lesions
may occur anywhere over the skin surface; however,
the most frequent sites of predilection are the flexural
surfaces of the arms and the wrists, lower abdomen,
breasts, the glans and shaft of the penis, and other
areas of the genital region. Infrequently lichen nitidus
is a generalized eruption.
Rare sites of involvement include mucous membranes, nails, palms, and soles. Rare clinical variants
include vesicular, hemorrhagic and purpuric, spinous
follicular, linear, generalized, and lichen nitidus actinicus types.1116 (See Table 27-2.)
Chapter 27
Once considered a tuberculoid reaction, lichen nitidus

is currently regarded as a disorder of unknown etiology. The relationship between lichen nitidus and lichen
planus has been debated for many years.4 The coexistence of both diseases in some patients, development
of lichen planus following generalized lichen nitidus,5
and the clinical similarities to small lichen planus papules were used to support the view that lichen nitidus is
a variant of lichen planus. However, most experienced
clinicians, as well as research studies, favor the separation of these two diseases as distinct entities based
on both clinical and immunodermatopathologic differences and the characteristic and distinctive histologic
changes. Table 27-1 summarizes some of these differences and similarities. Another etiologic theory of lichen
nitidus proposes that an allergen may cause epidermal
and dermal antigen-presenting cells (e.g., Langerhans
cells) to activate a cell-mediated response, initiate lymphocyte accumulation, and form discrete inflammatory
papules. The presence of large numbers of Langerhans
cells in the infiltrate supports this theory.6 Specific cytokines produced by the inflammatory cells influence
the immune response and may shift the T lymphocyte
response toward the T helper 2 subset that has the
potential to produce the superficial dermal granulomas
seen in lichen nitidus.7 Functional impairment in cellular immunity has been reported in generalized lichen
nitidus,8 and lichenoid photoeruptions similar to lichen
nitidus were seen in a patient with HIV infection.9 Rare
cases of lichen nitidus associated with atopic derma-
titis, Crohns disease, and juvenile chronic arthritis

have been reported. Induction of allergic contact dermatitis by topical application of dinitrochlorobenzene
in a patient with lichen nitidus cleared the eruption,
presumably by altering the cellular immunity, cellular
infiltration, and cytokine expression.7
A rare familial presentation of lichen nitidus has
been reported, although no genetic factors of the disease have been identified.10
TABLE 27-1
Comparison of Features Between Lichen Nitidus and Lichen Planus

Lichen Nitidus
Lichen Planus
Incidence
Rare
Common
Lesion
Size
Shape
Color
Wickham striae
Mucosal changes
Pruritus
Usually 12 mm
Round
Flesh, pink, redbrown
Absent
Rare
Uncommon
Variable, usually larger

Polygonal
Erythematous to violaceous
Present
Variably present
Usually present, marked
Histopathology
Hyperkeratosis
Parakeratosis
Infiltrate
Lymphocytes
Histiocytes
Giant cells
Dyskeratotic
Variable and focal

Mostly present
Focal in one to three papillary bodies
Variable
Variable, almost always present
Occasional
Occasional
Usually present
Not found
Band-like, extends through many rete ridges
Vast majority of cells
Almost none
None
Very common
Immunopathology
Cytoids
Basement membrane
Usually negative
Usually negative
Immunoglobulin M and other conjugates

Fibrinogen, other conjugates
Immunohistochemistry
CD4+ lymphocytes
CD68+ cells
Majority of cells
Common
Majority of cells
Uncommon
313
Section 4
Figure 27-1 Lichen nitidus. A. Pinpoint to pinhead, discrete, dome-shaped papules over upper back, shoulder, and arm.
Side-lighting, as performed here, enhances visualization of multiple small lesions. B. Individual papules, flesh- to pinkcolored over chest and arm, becoming more grouped over anterior axilla.
::
Actinic lichen nitidus appears in patients with dark

skin in areas with significant sun exposure such as face
and arms. It can recur with repetitive exposure to the
sun and show seasonal pattern.17 It has been reported
in the literature under summertime lichenoid actinic
eruptions.18 Palmoplantar involvement may manifest
several morphologic forms that range from pinpoint
papules to keratoderma.19 Bilateral hyperkeratosis of
palms and soles with erythema, fissuring, and a texture resembling fine sandpaper has been observed.14,19
Occasionally, minute keratotic spicules on the palmar
surfaces or multiple pinpoint papules that extend
to the dorsa of the extremities occur (Fig. 27-2). Nail
abnormalities usually manifest as longitudinal, beaded
ridging, and terminal splitting with or without irregular pitting.20 Lichen nitidus is usually asymptomatic;
however, pruritus is occasionally present and sometimes intense. There are no constitutional symptoms
or systemic abnormalities associated with the disease.
keratotic cells is usually observed. Occasionally, the

epidermis may partially detach from the dermis. Colloid bodies are rarely seen. The dermal infiltrate is well
circumscribed and composed of closely associated
histiocytes, few lymphocytes, and occasional foreign
body or Touton-type giant cells. Usually, no plasma
cells or eosinophils are seen. Palmar lesions may show
a deep parakeratotic plug. Transepithelial elimination of the inflammatory infiltrate has been described
(perforating lichen nitidus).21 Purpuric or hemorrhagic
lesions are associated with capillary wall degeneration
and red blood cell extravasation.12
The majority of the cells in the infiltrate are T
lymphocytes (CD4+ cells predominate over CD8+)
PATHOLOGY
A dense mass of infiltrating lymphohistiocytic cells is
situated immediately below the epidermis and results
in widening of the papillary dermis with elongation
and the appearance of embracement by neighboring rete ridges (Fig. 27-3). The overlying epidermis is
thinned and occasionally demonstrates central parakeratosis without hypergranulosis. This is a characteristic diagnostic finding, when observed (see Fig.
27-3B). Minimal hydropic degeneration with few dys-
TABLE 27-2
Rare Forms of Lichen Nitidus
314
Site of Involvement
Clinical Variant
Generalized
Palmar
Plantar
Linear
Nail involvement
Actinic
Vesicular
Hemorrhagic
Spinous follicular
Perforating
Purpuric
Figure 27-2 Lichen nitidus. Wrist and palmar involvement with development of hyperkeratotic lesions.
Chapter 27
Figure 27-3 Lichen nitidus. A. Distinctive, circumscribed infiltrate of papillary dermis situated directly beneath thinned
epidermis. Many histiocytes mingle with lymphocytes that are enveloped by bordering rete ridges. (Hematoxylin and
eosin 40.) B. Central parakeratosis, epidermal thinning, and loss of granular layer with focus of granuloma-appearing,
inflammatory cells and reactive, finger-like extensions of epidermis. (Hematoxylin and eosin 80.)
::
Differential diagnosis of lichen nitidus is summarized
in Box 27-1.

COURSE
Lichen nitidus is typically a focal, asymptomatic,
chronic inflammatory reaction that eventually resolves
spontaneously after months to 1 year in two-thirds of
patients or, less frequently, over a few years. Rarely,
the eruption may persist indefinitely. New lesions may
continue to develop as older lesions resolve. Lesions
heal without scar formation or pigmentary abnormalities.
TREATMENT
Because the disease is asymptomatic and self-limiting,
no intervention is required in most cases. Treatment
of lichen nitidus is warranted when it is associated
with protracted pruritus, become generalized or for
cosmetic reasons.23 Topical glucocorticoids may yield
favorable results. A short course of oral glucocorticoids
may also be helpful and hasten resolution of more
extensive, generalized, or symptomatic disease.24 Psoralen and ultraviolet A light (UVA),25 UVA and UVB
phototherapy,24 astemizole,26 acitretin or etretinate,20,27
low-dose cyclosporine,28 and oral itraconazole29 have
also been used successfully when indicated for more
problematic disease. Oral retinoids and local PUVA are
effective treatments in palmoplantar type.19
Narrowband UVB could be a safe and effective treatment in generalized lichen nitidus.30,31 Tacrolimus ointment was also reported to be effective after 1 month
of therapy.32 History of exposure to tuberculosis in the
setting of lichen nitidus should be investigated and,
when appropriate, treated with antituberculous medications.33 Low-molecular-weight heparin was used
safely and successfully at weekly dose of 3 mg subcutaneously.34 Various treatment modalities are summarized in Table 27-3.
Lichen Nitidus
intermixed with few to many histiocytemacrophages

(CD68 positive), as well as epidermal Langerhans cells
and indeterminate cells (S100 protein positive). Direct
immunofluorescence examination of lichen nitidus is
usually negative.22

of Lichen Nitidus
Most Likely
Lichen planus
CD8 lymphocytes predominate
No granulomatous inflammation
Psoriasis
Plaques have silvery scale
Verruca plana
Variable in size
Verrucous surface
Fewer lesions than lichen nitidus
Less likely to involve multiple anatomic areas
Keratosis pilaris
More keratotic and scaling
Hand dermatitis
Palmoplantar involvement of lichen nitidus
Consider

Lichen spinulosus
Papular eczema
Lichen scrofulosorum
Lichenoid syphilitic lesions
Bowenoid papulosis
Sarcoidosis
Lichen amyloidosus
315
TABLE 27-3
Treatment of Lichen Nitidus
First line
Topical
Physical
Systemic
Topical steroids
Sun protection for actinic type
Topical tacrolimus
Narrowband UVB
Local PUVA
UVA and UVB phototherapy
Antihistamines
Psoralen plus UVA
Oral steroids
Oral retinoids
Cyclosporine 4 mg/kg/day
Itraconazole
Antituberculous agents
Astemizole
Enoxaparin Sodium 3 mg SC
weekly
Second line
Section 4
::
KEY REFERENCES

4. Smoller BR, Flynn TC: Immunohistochemical examination
of lichen nitidus suggests that it is not a localized papular
variant of lichen planus. J Am Acad Dermatol 27:232, 1992
5. Di Lernia V: Lichen planus appearing subsequent to
generalized lichen nitidus in a child. Pediatric Dermatol
24(4):453, 2007
Chapter 28 :: Graft-Versus-Host Disease

:: Edward W. Cowen
GRAFT-VERSUS-HOST DISEASE AT A GLANCE
Acute graft-versus-host disease (GVHD)
is a serious and potentially life-threatening
sequelae of allogeneic hematopoietic stem cell
transplantation. Skin manifestations range from
a mild, asymptomatic exanthem-like eruption
to full-thickness skin loss resembling toxic
epidermal necrolysis. Hepatic involvement
is characterized by elevated total bilirubin.
Gastrointestinal disease manifests as abdominal
pain, nausea/vomiting, and secretory diarrhea.
The most important risk factor for chronic
GVHD is a history of acute GVHD.
Traditionally, acute features present prior
to day 100 posttransplantation, and chronic
manifestations after 100 days; however,
overlap between classic acute and chronic
features may occur.
Chronic GVHD of the skin is remarkably
variable in clinical presentation. Epidermal
316
19. Thibaudeau A et al: Palmoplantar lichen nitidus: A rare

cause of palmoplantar hyperkeratosis. Ann Dermatol Venereol 131(8-9):822, 2004
23. Efstathios Rallis MD et al: Generalized purpuric lichen
nitidus. Report of a case and review of the literature. Dermatol Online J 13(2):5, 2007
31. Park JH et al: Treatment of generalized lichen nitidus with
narrowband ultraviolet. Br J Am Acad Dermatol 54:545,
2006
34. Cholongitas E et al: Persistent generalized lichen nitidus
successfully treated with Enoxaparin Sodium. Am J Clin
Dermatol 9:349, 2008
involvement may resemble lichen planus,

keratosis pilaris, or psoriasis. Sclerotic
changes may resemble lichen sclerosus,
morphea, systemic sclerosis, or eosinophilic
fasciitis.
The pathogenesis of chronic GVHD is
poorly understood and nearly every organ
system is at risk. The skin, oral mucosa
eyes, gastrointestinal tract, and lungs are
most frequently involved. In many cases,
organ system disease resembles known
autoimmune conditions.
Optimal dermatologic management of
chronic GVHD of the skin requires an
understanding of other organ involvement,
infection status, and cancer relapse risk. Close
communication with the transplant physician
and a team approach to multispecialty
management is needed.
EPIDEMIOLOGY
Graft-Versus-Host Disease
HLA-incompatibility
Patient age (elderly > adult > pediatric)
Female donor (especially multiparous)/male recipient
Stem cell source (peripheral blood > bone marrow >
cord blood)
T-cell replete graft
Unrelated donor
Donor leukocyte infusion
Interruption or rapid tapering of immunosuppression
::
BOX 28-1 Major Risk Factors

for the Development of GraftVersus-Host Disease
Chapter 28
Approximately 50,000 hematopoietic stem cell transplantation (HCT) procedures are performed worldwide each year for an expanding array of hematologic
malignancies and marrow failure syndromes, metabolic disorders, and immunodeficiencies. HCT may
utilize autologous, syngeneic, or allogeneic donor
hematopoietic stem cell (HC). During autologous
transplantation the patients own HC are returned to
the patient following preparative chemotherapy. Syngeneic transplantation is the transfer of HC between
identical twins. Allogeneic HCT (allo-HCT) is the
transfer of HC from a related (nonidentical) or unrelated donor to a recipient. Graft-versus-host disease
(GVHD) is the primary cause of nonrelapse-related
morbidity and mortality in allo-HCT and also rarely
occurs following transplantation of solid organs or
transfusion of blood products.
Transplantation regimens have advanced rapidly
since the first successful allo-HCT was performed in
1968.1 Peripheral blood, rather than bone marrow, is
now the primary source of donor HC at many transplant centers, and reduced intensity (nonmyeloablative) conditioning has permitted older patients and
others who would not tolerate myeloablative chemotherapy a chance for cure with HCT. More recently,
umbilical cord blood has gained prominence as a stem
cell source in both pediatric and adult HCT. Donor
leukocyte infusions (DLI), the administration of additional donor HC to the recipient weeks or even months
after HCT, are also frequently utilized to augment
graft-versus-malignancy effect.
These evolving trends in HCT, in conjunction with
other known donor/recipient risk variables (Box 28-1),
contribute to a wide range of reported GVHD incidence. Nevertheless, the degree of HLA-mismatch
between donor and recipient remains the single most
important predictor of GVHD.2 Acute GVHD develops
in approximately 40% of fully matched sibling donor
HCT, whereas 80% of mismatched unrelated HCT result
in acute GVHD.3,4 Risk estimates of chronic GVHD also
vary widely and confounding factors such as improving early posttransplant survival may be influencing
the apparent trend in increasing chronic GVHD incidence.5 The most significant additional risk factor for
chronic GVHD is a history of antecedent acute GVHD.5
Skin involvement is often the first indicator of acute
GVHD (81%), followed by gastrointestinal (54%) and
liver disease (50%).6 Similarly, the majority of patients
who develop chronic GVHD manifest skin symptoms at some point in their disease course. The risk
of chronic skin involvement is increased by the use of
peripheral blood HCT (PB-HCT) compared with bone
marrow HCT (BM-HCT). At one center, approximately
90% of patients who developed chronic GVHD following PB-HCT manifested skin symptoms.7 In most
published reports, the incidence of sclerotic versus
nonsclerotic chronic skin manifestations has not been
differentiated. Although sclerotic involvement is less
common than lichenoid GVHD and tends to occur
later post-HCT, sclerotic features, particularly deepseated fascial changes, may have an insidious onset,
and lichenoid involvement is not a prerequisite to
the development of sclerotic features. In one series of
196 patients post-HCT, only 7 (3.6%) developed sclerotic manifestations (mean 2.0 years after HCT).8 In a
review of 133 patients who survived at least 4 months
after allo-HCT, the 5-year cumulative incidence of sclerotic GVHD was 10.5% (15.5% among patients with
chronic GVHD). In this series, only 21% manifested
lichenoid changes prior to the onset of skin sclerosis.9 In a referral setting for patients with primarily
refractory disease at the NIH, 81/110 (74%) consecutive patients had skin involvement, 58/110 (53%) of
whom had sclerotic manifestations.10

In 1966, Billingham proposed three basic requirements
for GVHD: (1) immunocompetent transplanted cells,
(2) host antigens recognizable by the transplanted cells
and lacking in the donor, and (3) a host incapable of
mounting an immune response to the transplanted
cells.11 The immunocompetent cells are now known
to be T-cells, which target human leukocyte antigens
(HLAs) expressed on host tissues. GVHD still develops in 40% of recipients of HLA-identical grafts, however. In this setting, GVHD is due to mismatch of key
minor histocompatibility antigens (e.g., HY, HA-3).12
Tissue damage from the recipients underlying disease,
infection, and pretransplant conditioning also plays a
key role in induction of the inflammatory response
through pro-inflammatory cytokine production and
antigen-presenting cell (APC) activation.13,14
Following activation of host APCs, T-cell activation and differentiation drives the response in acute
GVHD. This appears to be primarily a Th1-driven process with massive release of interferon-, interleukin-2
(IL2), and TNF-.14 Genetic polymorphisms in tumor
necrosis factor (TNF)-, interleukin-10, interferon-,
and transforming growth factor (TGF)- have been
linked to increased risk and severity of GVHD.1517
Although many therapies for acute GVHD target IL-2
or its receptor (CD25), these approaches (calcineurin
inhibitors, daclizumab) may have the unintended
317
Section 4
::
318
consequence of adversely impacting the CD4+CD25+

regulatory T-cell population.14,18 Decreased T-regulatory cells are associated with severity of acute GVHD
and poor response to GVHD treatment.19 The final
effector phase of acute GVHD is characterized by cell
damage via cytotoxic T-cells, natural killer cells, and
soluble inflammatory mediators, including TNF-,
interferon , and interleukin-1.14
In comparison to acute GHVD, the pathophysiology
of chronic GVHD is less well understood. Features of
alloimmunity and autoimmunity and the broad spectrum of disease manifestations implicate multiple
immunological pathways beyond T-cell alloreactivity. In fact, in contrast to acute GVHD, T-cell depletion
of the graft does not necessarily reduce the incidence
of chronic disease.20 Murine models of GVHD have
demonstrated both Th1 and Th2 responses, depending
on the setting; however, these models typically demonstrate specific aspects of GVHD, but do not recapitulate the full breadth of immunological and clinical
abnormalities seen in human disease.21
The role of B-cell function in chronic GVHD has
garnered renewed interest following the success of
the anti-CD20 antibody rituximab in chronic GVHD.22
Autoantibody formation (e.g., antinuclear antibody,
anti-ds DNA antibody) is a frequent finding in chronic
GVHD, although the antibodies lack the specificity of
typical autoimmune disease. B-cells may play several
key roles in facilitating the T-cell response in chronic
GVHD. Acting as APCs, B-cells prime T-cells to
respond to minor histocompatibility antigens (mHA),
and high-titers of antibodies directed against mHA are
associated with cGVHD.23,24 Similarly, soluble levels
of B-cell activating factor of the TNF family (BAFF), a
cytokine which inhibits apoptosis of B-cells and promotes differentiation into plasma cells, correlate with
cGVHD activity. 25,26
The mechanisms responsible for chronic GVHDinduced fibrosis in the skin and elsewhere (e.g., bronchiolitis obliterans) remains uncertain. A two-phase
model has been proposed in which the innate pathway is activated through toll-like receptors, leading to
an alloreactive T-cell response. This is followed by a
fibrotic phase driven by platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR), which in
turn activates TGF-.21 TGF- is a potent profibrotic
cytokine, capable of stimulating collagen production, abrogating metalloproteinase activity, and sensitizing fibroblasts to a constitutive-activated state
via autocrine signaling.27 Furthermore, stimulatory
antibodies directed against PDGFR have been identified by one group in patients with chronic GVHD as
well as patients with systemic sclerosis.28,29 This has
led to significant interest in imatinib mesylate, a multikinase inhibitor with potent activity against PDGFR
signaling (and other receptors), for the treatment of
GVHD-related fibrosis.30,31 However, to date, detection
of PDGFR antibodies in sclerotic skin disease has not
been replicated by other groups,32 and administration
of imatinib prior to the onset of GVHD does not appear
to eliminate the risk of developing skin sclerosis.33 The
mechanism of action of imatinib therefore, remains
unclear, and other mechanisms, including T-cell
inhibition34 and inhibition of fibrosis via nonclassic

pathways downstream of TGF-, such as cellular Abelson (c-Abl) may be relevant.27
CLINICAL FINDINGS
HISTORY
Accurate diagnosis of acute GVHD requires clinicopathologic correlation. Because the skin eruption (and
histology) may be nonspecific at the time of first presentation, a careful history is invaluable. Key donor/
recipient characteristics include degree of HLA-match,
use of related versus unrelated donor, and T-cell depletion of the graft. Reduced-intensity conditioning may
delay the onset of acute GVHD symptoms beyond the
100-day period.35 The timing of neutrophil engraftment,
new medication exposures, and evidence of other organ
involvement (e.g., elevated total bilirubin, diarrhea) provide additional data for clinicopathologic correlation.
Features of acute GVHD following recent blood
transfusion should raise concern for transfusionassociated GVHD (TA-GVHD). TA-GVHD is an often
fatal sequelae of administration of cellular blood products to immunocompromised HCT recipients, and
therefore all blood products in these patients are now
irradiated. TA-GVHD may also occur following transfusion of unirradiated blood products to children with
congenital immunodeficiency, including Wiskott
Aldrich and ataxia-telangiectasia, as well as in the
immunocompetent setting. In the latter scenario,
the diagnosis may be easily missed. TA-GVHD in the
immunocompetent setting follows transfusion of an
unirradiated blood product that contains donor lymphocytes that are homozygous for the HLA haplotype
of the recipient. A history of blood product transfusion
from a relative or genetically similar population is an
important feature. For example, in Japan, the estimated
risk of randomly receiving blood from a homozygous
donor is 1 in 874.36 In this form of TA-GVHD, the donor
lymphocytes in the blood product are not recognized
as foreign, leading to a GVHD reaction similar to classic acute GVHD. Beginning 10 days after transfusion,
fever and skin rash (histologically consistent with
GVHD) develops, followed by liver dysfunction and
diarrhea. Death from pancytopenia usually occurs
within several weeks.37
As with acute disease, a new diagnosis of chronic
GVHD is best made based on history, cutaneous examination, and histology. A previous history of acute
GVHD is the single greatest risk factor for chronic
disease. Because acute symptoms may develop after
100 days posttransplant and chronic symptoms may
develop before then, the revised classification of acute
and chronic GVHD symptoms includes additional subtypes of GVHD with overlapping features or timing of
acute and chronic symptoms (Fig. 28-1).38 Recent tapering of immunosuppressant medication or DLI given to
augment the graft-versus-malignancy response are two
common triggers of skin activity. DLI, in particular may
present with an acute GVHD skin eruption consistent
Revised classification of acute and chronic GVHD
GVHD manifestation
cGVHD diagnostic feature, or

distinctive feature (if bx proven)
aGVHD feature
100 days post-HCT
Persistent
aGVHD
Recurrent
aGVHD
Additional aGVHD
feature
Delayed
aGVHD
No features of aGVHD
Overlap
syndrome
Classic
cGVHD
CUTANEOUS LESIONS
Acute GVHD initially presents with erythematousdusky macules and papules of the volar and plantar
surfaces and ears that may rapidly become a diffuse
morbilliform exanthema (Fig. 28-2A and 28-2B; Box
28-2). Very early involvement may manifest as erythema limited to hair follicles (Fig. 28-2C). Pruritus is
variable and is not useful to distinguish acute GVHD
from other causes. Erythroderma may develop, and, in
severe cases, spontaneous bullae with skin sloughing

resembling toxic epidermal necrolysis. Widespread
erythrodermic involvement, particularly the presence
of skin sloughing portends a very poor prognosis. In
contrast to chronic disease, postinflammatory pigmentary changes following acute GVHD are uncommon.
In appreciation of the tremendous variability in clinical presentation of chronic skin GVHD, it is no longer
useful to dichotomize chronic GVHD of the skin into
either lichenoid or sclerodermoid categories. In
the transplant community, the term lichenoid has
been utilized to denote any involvement of the skin
in which erythema or scaling is present; however,
with acute GVHD rather than the papulosquamous

eruption of chronic disease (Fig. 28-2D). Cutaneous
or systemic infection may also induce a flare of skin
GVHD, as will drug exanthems, which can result in a
diagnostic challenge given the clinical and histologic
similarities between viral exanthem, drug eruption,
and GVHD.39 Important clues to sclerotic and fascial
disease includes a history of edema of an extremity, muscle cramping, decreased flexibility, and complaints of skin tightness, particularly at the waistband
and brassiere-line.10 Although GVHD in other organ
systems may not necessarily flare in synchrony with
skin involvement, the presence of other organ system
involvement is helpful when the cutaneous features
are nondiagnostic. Common GVHD symptoms include
oral and ocular sicca and oral pain, particularly with
spicy foods. Also common, but less specific, are symptoms of fatigue, poor appetite, and weakness. Dysphagia may indicate the presence of esophageal strictures
or webbing. Bronchiolitis obliterans manifests as dry
cough, wheezing, and dyspnea, but requires pulmonary function tests and computerized tomography (CT)
scans to rule out infection and other etiologies. Finally,
it is important to remember that despite the phenotypic
variability in chronic GVHD of the skin, not every skin
manifestation in a patient after HCT is due to GVHD,
so a careful dermatologic history to detect other possible diagnoses is prudent.
::
Figure 28-1 Revised classification of acute and chronic GVHD. (Adapted from Filipovich AH et al: National Institutes of
Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and
staging working group report. Biol Blood Marrow Transplant 11(12):945-956, 2005.)
Chapter 28
Classic
aGVHD
> 100 days post-SCT
BOX 28-2 Acute GVHD Organ

System Manifestations
SKIN

Erythema of palms, soles, ears

Perifollicular erythema
Generalized exanthem
Bullae/necrolysis
GASTROINTESTINAL

Abdominal pain
Anorexia
Ileus
Mucositis
Vomiting
Secretory diarrhea
LIVER
Endothelialitis
Pericholangitis
Cholestatic hyperbilirubinemia
319
Section 4
::
Figure 28-2 Spectrum of acute graft-versus-host skin manifestations. Acute cutaneous graft-versus-host reaction.
Erythematous macules involving the ears (A), palms (B), and soles are characteristic of early cutaneous involvement.
C. Follicular graft-versus-host disease. Perifollicular invovlement is an early manifestation of skin involvement. D. GVHDassociated necrolysis. Acute GVHD with bullae formation and skin sloughing following donor leukocyte for relapsed acute
lymphoblastic leukemia 10 months following allogeneic HCT.
320
lichenoid is a histologic pattern, not a clinical one,

and, therefore, usage of it is best reserved to pathologic
description. Futhermore, although chronic GVHD may
resemble lichen planus (Fig. 28-3), other patterns are
frequently observed, such as poikiloderma (Fig. 28-4)
and skin lesions resembling lupus erythematosus, keratosis pilaris, or psoriasis.40 Postinflammatory hyperpigmentation is common following the resolution of
epidermal involvement, particularly in darkly pigmented individuals, and may persist for many months
after the skin disease becomes quiescent.
The fibrotic changes of chronic GVHD are also
remarkably variable, and the term sclerodermoid
is an inadequate descriptor of the varied sclerotic tissue abnormalities in the dermis, subcutaneous tissue,
and fascia (Fig. 28-5). As in systemic sclerosis, an
Figure 28-4 Poikilodermic chronic GVHD. Hypopigmentation, hyperpigmentation, and erythema on the chest
and proximal arms.
Chapter 28
Figure 28-3 Lichen planus-like chronic GVHD. Reticulate

violaceous plaques with dry scale on the posterior neck
and upper back.
::
Figure 28-5 Clinical spectrum of sclerotic GVHD skin manifestations. A. Guttate white plaques on the upper back resembling lichen sclerosus. B. Morphea-like sclerotic plaques at sites of previous indwelling line placement near the clavicle
(isotopic response). C. Diffuse dermal sclerosis resembling scleroderma on the anterior torso with patchy hyperpigmentation. D. Subcutaneous fibrosis of chronic GVHD. There is prominent rippling with a firm nodular texture extending along
the medial arm resembing eosinophilic fasciitis. There is associated decreased range of motion at the elbow.
321
Section 4
::
322
edematous phase may herald the onset of skin fibrosis,

but fingers and toes are usually spared and the typical
acral to proximal progression characteristic of systemic
sclerosis is not seen in chronic GVHD. In constrast to
systemic sclerosis, facial involvement is rarely involved
in sclerotic-type GVHD. As mentioned above, fibrosis
may occur primarily in the upper dermis, through the
full-thickness of dermis, or in the subcutaneous fat and
fascia. Early superficial fibrotic involvement resembles
lichen sclerosus, often manifesting as porcelain-white
atrophic plaques on the upper back (Fig. 28-5A). A
common pattern of GVHD-associated fibrosis involves
patchy sclerotic plaques with hypo- and hyperpigmentation mimicking morphea. Sclerosis of this type may
exhibit an isomorphic response, localizing to the sites
of minor skin trauma, particularly the waistband area,
or may develop at sites of previous scar formation (Fig.
28-5B).41 Diffuse dermal involvement may result in a
pipe-stem appearance of the lower extremities with
marked reduction in limb volume and overlying shiny
hidebound skin with loss of hair resembling scleroderma
(Fig. 28-5C). Deeper involvement of the subcutaneous
fat results in irregular hyperpigmented sclerotic plaques
with intervening areas of edematous skin closely resembling deep morphea/morphea profunda.42 Bullae may
develop at sites of fibrosis, particularly on the lower
legs, as a result of dermal edema, as has been described
in bullous morphea profunda.43 Patchy hyperpigmentation (leopard spots) may be visible prior to the diagnosis of dermal sclerotic involvement.44
Primary involvement of the subcutaneous fat and
fascia results in a diffuse firm, rippled pattern to the
skin resembling eosinophilic fasciitis (Fig. 28-5D).45
Features of overlying epidermal GVHD involvement and pigmentary changes may be absent. Fascial
involvement is often most visible on the medial arms
and thighs and be accentuated by abduction and supination of the arm. Prominent grooving demarcating
fascial bundles and along the path of superficial vessels may be observed. Careful palpation of the skin is
helpful in detecting deep-seated irregularities in skin
texture and differentiation from cellulite. Dermal fibriosis or fascial involvement without overlying dermal
thickening may lead to progressive loss of joint range
of motion and contracture formation.
Nail involvement in chronic GVHD typically results
in longitudinal ridging and thin, easily broken nails.
Partial or complete anonychia and dorsal pterygium
formation may occur. Other unusual skin sequelae of
chronic GVHD include milia formation, porokeratosis,
often on the buttock area,46 angioma formation at sites
of skin sclerosis,47 nipple hyperkeratosis,48 vitiligo,49 and
alopecia, either diffuse or focal areas of alopecia areata.50
Different manifestations of sclerotic and and nonsclerotic skin disease may be present in the same
individual, making accurate quantification of disease
activity challenging. The chronic GVHD NIH Consensus Development Project provided more precise terminology for organ system involvement and defined
features specific for diagnosis of chronic GVHD in the
setting of HCT (Box 28-3). Diagnostic cutaneous features of GVHD include poikiloderma, lichen-planuslike lesions, and sclerotic skin changes.38

Acute GVHD is primarily a disorder of the skin, GI
tract, and liver (Box 28-2), typically presenting with
skin rash, new onset elevation of total bilirubin, and/
or voluminous diarrhea. By contrast, chronic GVHD
is remarkably diverse in its breadth of organ system
manifestations (Box 28-3). The most frequently affected
sites are skin and nails, oral mucosa, eyes, liver, lungs,
and marrow (usually thrombocytopenia).5 Esophageal webs/strictures, vagino-vulvar disease, myositis,
nephrotic syndrome, and pericarditis are less frequent
sequelae of chronic disease.
Mucosal disease is second only to skin involvement
in frequency in chronic GVHD. Mucoceles are common, as are erosions, lichen-planus-like changes with
Wickhams striae, and sicca symptoms. Dryness and
violaceous erythema of the lips are common. Genital involvement significantly impairs sexual function
and quality of life and may be overlooked if a specific
examination and directed questions regarding genital symptoms are not undertaken. Involvement of the
penis may induce phimosis. Vulvo-vaginal involvement presents as erythema, erosions/fissures, vestibulitis, vaginal stenosis, labial resorption, or complete
agglutination of the introitus leading to hematocolpos
(Fig. 28-6).51
Figure 28-6 Severe chronic GVHD of the vulva. The labia

minora are partially resorbed with residual vulvitis and
atrophic mucosa. Surrounding reticulate hyperpigmentation of the nonmucosal skin is consistent with postinflammatory changes of chronic GVHD.
BOX 28-3 Signs and Symptoms of Chronic GVHD Based on NIH

Consensus Criteria
::
OTHER ORGAN SYSTEM INVOLVEMENT

Cardiovascular
Pericardial effusion
Cardiac conduction abnormality
Cardiomyopathy
Ophthalmologic
Blepharitis
Cicatricial conjunctivitis
Confluent punctuate keratopathy
Keratoconjunctivitis sicca
Photophobia
Gastrointestinal
Esophageal weba
Esophageal stricture/stenosisa
Exocrine pancreatic insufficiency
Hematopoeitic
Eosinophilia
Hypo-/hypergammaglobulinemia
Lymphopenia
Thrombocytopenia
Hepatic
Elevated total bilirubin
Elevated alkaline phosphatase
Elevated transaminases
Musculoskeletal
Arthralgia
Arthritis
Edema
Myalgia
Myositis/polymyositis
Neurologic
Peripheral neuropathy
Pulmonary
Bronchiolitis obliterans +/ organizing
pneumoniaa
Pleural effusion
Renal
Nephrotic syndrome
Rheumatologic
Autoantibodies
Myasthenia gravis
Chapter 28
SKIN AND MUCOSAL INVOLVEMENT

Skin
Alopecia
Angiomatous papules
Bullae
Erythema
Hypo- or hyperpigmentation
Ichthyosis-like
Keratosis-pilaris-like
Lichen planus-likea
Lichen sclerosus-likea
Maculopapular
Morphea-likea
Poikilodermaa
Scleroderma-likea
Sweat impairment
Ulceration
Nails
Brittleness
Longitudinal ridging or splitting
Onycholysis
Pterygium unguis
Subcutaneous tissue
Fasciitisa
Panniculitis
Oral mucosa
Erythema
Gingivitis
Hyperkeratotic plaquesa
Lichen planus-likea
Mucocele
Mucosal atrophy
Mucositis
Pseudomembrane
Restriction of oral opening from sclerosisa
Ulcer
Xerostomia
Genital mucosa
Lichen planus-likea
Vulvar erosions/fissures
Vaginal scarring/stenosisa
Diagnostic features of cGVHD based on NIH Consensus Criteria. Other signs and symptoms listed are not considered sufficient to establish a
diagnosis of chronic GVHD without further testing or evidence of other organ system involvement. The most common GVHD manifestations
are shown in bold.
Adapted from Filipovich AH et al: National Institutes of Health consensus development project on criteria for clinical trials in chronic graftversus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11(12):945-956, 2005.
HISTOPATHOLOGY. The histological grading

scale for acute GVHD is shown in Table 28-1. The
hallmark feature of acute GVHD is the presence of
necrotic keratinocytes accompanied by a dermal lymphocytic infiltrate (usually sparse) and basal vacu-
olar alteration (Fig. 28-7). Early GVHD involvement

with follicular erythema correlates with involvement
limited to the hair follicle. Subepidermal cleft formation (Grade III) is indicative of more severe involvement, whereas complete separation of epidermis
323
TABLE 28-1
Histologic Grading of Acute GVHD

Histologic Grading Scheme for Acute
Cutaneous Graft-Versus-Host Reaction
Section 4
::
Grade
Description
Normal skin or changes not referable to graftversus-host disease
Basal vacuolization of the dermalepidermal

junction
Basal vacuolization, necrotic epidermal cells,

lymphocytes in the dermis and/or epidermis
Subepidermal cleft formation plus grade 2

changes
Separation of epidermis from dermis plus

grade 2 changes
Adapted from Lerner KG et al: Histopathology of graft-versus-host

reaction (GVHR) in human recipients of marrow from HLA-matched
sibling donors. Transplantation 18:367, 1974.
from dermis (Grade IV) correlates with clinical findings resembling toxic epidermal necrolysis. Grade
IV involvement may be impossible to differentiate
histologically from drug-induced toxic epidermal
necrolysis and requires careful clinical correlation.
The presence of eosinophils has been used in the past
to argue against a diagnosis of GVHD; however, the
presence of scattered eosinophils may lead to a false
diagnosis of drug eruption52 and, unless very large
numbers of eosinophils are present, this feature cannot be used as a reliable indicator of a drug hypersensitivity reaction.53 Engraftment syndrome is a poorly
understood phenomenon at the time of neutrophil
engraftment following autologous-HCT or allo-HCT
characterized by a nonspecific erythematous skin
eruption, fever, and pulmonary edema.54 Histologi-
324
Figure 28-7 Histopathologic features of acute cutaneous

graft-versus-host disease, Grade II. Inflammation of the
upper dermis is present, with extension of lymphocytes
into the dermis and interface change.
cally, it may not be possible to distinguish engraftment rash from early (Grade I) acute GVHD.
Epidermal changes in chronic GVHD may be indistinguishable from those of acute disease (Fig. 28-8A).
Acanthosis and wedge-shaped hypergranulosis may
be seen. Sclerotic involvement of the upper dermis
may resemble lichen sclerosus, with atrophy, hyperkeratosis, follicular plugging, and pale, homogenized
appearance of the upper dermis collagen (Fig. 28-8B).45
If epidermal changes of GVHD are not present, dermal
fibrosis with thickened collagen bundles and loss of
periadnexal fat involvement may be indistinguishable
from morphea/scleroderma. Subcutaneous and fascial
involvement accordingly demonstrates changes in the
fat septae and fascia, including thickening, edema, and
fibrosis. Variable lymphocytes, histiocytes, and eosinophils may be seen.45
Histology of involvement of the oral mucosa reflects
similar interface changes as those seen in epidermal
GVHD, but without associated acanthosis.55 Lymphocytic infiltration of the salivary glands resembles
changes seen in Sjgrens syndrome.
Figure 28-8 Histologic features of epidermal and sclerotic-type chronic cutaneous graft-versus-host disase. A. Histopathologic features of a lichen planus-like reaction. Acanthosis, hypergranulosis, hyperkeratosis, and pointed rete ridges
are present. The inflammatory infiltrate is less dense than that usually seen in idiopathic lichen planus. B. Sclerotic-type
GVHD. There is mild, compact hyperkeratosis or the epidermis with keratin plugging. There is hyalinization of the collagen
throughout the dermis with loss of appendegeal structures.
LABORATORY TESTS
Suspicion of subcutaneous sclerotic and fascial disease

and myositis may be confirmed by magnetic resonance
imaging, particularly in cases in which definitive sclerotic changes are not observed or when a fascial or
muscle biopsy is deferred.45,59,60
See Box 28-4.
COMPLICATIONS
::
Skin erosions and ulceration due to chronic GVHD

may lead to secondary infection. Sclerotic changes
resulting in restriction in joint function lead to functional disability and joint contractures. Restrictive lung
disease may result from sclerotic involvement of the
torso. HCT survivors are at increased risk for melanoma61 and nonmelanoma62 skin cancer due to previous exposure to ionizing radiation, GVHD-associated
immunodysregulation, and immunosuppressive treatment for GVHD. The risk of cutanous squamous cell
carcinoma (SCC) may also be increased by long-term
treatment with voriconazole, a potent photosensitizer,
which may be employed for antifungal treatment or
prophylaxis.63 Multiple SCC have also been reported
after PUVA for GVHD.64
Chapter 28
Diagnosis of acute GVHD skin involvement is based

on histopathologic correlation, particularly exclusion
of drugs and infectious causes. The presence of a normal leukocyte count is indicative of engraftment but
no specific laboratory testing is diagnostic. Liver function testing and total bilirubin levels and quantification of diarrhea volume are used in conjunction with
skin disease to stage the disease (Table 28-2).
Although autoimmune markers are seen in the
majority of patients after alloHCT, their presence is
generally not specific for the development of chronic
GVHD manifestations, with the possible exception
of sclerotic disease. In one study, elevated ANA titer
was detected in 70% of patients with limited chronic
disease and 94% of patients with extensive chronic
disease compared to 23.5% of patients who did not
develop chronic GVHD.56 The presence of more than
one autantibody also correlated with risk of extensive
disease (p = 0.04); however, ANA titer does not correlate with disease severity. In this study, the presence
of a nucleolar ANA pattern also indicated a potential association with sclerotic disease (p = 0.06).56 In
another multivariate analysis limited to sclerotic-type
chronic GVHD patients, the presence of autoantibodies and serum eosinophilia were both associated with
increased risk of sclerotic-type chronic GVHD.9
Identifying specific biomarkers of disease activity
is an area of research emphasis in acute and chronic
GVHD.57 Plasma levels of elafin, a protease secreted
in response to IL-1 and TNF-, was recently identified
as a candidate marker capable or differentiating acute
GVHD skin from rashes of other etiologies. In this
study, immunohistochemical staining of skin biopsies
for elafin also discriminated acute GVHD from drug
exanthem, suggesting a potential diagnostic application of this biomarker.58
SPECIAL TESTS (INCLUDING

IMAGING STUDIES)
Although the presence of GVHD is associated with
decreased risk of malignancy relapse, GVHD is also a
cause of significant morbidity and mortality, particularly
TABLE 28-2
Staging and Grading of Acute GVHD Clinical and Laboratory Manifestations

Stage
Skin
Liver
Gut
Rash <25% BSA
Bilirubin 2 mg/dL to <3 mg/dL
Diarrhea 5001,000 mL/day or

persistent nausea
Rash 25%50% BSA
Bilirubin 36 mg/dL
Diarrhea 1,0001,500 mL/day
Rash >50% BSA
Bilirubin 615 mg/dL
Diarrhea >1,500 mL/day
Erythroderma w/bullae formation
Bilirubin >15 mg/dL
Severe abdominal pain with or

without ileus
Stages 12
None
None
II
Stage 3
Stage 1
Stage 1
Stages 23
Stages 24
Grade
III
IV
Stage 4
Stage 4
Adapted from Przepiorka D et al: 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15(6):825-828, 1995.
325

of Graft-versus-Host Disease
BOX 28-5 Systemic Treatment of

Acute Cutaneous GVHD
Acute GVHD
FIRST LINE
Corticosteroids (IV methylprednisone 2 mg/kg/
day)112,113
Tacrolimus (usually on prophylactic treatment)114
Cyclosporine (usually on prophylactic treatment)115
Drug eruption
Rash of engraftment syndrome
Transient acantholytic dermatosis
Toxic epidermal necrolysis (for Stage IV disease)
Viral exanthem
Chronic GVHD
Section 4
::
326
Epidermal involvement
Drug eruption
Lichen planus
Psoriasis
Sclerotic involvement
Eosinophilic fasciitis
Lichen sclerosus
Morphea
Nephrogenic systemic fibrosis
Radiation dermatitis
Systemic sclerosis
in patients who develop refractory disease. A number of

systemic risk factors portend a poor prognosis, including a history of progressive involvement from acute to
chronic GVHD,65 thrombocytopenia (fewer than 100,000
cells/mL),66 elevated bilirubin,67 older age, gastrointestinal symptoms, and lack of response to therapy at 6
months.68 The two primary dermatologic features associated with poor prognosis are extensive (>50%) skin
involvement69 and lichenoid skin histology.65
TREATMENT
MANAGEMENT OF ACUTE GVHD
Treatment of acute GVHD is usually undertaken in
the hospital, given the proximity to the date of HCT
and the need for close observation. Patients with mild
(Grade I) skin involvement without hepatic or gastrointestinal symptoms may respond to high-potency
topical steroids. However, more severe skin involvement or the presence of internal organ involvement
necessitates treatment with systemic corticosteroids
(methylprednisone 2 mg/kDa/day). Patients with
skin sloughing require meticulous skin care, infection
surveillance, and fluid management similar to toxic
epidermal necrolysis. Approximately 50% of patients
respond to systemic corticosteroidshowever, those
who require salvage therapy typically receive one or
more immunosuppressive agents, including calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil, and sirolimus, which are of variable
success (Box 28-5).70 Phototherapy (PUVA,71 NB-UVB,72
SECOND LINE

Mycophenolate mofetil116,117
Etanercept74,118
Infliximab119,120
Denileukin diftitox121
Pentostatin122
Antithymocyte globulin123,124
OTHER SALVAGE THERAPY

Extracorporeal photopheresis125,126
Alefacept127
Mesenchymal stem cell therapy76,77
Anti-CD25 antibodies
Daclizumab128
Inolimomab129
Baxiliximab130,131
ABX-CBL (anti-CD147)132
Anti-CD3 (visilizumab)133
Anti-CD52 (alemtuzumab)134,135
Psoralen plus UVA (PUVA)71,136
Narrowband-UVB72
Ultraviolet A1 (340400 nm)73
UVA173) has also been used in small series for acute

GVHD, but is logistically challenging in the inpatient
setting and should be administered cautiously to avoid
inducing erythema.
Extracorporeal photopheresis (ECP), anti-TNF
therapy, and multipotent mesenchymal stromal cells
(MSC) are additional strategies that have shown recent
success for the treatment of acute skin GVHD. In a
review of salvage therapies for acute GVHD, 60%
76% of patients with skin involvement responded to
ECP; however, responses decreased with increasing
skin severity.70 Levine et al74 demonstrated complete
remission (CR) of skin symptoms in 81% of patients
treated with steroids and etanercept compared to steroids alone (CR = 47%). Similarly, infliximab has also
shown variable success in acute treatment-refractory
skin GVHD (33%60%).70 Finally, preliminary reports
of the success of MSC, bone marrow-fibroblast derived
cells capable of differentiation into adipocytes, chondrocytes, and osteoblasts, in patients with refractory
acute GVHD has generated significant interest in this
novel therapy.7577 In a 2008 study, 39/55 (71%) of participants with steroid-resistant acute GVHD sustained
a complete or partial response to MSC infusion.77
Responses were seen regardless of MSC source (HLAmatched, haploidentical, or third party unmatched
donors), and immunogenicity was not observed. The

immunomodulatory mechanism of MSC is unclear,
but may be through induction of regulatory T-cells.78,79
Several MSC studies are underway for the treatment
or prophylaxis of acute and chronic GVHD as well as
for other chronic conditions, including Crohns disease, multiple sclerosis, systemic sclerosis, and lupus
erythematosus.
MANAGEMENT OF CHRONIC GVHD
TABLE 28-3
Systemic Treatment of Chronic Cutaneous GVHD

Type of Chronic Skin
Involvement
Treatment
First line
Prednisone PO 1 mg/
kg/day
Tacrolimus
Cyclosporine
Sc137
Ns137
Sc138
Not specified139
Ns138
Sc100,140
Ns100,140
Nsa141
Sc117
Ns117
Sc142
Sc143,144
Ns142
Ns143,144
Sc22,145
Scb89
Sc91
Ns90
Sc97,98
Ns22,145
Nsb89
Ns91
Not specified146
Sc147
Sc30,31
Sc44
Sc149
Not specified118,150
Sc104
Sc107
Not specified151,152
Not specified153
Sc154
Ns98
Other
Daclizumab
Methotrexate
Imatinib mesylate
Azathioprine
Clofazamine
Etanercept
Etretinate
Mesenchymal stem
cells
Thalidomide
Alefacept
Total lymphoid
irradiation
Nonsclerotic
::
Second line
Extracorporeal
photopheresis
Hydroxychloroquine
Mycophenolate
mofetil
Pentostatin
Rapamycin
(sirolimus)
Rituximab
PUVA
UVB
NBUVB
UVA1
Sclerotic
Features
Chapter 28
Among the myriad topical, phototherapy-based, and

systemic treatments that have been used in patients
with chronic GVHD who cannot be tapered from systemic corticosteroids or who are steroid-refractory, no
single treatment has demonstrated proven superiority
(Table 28-3). Determination of a preferred second-line
agent has been complicated by poor understanding
of the disease process and a lack of high-quality clinical trials. The need to spur clinical trial development
in the field of chronic GVHD was acknowledged by
the chronic GVHD NIH Consensus Project, which
included a standardized system of organ system
assessments and recommendations for clinical trial
design80 Unfortunately, validated measures of cutaneous disease activity are still lacking, and the most common skin assessments tools, body surface estimates
and use of Rodnan scoring (derived from systemic
sclerosis trials) are not applicable for all manifestations
of chronic GVHD skin activity.81 Ideally, dermatologic
collaboration in future therapeutic trials will permit
better quantification of cutaneous disease response.
The dermatologist should play a key role in the
multidisciplinary approach to chronic GVHD management, beginning with careful assessment of the subtype and extent of skin involvement. Together with an
understanding of other organ system activity, infection
risk, relapse risk, and GVHD prognostic risk factors,
a decision regarding the appropriateness of topical,
physical (e.g., phototherapy), and systemic therapy
can then be made. If systemic therapy is prescribed by
the transplant physician, periodic dermatologic monitoring is advised to differentiate adverse drug reactions or other new skin disease from GVHD,82 to assess
cutaneous disease response, and to monitor for infection and skin malignancy.
Nonsclerotic lichen-planus like and other papulosquamous chronic GVHD manifestations may respond
well to topical steroid treatment and serve to reduce
exposure to systemic immunosuppression.83 Topical
emollients and antipruritic agents may provide relief
of pruritus and skin irritation; however, oral antihistamines may worsen sicca symptoms in patients with
oral and ocular dryness. Choi and Nghiem84 described
a response to topical tacrolimus 0.1% ointment in 13/18
patients with chronic GVHD; however, all patients
eventually required other therapy to control their
skin disease. Subsequent reports have also described
response to topical pimecrolimus 1% cream.85,86 Topical
calcineurin inhibitors are particularly useful for treatment of areas at high risk of skin atrophy, such as the
face (including the lips) and intertriginous surfaces.
Ns147,148
Ns149
Ns154
Sc: sclerotic skin disease; Ns: Nonsclerotic skin disease.

a
Sclerotic and nonsclerotic disease treated in this study; however,
sclerotic disease did not respond.
b
Bath-PUVA.
Topical tacrolimus may not be tolerable at sites of significant inflammation or erosions. Hydroquinone in
combination with tretinoin and topical dexamethasone
has anecdotally been reported to improved periocular
lichenoid type chronic GVHD and hyperpigmentation.87 Topical tretinoin may also benefit milia formation following GVHD skin activity.
Phototherapy may be of benefit for both sclerotic
and nonsclerotic chronic GVHD, but data are limited
to anecdotal cases and a small number of noncontrolled case series. Vogelsang88 described improvement
in 31/40 patients treated with PUVA.88 Three patients
in this series had skin sclerosistwo demonstrated
327
Section 4
::
328
transient benefit, but developed severe phototoxicity,

and the third did not respond to treatment. Smaller
series with PUVA-bath (6 patients),89 narrow-band
UVB (10 patients, pediatric),90 and UVB (5 patients),91
have also described chronic GHVD responses, primarily in patients with lichenoid disease. Over the last
several years, however, there has been growing experience with UVA1 for sclerotic skin conditions, suggesting potential application in chronic GVHD. Longer
wavelength UVA1 (340400 nm) does not require
psoralen ingestion/topical application and penetrates
deeper into the dermis than full spectrum UVA. Several reports have described skin softening following UVA1 treatment of lichen sclerosus,92 localized
morphea,9395 and sclerotic-type GVHD.73,9698 Wetzig
et al73 used medium-dose UVA-1 phototherapy in seven
patients with lichenoid GVHD and three with sclerotic
GVHD. All three patients with sclerotic GVHD demonstrated partial response or improvement. Stnder
et al97 described softening of skin lesions, improved
joint mobility, and healing of skin erosions in five adult
patients with medium-dose UVA-1 and one child
treated with low-dose UVA-1. Calzavara Pinton et al98
described five patients with sclerotic involvement
treated with MD UVA-1 therapy leading to complete
resolution in three patients and partial response in two
patients. UVA-1 may accentuate pigmentary abnormalities.99 Although UVA-1 is not yet widely available
in the Unites States, it appears to be well tolerated,
acceptable for pediatric use,96 and is not associated
with persistent photosensitivity or potential gastrointestinal issues that may occur with oral psoralen use.
Phototherapy may be appropriate for patients
with limited epidermal or sclerotic disease in whom
systemic therapy is not otherwise warranted (e.g.,
without internal organ system involvement), or in
whom systemic immunosuppressive therapy is contraindicated (e.g., active infection); however further
controlled trials are needed to directly compare phototherapy modalites and to determine the optimum
dose and treatment schedule. Skin cancer risk assessment and concurrent use of photosensitizing medications should also be considered. Multiple squamous
cell carcinomas have been reported following PUVA
treatment for chronic GVHD 64 and the risk of melanoma is elevated in patients following HSCT.61 Photosensitizing medication use is common, including
voriconazole therapy, which may further increase the
risk of squamous cell carcinoma formation in the setting of chronic GVHD.63
Extracorporeal photopheresis (ECP) is another
option for patients with cutaneous disease, particularly patients with extensive or sclerotic involvement.
During ECP, the white cell compartment of the blood
is removed from the patient via pheresis, mixed with
8-methyoxypsoralen, irradiated with UVA light, and
then returned to the patient. In a retrospective review
of 71 chronic GVHD patients who were treated with
ECP, 59% of patients with cutaneous involvement
responded, including 67% of those patients categorized as sclerotic involvement.100 ECP may be particularly useful for patients with deep-seated sclerotic
involvement of the subcutaneous tissue and fascia.
Although GVHD-related fasciitis resembles eosinophilic fasciitis (EF), in contrast to EF, it does not
respond well to steroid therapy and may result in significant long-term functional disability. Several case
reports describe successful use of ECP for EF,101 and
GVHD-related fasciitis.41,102,103 ECP is a time-consuming procedure and requires a dedicated pheresis center which is not available at all medical facilities. As
with phototherapy, the optimal frequency and duration of ECP treatment is unclear. Typically, intensive
treatment (2 weekly or every other week) is initiated,
followed by an attempt to decrease frequency if a
response is achieved.
Limited data are available supporting the use of systemic retinoids for chronic GVHD. Marcellus et al104
reported improvement in 20/27 evaluable patients
with sclerotic disease treated with etretinate; however,
six patients could not tolerate the treatment due to
scaling or skin breakdown. Ghoreschi et al105 described
PUVA-bath treatment in 14 patients with sclerotic-type
GVHD, five of whom received concurrent treatment
with isotretinoin 1020 mg/daily. Overall improvement was reported in 7/14 patients; however, skin
ulceration was a significant issue in both PUVA-bath
only and combination treatment groups, and the small
sample size precluded statistical comparison between
groups.105 Further prospective studies are needed to
determine the tolerability and efficacy of systemic retinoid therapy.
Imatinib mesylate, a multikinase inhibitor with activity against bc-abl, c-kit, PDGFR, and other kinases, has
been reported to benefit patients with sclerotic GVHD
in a small number of case reports.30,31,106 The drug is
generally well tolerated in the setting of treatment for
chronic myelogenous leukemia; however, the tolerability and efficacy of the drug in chronic GVHD is an
area of ongoing clinical trial investigation. Common
side effects include peripheral and periorbital edema,
myalgia, and fatigue. Second generation agents with
similar targeted tyrosine kinase inhibitory activity
(nilotinib, dasatinib) also hold potential as therapeutic
options for sclerotic disease, as does the use of MSC,
based on the experience with acute GVHD. Recently, a
single case of sclerotic-type GVHD was reported with
a response to MSC therapy.107
TREATMENT OF CHRONIC ORAL

AND VULVO-VAGINAL DISEASE
Limited oral mucosal disease can be controlled with
application of high-potency topical corticosteroid gel
(fluocinonide gel 0.05%, clobestasol gel 0.05%). Refractory lesions may respond to intralesional triamcinolone injection (0.30.4 mL/L cm2).83 Topical application
of tacrolimus 0.1% ointment may also be used;108 however, systemic absorption has been reported109 and,
therefore, serum tacrolimus levels are reasonable following initiation of intra-oral treatment. Generalized
oral disease can significantly impair oral intake and
quality of life and often result in the need for systemic
intervention. Corticosteroid rinses (dexamethasone
0.5 mg/mL; prednisolone 15 mg/mL) are beneficial

PREVENTION
GVHD prevention begins prior to transplantation
with the selection of the most closely HLA-matched
donor, the GVHD prophylaxis regimen and, in some
cases, manipulation of the T-cell content of the graft.
T-cell depletion is accomplished through ex vivo T-cell
negative selection or enrichment of the CD34+ stem
cell population, or through in vivo treatment with
anti-T-cell therapy. The benefits of T-cell depletion,
however, are offset by higher rates of graft failure,
cancer relapse, and infection.14 Prophylactic immunosuppressive therapy is initiated concomitantly with
the administration of the hematopoietic graft, but, as
with T-cell depletion, such therapy must be balanced
with potential for diminished graft-versus-leukemia/
lymphoma effect and long-term infection risks. In general, available strategies for the prevention of acute
GVHD are rarely effective in the prevention of chronic
GVHD, emphasizing the distinct pathophysiology of
these two GVHD manifestations. Ideally, personalized
14. Ferrara JLM et al: Graft-versus-host disease. The Lancet

373(9674):1550-1561, 2009
38. Filipovich AH et al: National Institutes of Health consensus development project on criteria for clinical trials in
chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant
11(12):945-956, 2005
40. Hymes SR et al: Cutaneous manifestations of chronic
graft-versus-host disease. Biol Blood Marrow Transplant
12(11):1101-1113, 2006
45. Schaffer JV et al: Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease:
Expanding the sclerodermoid spectrum. J Am Acad Dermato 53(4):591-601, 2005
80. Pavletic SZ et al: Measuring therapeutic response in
chronic graft-versus-host disease: National Institutes of
Health Consensus Development Project on Criteria for
Clinical Trials in Chronic Graft-versus-Host Disease: IV.
Response Criteria Working Group report. Biol Blood Marrow Transplan 12(3):252-266, 2006
83. Couriel D et al: Ancillary therapy and supportive care of
chronic graft-versus-host disease: National institutes of
health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary
Therapy and Supportive Care Working Group Report.
Biol Blood Marrow Transplant 12(4):375-396, 2006
KEY REFERENCES
::
immunogenomics will evolve to allow careful titration

of T-cell graft content and prophylactic immunosuppression to maximize graft acceptance and graft-versus-leukemia effect and at the same time minimize
infection risk and other complications associated with
long-term immunosuppression.
Similar to solid-organ transplantation, skin cancer
screening and patient education regarding photoprotective measures is a key preventive strategy in
patients with chronic GVHD.83 Patients are also at
elevated risk of systemic infection, and therefore,
implementation of preventive infectious disease recommendations and careful monitoring for cutaneous
infection, particularly in patients with chronic skin
erosions/ulcerations, is prudent.83 Finally, patient
education regarding early signs of skin sclerosis
and fascial involvement, including skin tightness,
edema, muscle cramping, and range of motion
restriction, may facilitate early diagnosis and initiation of treatment.
Chapter 28
for widespread involvement and should be swished in

the mouth 46 minutes 46 times daily.83 Cyclosporine
and azathioprine rinses may also be used for refractory disease, but require pharmacy compounding. As
mentioned above, patients with salivary gland disease
should avoid oral antihistamines as well as other xerogenic medications (SSRIs, tricyclic antidepressants).
Dental hygiene is very important in patients with
decreased salivary function and home fluoride treatment is frequently recommended. Salivary stimulants
(e.g., sugar-free gum) and sialogogue therapy (cevimeline, pilocarpine) are recommended for patients with
severe salivary gland dysfunction.83 Although sclerotic
involvement of perioral skin involvement is uncommon, in this setting aggressive systemic therapy is
indicated.
Genital erosions and fissures associated with chronic
vulvo-vaginal disease may be treated with clobetastol
proprionate ointment nightly, which should be tapered
to a maintenance level of 23 times weekly. If estrogen is not contraindicated, hormone replacement via
topical cream, vaginal ring, or oral replacement may
improve genital skin integrity. Limited vaginal scarring/synechiae can be treated with dilators or manual
lysing; however, thick vaginal scarring may require
surgical intervention.110
329
Chapter 29 :: S
kin Disease in Acute and Chronic
Immunosuppression

:: Benjamin D. Ehst & Andrew Blauvelt
SKIN DISEASE IN ACUTE AND CHRONIC
IMMUNOSUPPRESSION AT A GLANCE
Section 4
::
330
Skin manifestations in patients who have

hematologic malignancies, have undergone
bone marrow transplantation, or are
immunosuppressed by drugs are common
and varied.
Many of these skin diseases occur in
immunocompetent individuals as well.
In patients with acute immunosuppression,
infections occur that are normally controlled
by neutrophils and macrophages.
In patients who have long-term
immunosuppression, T-cell function is
impaired and skin diseases are often similar
to those seen in patients with human
immunodeficiency virus infection.
Salient dermatologic features particularly
associated with immunosuppression are
important diagnostic signs and indicators for
therapy.
Impairment of the bodys immune system results from

a variety of causes, including natural aging, ultraviolet radiation, diabetes, malnutrition, cancer, and iatrogenic suppression. While few skin conditions appear
solely in immunocompromised individuals, clinical
presentations may be morphologically atypical, follow
unusual clinical courses, or prove harder to treat than in
individuals with intact immunity. This chapter focuses
on dermatologic manifestations in immunosuppressed
patients without human immunodeficiency virus
(HIV) disease, predominantly in those with immunosuppression induced by drugs, conditions surrounding solid organ and bone marrow transplantation, and
hematologic malignancy. Skin manifestations of HIV
disease are described in Chapter 198. Other chapters
cover graft-versus-host disease (see Chapter 28), skin
signs associated with primary immunodeficiency disorders (see Chapter 143), and detailed side effects of
medications, including corticosteroids, cancer chemotherapeutic agents, immunosuppressants, and cytokines (see Chapters 224, 227, 233, and 234). The salient
clinical features particularly associated with immunosuppression are emphasized here.
While a variety of inflammatory skin diseases
and paraneoplastic processes occur in the setting of
immunosuppression, infections, and malignancy are

most commonly seen and are discussed herein. When
approaching an immunocompromised patient, it is
helpful to determine the time frame of the immune
loss as well as the specific immune defect. This chapter is divided into two major subsections based on
this concept: acute immunosuppression and chronic
immunosuppression. When patients are acutely immunosuppressed, usually from iatrogenic ablation of the
immune system or from acute leukemia, infections
occur that are normally controlled by innate immunity,
which typically involve neutrophils and macrophages.
In chronically immunosuppressed individuals, such as
organ transplant patients and those taking corticosteroids on a long-term basis, T-cell function is impaired,
and diseases will often be similar to those observed
in HIV disease. Thus, it is helpful to understand the
underlying immune defects associated with the medical conditions of each patient (Table 29-1), because it
helps to focus the history taking and physical examination toward skin manifestations of specific pathogens.
In ill-immunosuppressed patients, disease often
manifests in the skin. Appropriate evaluation and
diagnosis of skin lesions are critical to the overall
health of these individuals, because the skin is often a
window to more severe systemic illness. In particular,
unusual presentations of infection with typical pathogens and infections with rare opportunistic pathogens
are common in these patients. Diagnosis is also made
more difficult by the variety of organisms that share
similar morphologies and the wide variety of morphologic presentations of a single organism (Table 29-2).
This makes prompt clinical evaluation and extensive
use of skin biopsy and culture necessary to make an
accurate diagnosis and initiate prompt treatment to
obviate significant morbidity and mortality.
ACUTE IMMUNOSUPPRESSION
The prototype of an acutely immunosuppressed
patient needing dermatologic evaluation is the neutropenic patient undergoing chemotherapy around the
time of hematopoietic transplantation. Pancytopenia
and neutropenia in particular predispose to invasive
infections caused by gram-negative and -positive bacteria and the fungal organisms Candida and Aspergillus.1 These complications from many cancer therapies
often pose a more immediate threat to survival than
the malignancy itself. In the past two decades, overall
mortality due to infection among patients undergoing
hematopoietic transplantation has decreased significantly with the use of better prophylaxis and nonmyeloablative regimens, but still represents an ongoing
risk to survival. The causes of infection-related death
TABLE 29-1
Opportunistic Infections that are Commonly Associated with Specific Underlying Immune Defects
Common Bacterial
Pathogens
Common Viral
Pathogens
Common Fungal
Pathogens
Defective cellmediated immunity
Organ transplantation,
metastatic cancer, Hodgkin
disease, glucocorticoid, or
cyclosporine therapy
Listeria, Salmonella, Nocardia,

Mycobacterium aviumintracellulare, M. tuberculosis,
Legionella
Cytomegalovirus,
herpes simplex
virus, varicella
zoster virus
Candida,
Cryptococcus,
Histoplasma,
Coccidioides
Defective humoral
immunity
Multiple myeloma, chronic

lymphocytic leukemia
Streptococcus pneumoniae,
Haemophilus influenzae,
Neisseria meningitidis
Enteroviruses
Neutropenia
Cancer chemotherapy, acute

leukemia, adverse drug
reaction
Aerobic Gram-negative
bacteria; Staphylococcus
aureus, Streptococcus viridans,
Staphylococcus epidermidis
Herpes simplex
virus
Candida, Aspergillus
Defective
neutrophil function
Chronic granulomatous
disease, myeloperoxidase
deficiency
Catalase-positive bacteria:
S. aureus, Escherichia coli
Candida
Hyposplenism
Splenectomy, hemolytic
anemia
S. aureus, Streptococcus
Candida
Defective
complement
components
Congenital or acquired
deficiencies
S. pneumoniae (C2, C3, C5

alternate), H. influenzae (C2,
C3, alternate), S. aureus (C5),
Enterobacteriaceae (C5),
Salmonella(alternate),
N. meningitidis (C6C8)
Skin barrier
disruption
Intravascular catheters,
decubitus ulcers, burns
Staphylococcus, M. fortuitum,
Gram-negative bacteria,
anaerobes
Candida, Aspergillus,
Mucor
::
Usual Conditions
Cutaneous Morphologies and Associated Organisms in Immunosuppressiona
Bacteria
Pseudomonas aeruginosa
Streptococcus viridians
Staphylococcus sp.
Aeromonas hydrophilia
Nocardia spp.
Vibrio vulnificus
Fungi
Aspergillus sp.
Zygomycetes organisms
Fusarium sp.
Cryptococcus neoformans
Histoplasma capsulatum
Coccidioides immitis
Viruses
Herpes simplex virus
Varicella zoster virus
Cytomegalovirus
a
Ecthymatous
Lesions
Morbilliform
Eruption
X
X
X
X
X
X
Vesicles
Erythemas
(Cellulitic
Patches and
Plaques)
Ulcers
Skin Disease in Acute and Chronic Immunosuppression
TABLE 29-2
Organism
Chapter 29
Immune Defect
X
X
X
X (facial)
X
X
X (facial)
X (necrotic)
X (necrotic)
X
X
X
X (mucosal)
X
X
X
X
X (mucosal)
X (hemorrhagic)
X
X
X
Each organism has a wide variety of presentations, and not all are included in this table.
331
have remained relatively stable, with death due to

bacterial infections being the most common (36%),
followed by deaths due to infection by viruses (31%),
fungi (28%), and parasites (5%).2,3 Infections in the
acute period following solid organ transplantation are
less opportunistic and tend to reflect the usual nosocomial pathogens associated with surgical procedures
and hospitalization.4
BACTERIAL INFECTIONS
Section 4
::
332
Bacteria are responsible for most infections during

acute neutropenic episodes. Empiric antimicrobial
therapy for fever and neutropenia was first introduced
in the 1970s when 60%70% of infections were due to
Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species. Dramatic shifts
have occurred since that time, such that over 50% of
bacterial infections in cancer patients are now caused
by Gram-positive organisms, and 75%80% in patients
that are bacteremic.5,6 The use of indwelling intravascular catheters, medications predisposing to mucositis, and prophylactic fluoroquinolones are all thought
to play a role in the shift to Gram-positive organisms,
such as coagulase-negative staphylococci, Staphylococcus aureus, Enterococcus species, and viridians group
streptococci.7 The emergence of drug-resistant organisms, including methicillin-resistant Staphylococcus
aureus and vancomycin-resistant Enterococcus, as well
as polymicrobial infections also complicates the situation.6
Routine cellulitis from staphylococcal and streptococcal organisms is a common manifestation of skin
infection in the acutely immunocompromised host.
Muted clinical signs and symptoms can be found
in this population, so care must be taken to rule out
deeper involvement as occurs in necrotizing fasciitis.8 Bacteremia may result from skin and soft-tissue
infections such as folliculitis, furuncles, and wound
infections. Bone marrow transplant patients and other
patients with neutropenia are prone to streptococcal
bacteremia and may develop facial flushing, a widespread erythematous, petechial or purpuric eruption
of macules and papules, and desquamation of the
palms and soles.9 Staphylococcal scalded-skin syndrome, which typically occurs in children (see Chapter
177), can occur in immunosuppressed adults.10
Ecthyma gangrenosum is one of the more specific
clinical signs of bacteremia and is characterized by a
painful erythematous to dusky nodule or plaque that
rapidly develops a central pustule or hemorrhagic
vesicle, followed by necrosis (Fig. 29-1). The groin,
perianal area, and axillae are the most common locations. There may be one or many lesions. Classically
described in patients with Pseudomonas septicemia, it is
now recognized that other bacterial and fungal organisms, including S. aureus, Aeromonas hydrophilia, Serratia marcescens, K. pneumoniae, E. coli, Aspergillus, and
Mucor species, can also cause similar lesions.11,12 Necrosis is secondary to underlying focal vasculitis, which
can be observed in skin biopsy specimens. Diagnosis
is made by culture of the organism from skin or blood.
Figure 29-1 Ecthyma gangrenosum secondary to Pseudomonas aeruginosa infection in a bone marrow transplant patient.
Patients with neutropenia, cystic fibrosis, or extensive burns are particularly susceptible to systemic P.
aeruginosa infection (see Chapter 180).13 The mortality
rate of P. aeruginosa bacteremia in transplant patients is
high at upwards of 40%.14 Other cutaneous manifestations of P. septicemia may appear initially as grouped
vesicles, cellulitis, subcutaneous nodules, petechiae,
purpura, or folliculitis.15 Progression to ulcerative and
necrotic lesions that are more characteristic of ecthyma
gangrenosum may occur. Primary cutaneous infection, usually at the site of a medical procedure, can
also cause ecthyma gangrenosum-like lesions. As is
common with other infections in neutropenic patients,
primary lesions can lead to bacteremia and should be
treated aggressively.
FUNGAL INFECTIONS
In the acute transplant setting, invasive fungal infections are less common than bacterial infection, but
cause much greater mortality. Mortality rates range
from 40% to close to 100%, especially when treatment
is delayed.16 Prolonged neutropenia is a significant
risk factor and recovery from disseminated fungal
infections is rare unless neutropenia resolves. Candidiasis and aspergillosis represent the two most common invasive fungal infections that occur in patients
who are undergoing cytotoxic chemotherapy or stem
cell transplantation or who have acute myeloproliferative disorders.17 However, they are not unique to the
neutropenic patient and are encountered in settings
such as surgical and neonatal intensive care units,
and in patients with cell-mediated immune dysfunction such as those undergoing long-term immunosuppression after solid organ transplantation. Additional
risk factors for opportunistic fungal infection include
hyperalimentation, antibiotic use, hyperglycemia,
corticosteroid use, and central venous catheter use.
Other fungal organisms causing infection in hosts
with acute neutropenia include Trichosporum species,
Fusarium species, and organisms in the Zygomycetes
class.18
CANDIDIASIS.
ASPERGILLOSIS. While aspergillosis remains the

second most common cause of opportunistic fungal
infection in immunosuppressed patients as a whole, it
has now surpassed Candida as the most common cause
of invasive fungal infection in hematopoietic stem cell
transplant patients and certain hematologic malignancies.15,16,20 Incidence rates vary in different immunosuppressed groups, but may reach 25% in acute leukemia
and organ transplant patients.28 Persistent neutropenia
and neutrophil dysfunction are risk factors for disseminated infection. Infection rates are also high for
patients undergoing allogeneic stem cell transplantation, and risk factors in this group are expanded to
include immunosuppression for graft-versus-host disease prophylaxis, graft-versus-host disease itself, and
other infectious diseases, especially cytomegalovirus
(CMV) infection. Invasive infection with Aspergillus
was classically seen during acute periods of neutropenia, but shifts in conditioning regimens and other
strategies to promote earlier engraftment have led to
infections after 3040 days posttransplantation.20 This
observation emphasizes that immune defenses other
than those mediated by granulocytes are important
for protection against invasive fungal infections, and
against Aspergillus infections in particular.
The incidence of invasive aspergillosis is also
increasing in nonclassic immunocompromised hosts
such as critically ill patients in the intensive care unit.
Environmental factors also clearly contribute to the
development of aspergillosis, especially in primary
cutaneous disease. These include hospital construction
(which increases spore counts in ventilation systems),
the use of indwelling catheters (which provide portals
of entry for organisms), and contamination of tape and
arm boards used to secure catheters. Mortality rates
have improved with the introduction of newer antifungal agents, but remain higher than 50% in stem cell
and organ transplant recipients.28,29
A. fumigatus is the most common cause of disseminated infections, although emerging strains of A. flavus,
A. niger, and A. terreus are accounting for more disease.20
Reports suggest that A. flavus is associated most commonly with primary cutaneous disease.30 A. terreus is
more likely to be resistant to amphotericin B, and multiple tri-azole resistant A. fumigatus has been described.28
Primary cutaneous aspergillosis often develops at
paronychial locations, sites of intravenous catheters,
or under areas of occlusion. Lesions initially appear as
::
Figure 29-2 Early cutaneous lesion of disseminated candidiasis in a neutropenic patient after chemotherapy for
non-Hodgkin lymphoma.
with a scalpel or small-diameter curette for slide examination and can be an invaluable aid in making a rapid
diagnosis in an acutely ill patient.
The treatment of choice for presumed disseminated
candidiasis is usually intravenous liposomal amphotericin B, although the new class of echinocandins
are also being evaluated.25,26 Culture results are again
important since C. glabrata, C. albicans, C. tropicalis, and
C. parapsilosis are showing resistance to fluconazole,
and C. krusei is naturally resistant.22 Newer azoles,
including voriconazole and posaconazole, are effective against Candida species, although breakthrough
infections with resistant C. glabrata have already been
reported with voriconazole (see Chapter 232).27
Chapter 29
Candidiasis (see Chapter 189)

remains the most common opportunistic fungal infection worldwide, although its role in invasive infections
is changing in certain immunosuppressed populations.19 Candida species still account for more than half
of invasive fungal infections in solid organ transplant
recipients, but aspergillosis has become more common
in hematopoietic stem cell transplant recipients.2022
Historically, most candidal infections were due to Candida albicans, but there has been an emergence of other
organisms in recent years, including C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis.17 In certain populations of patients with hematologic malignancy or stem
cell transplantation, non-C. albicans species now predominate, so awareness of local and regional patterns
of infection is important.20,23
The classic triad of fever, myalgias, and erythematous skin lesions in a septic patient not responding to
antibiotic therapy is highly suggestive of disseminated
candidiasis. Fungi may seed numerous organs, causing myositis, meningitis, endocarditis, pneumonitis,
cerebritis, esophagitis, bursitis, osteomyelitis, arthritis, and endophthalmitis. Cutaneous lesions are present in only 5%10% of individuals with disseminated
candidiasis.15,24 Lesions are characteristically painless,
nonblanching, discrete, erythematous macules, papules, or nodules (Fig. 29-2) and may develop central
purpuric, pustular, or necrotic changes. Involvement is
usually generalized, but occasional patients have very
few lesions limited to the proximal extremities. The
major clinical differential diagnosis includes infections
caused by other opportunistic pathogens and drug
eruptions. Histologically, periodic acid-Schiff-positive
yeast forms are seen in the dermis, usually in association with vascular damage and mild inflammation.
Candida can be grown from sterile skin lesion samples
in approximately 50% of patients. Tissue scrapings
from dermal skin can be obtained at the time of biopsy
333
Section 4
::
334
Figure 29-3 Ecthymatous lesion of primary cutaneous

aspergillosis in a child after bone marrow transplantation. (Used with permission from Jonathan Alexander, MD,
Portland, OR.)
small cellulitic areas and progress quickly to necrotic
ulcers with black eschars (Fig. 29-3) due to the angioinvasive nature of the organism. In patients with Aspergillus sinusitis, necrotic ulcers with black eschars can
occur in the anterior nares and on the nasal septum,
palate, and skin overlying the nasal bridge. MRI may
be useful in diagnosing the underlying sinusitis, and
prior treatment with amphotericin B does not exclude
the diagnosis as surgical treatment may be needed in
this setting.3133
Pulmonary, and less often primary cutaneous or
sinus, infection can easily become invasive and lead to
disseminated disease in immunocompromised hosts.
Patients with disseminated aspergillosis often present with unremitting fever despite antibiotic use. The
central nervous system, heart, kidneys, and gastrointestinal tract may also be involved. Cutaneous manifestations of disseminated aspergillosis are uncommon,
occurring in only 5%10% of patients.30 Lesions begin
as single or multiple painful, erythematous papules,
nodules, or plaques. They rapidly expand and develop
central hemorrhagic vesicles or bullae, then eschar. In
tissue sections, diagnosis can be made by demonstration of nonpigmented septated hyphae that branch at
acute angles. Blood culture results often are not positive or reliable because Aspergillus is found commonly
as a laboratory contaminant. Voriconazole has become
the first-line agent for treatment of invasive aspergillosis. Alternatives include caspofungin, liposomal
amphotericin B, itraconazole, and posaconazole.29 Surgical removal of isolated lesions of primary cutaneous
aspergillosis can be attempted, although this may not
necessarily prevent secondary disseminated infection
in patients with persistent neutropenia.
ZYGOMYCOSIS. Zygomycosis is the third most

common opportunistic fungal infection in immunosuppressed hosts, and may account for closer to 50% of
invasive fungal infections in certain populations such
as renal transplant patients.18 The term zygomycosis is
used to describe a group of fungal infections caused
by ubiquitous Zygomycetes found in soil and decaying matter. Infections in humans are mostly caused
by the order Mucorales (mucormycosis) and include
the genera of Mucor, Rhizopus, Absidia, Rhizomucor,
and Cunninghamella. The term zygomycosis is now preferred over mucormycosis because it is broader and
more relevant when organisms are not identifiable.
Like aspergillosis, zygomycosis is rare in individuals
without underlying immunodeficiency or predisposing conditions. Host defenses usually prevent the germination of spores unless the inoculation is too great,
as in trauma or surgical wounds. Chronic medical
conditions that affect macrophage function, such as
diabetes or corticosteroid-induced immunosuppression, lead to an inability to inhibit spore germination,
and these patients are at increased risk of infection.
Additional risk factors besides immunosuppression
include iron overload, burns, intravenous illicit drug
use, and malnourishment. Recently, the use of voriconazole in immunosuppressed patients with presumed
or diagnosed aspergillosis may account for part of the
increase in zygomycotic infections.27
Primary infection can occur by inhalation, by direct
inoculation into damaged skin, or by ingestion. Patients
with prolonged neutropenia present most often with
pulmonary disease and dissemination. The mortality rate in these individuals is very high, approaching
100%.34 Diabetic patients with sustained hyperglycemia and metabolic acidosis are predisposed to primary
rhinocerebral (66%) and pulmonary (16%) infections.35
Malnutrition and gastrointestinal disease predispose
patients to primary gastrointestinal tract infection.
Wounds and burn injuries predispose to primary cutaneous infection. Each type of primary infection can
lead to hematogenous spread and disseminated infection of numerous organs (especially the brain).
The clinicopathologic hallmarks of cutaneous zygomycosis are vascular invasion, ischemic infarction,
and necrosis, which result in painful erythematous
nodules and plaques that ulcerate rapidly and form
central black eschars.34 Clinical manifestations of primary cutaneous disease can range from necrotic papules to cellulitis, to subcutaneous nodules with rapid
extension and dissemination especially in neutropenic patients.36 Rhinocerebral zygomycosis typically
begins with facial edema and erythema (Fig. 29-4),
bloody nasal discharge, and ulceration of the palate or
nasal septum. Within a few days, necrotic skin lesions,
headache, focal neurologic defects, exophthalmos, and
altered vision develop and can progress to seizures,
stupor, coma, and death. Disseminated disease from a
noncutaneous primary site infrequently presents with
skin findings.36
Diagnosis of zygomycosis is usually made by demonstration of nonseptated hyphae (with branching at
right angles) within infected tissue. The treatment of
choice for disseminated disease is lipid preparations of
TRICHOSPORONOSIS.
VIRAL INFECTIONS
FUSARIOSIS. Fusarium is a filamentous mold found

in soil and plants belonging to the fungal group of hyalohyphomycoses. Disseminated infections are found in
severely immunocompromised individuals, whereas
immunocompetent patients have localized lesions at
areas of skin breakdown. Neutropenic patients are particularly susceptible to infection and rapid dissemination.31 The source of infection in patients undergoing
acute immunosuppressive therapy is often the skin,
especially from cellulitis developing at the site of onychomycosis, local trauma, or insect bites. Nasal sinuses
are another source of primary infection that can lead to
dissemination following acute immunosuppression.18
In disseminated disease, patients present with multiple
painful erythematous papules and nodules, some with
central necrosis. Lesions are often at different stages of
development, and a specific presentation of papules
evolving into target-like lesions with a ring of normalappearing skin and an outer rim of erythema has been
observed.31 Skin lesions in disseminated disease often
precede fungemia and are found in approximately
75% of patients making dermatologic evaluation valuable.8 The mortality rate in patients who are persistently neutropenic is about 80%, compared with 30%
in patients whose immune systems recover. Disease in
solid organ transplant recipients may occur later than
in patients with hematologic malignancies. Newer triazole antifungals such as voriconazole have some efficacy against infection with Fusarium species, for which
treatment options have traditionally been limited.
Surgical resection of localized skin infection is useful.
Granulocyte transfusions may also play a role in treatment.18
intravenous amphotericin B and surgical debridement.

Some advocate the addition of posaconazole. If possible, reversal or removal of underlying predisposing
conditions should be attempted.18
::
Figure 29-4 Rapidly progressing zygomycosis in a man

with diabetes.
Viral infections are predominantly associated with

defects in cellular immune function and are not typically expected to cause problems in patients whose
main immunologic defect is neutropenia.4 The most
common viral infection that occurs in patients who are
undergoing induction chemotherapy for lymphoma or
an acute leukemia or who are in the first few weeks
after a hematopoietic stem cell transplantation is reactivation of latent herpes simplex virus (HSV) infection
(see Chapter 193).37 Clinical presentations in acutely
immunosuppressed patients include an increased
severity of oral mucositis, intraoral ulcers outside of
the gingival margin, and necrotizing gingivitis. Pneumonitis can occur from either contiguous spread from
the oropharynx or from viremia.37 Antiviral prophylaxis with acyclovir is very effective in preventing disease during chemotherapy and following hematologic
and solid organ transplantation. When disease does
occur in transplant patients, approximately 10% of
cases are resistant to acyclovir because of a mutation
in the gene coding for thymidine kinase, which is the
enzyme required for efficacy of acyclovir, valacyclovir,
and famciclovir (see Chapter 231).38 The treatment of
choice in these patients is foscarnet, although reports
of resistance to both agents is increasing.37,39,40
Reactivation of varicella zoster virus (VZV) (see
Chapter 194) usually occurs 3 months or longer after
transplantation and is relatively rare in the acutely
immunosuppressed patient. VZV infection in adults
with leukemia or after solid organ transplantation is
rarely primary, but more often represents reactivation
of latent virus. In this setting, patients are at increased
risk for both skin and systemic dissemination of virus
(Fig. 29-5).41 Before the use of antiviral prophylaxis in
bone marrow transplantation, disseminated primary
varicella or zoster infection was associated with mortality rates of 30%.42
Chapter 29
Trichosporon beigelii, a
yeast-like organism that causes white piedra in the
tropics, may produce acute systemic infection in immunosuppressed patients, most commonly in the setting
of neutropenia.31 Trichosporon is an emerging pathogen
in organ transplant recipients as well.18 Patients with
disseminated trichosporonosis are acutely ill. They
may have fever, hypotension, pulmonary infiltrates,
renal involvement, and hepatosplenomegaly. Skin
lesions occur in 30% of patients and appear similar to
cutaneous lesions of disseminated candidiasis (multiple red papules that may ulcerate). Definitive diagnosis is made by culture, and the treatment of choice is
fluconazole or itraconazole; amphotericin B resistance
is common.18
CHRONIC IMMUNOSUPPRESSION
Patients with chronic immunosuppression include
those that are iatrogenically immunosuppressed
because they are taking medications that impair the
335
Section 4
Figure 29-5 Disseminated varicella zoster virus in a

patient after induction chemotherapy.
::
immune system and those with chronic diseases that

are associated with immune dysfunction, such as
diabetes mellitus. Moreover, individuals with cancer
often have immune system defects before aggressive
cytotoxic, radiation, or surgical therapy.43 For example,
tumors can secrete immunosuppressive factors (e.g.,
transforming growth factor-1 and interleukin-10) or
induce T-cell anergy, which help them evade normal
immune responses and lead to further systemic immunosuppression.
The population of patients taking long-term immunosuppressive medications is growing as solid organ
transplantation becomes a therapeutic option for
many human diseases and the survival of patients in
the short and long term has improved. These individuals require lifelong therapy with immunosuppressive
drugs to maintain function of the transplanted organ.
Cyclosporine, tacrolimus, sirolimus, prednisone,
mycophenolate mofetil, azathioprine (see Chapters 227
and 233), and the newer agents daclizumab and basiliximab are the drugs used most commonly to prevent
graft-versus-host disease, predominately by inhibiting cell-mediated immunity (i.e., T-cell function).44
Humoral immunity (i.e., B-cell function) remains
relatively intact in these patients. Thus, opportunistic
diseases in most transplant patients are dominated by
viral and fungal infections, intracellular bacterial infections, and virus-associated malignanciesconditions
that are controlled predominantly by cell-mediated
immune mechanisms in immunocompetent hosts.
and severity, with the highest incidence (up to 5%) seen

in recipients of hematopoietic stem cell transplants.
One-third present with catheter-related infections,
although skin lesions are rare in this population. Skin
involvement is the most commonly reported manifestation of nontuberculous mycobacterial infections in
solid organ recipients except lung and heart transplant
recipients, who are more likely to have pulmonary
involvement. One-third of these patients have localized
or disseminated cutaneous disease and the rapid growing species M. chelonae, M. fortuitum, and M. abscessus
are most commonly isolated.45,46 Median time to infection varies depending on the type of transplant, ranging
from 4 months posttransplant in stem cell recipients, to
30 months in heart recipients.
Atypical mycobacterial infections in the skin are
characterized by diverse morphologies, including reddish brown nodules and plaques (eFig. 29-5.1 in online
edition), abscesses (Fig. 29-6), and ulcers.47 M. aviumintracellulare and M. haemophilum commonly cause
disseminated infection, which can involve the lungs,
lymph nodes, liver, spleen, bone marrow, and skin.
Organisms can be identified by special stains or by culture of specimens from affected skin. Specific antimycobacterial antibiotic treatment regimens are complex
and depend on the mycobacterial species, results of
sensitivity testing, extent and severity of disease, and
presence or absence of underlying immune defects.45,46
M. tuberculosis infection is a common worldwide
problem, especially in individuals with impaired
immunity. For example, individuals receiving highdose corticosteroids are prone to active pulmonary
tuberculosis. Cutaneous tuberculosis is usually more
common in the setting of immunosuppression. Specifically, scrofuloderma (tuberculous lymphadenitis with
extension to overlying skin) and numerous cutaneous
lesions of miliary tuberculosis may occur more commonly in patients with underlying immune defects.48
BACTERIAL INFECTIONS
336
MYCOBACTERIAL INFECTIONS. Atypical mycobacteria (see Chapter 184) are ubiquitous organisms
found in soil and water. The most common organisms
in this group include Mycobacterium marinum, M. chelonae, M. fortuitum, M. abscessus, M. kansasii, M. haemophilum, and M. avium-intracellulare. Before the epidemic of
acquired immunodeficiency syndrome (AIDS), most
cases occurred in persons with underlying pulmonary
disease. However, nontuberculous mycobacterial infections after transplantation are increasing in frequency
Figure 29-6 Mycobacterium chelonae infection in a patient

receiving long-term, high-dose glucocorticoid treatment.
NOCARDIOSIS. Nocardia species (see Chapter 185)
OTHER BACTERIAL INFECTIONS. (See Chapters

177180.) Cellulitis caused by Streptococcus pyogenes,
Streptococcus pneumoniae, or S. aureus may progress
rapidly and cause necrotizing fasciitis in immunosuppressed patients (Fig. 29-8). Solid organ recipients also
may develop recurrent cellulitis of the elbow, a condition termed transplant elbow that has been attributed
to staphylococcal infection.8,57
Individuals with underlying complement deficiencies (loss of late-phase components C5C9) or
alcoholism are susceptible to infection with Neisseria
meningitidis.58 Patients have acute septicemia, meningitis, disseminated intravascular coagulation, and widespread petechiae and purpura (Fig. 29-9).
Persons with underlying hepatic disease (commonly
alcoholic cirrhosis or hepatitis) are prone to infection
with Vibrio vulnificus, a Gram-negative bacillus commonly found in seawater, shellfish, clams, and oysters.59 Infection occurs by ingestion of contaminated
seafood or by direct cutaneous inoculation after contact with contaminated seawater. Patients classically
present with rapidly evolving septicemia and painful cellulitis, bullae, or ulcers on the lower extremities
(Fig. 29-10). Aeromonas can cause a similar picture in
immunosuppressed patients.15,60
Capnocytophaga canimorsus is a commensal bacterium
found in the saliva of dogs and cats that is transmitted to humans by bites or scratches. Hosts particularly susceptible to septicemia and widespread organ
::
Figure 29-7 Nocardiosis in a man with glioblastoma.
BACILLARY ANGIOMATOSIS. Bacillary angiomatosis (see Chapter 182) is caused by infection with
the bacterium Bartonella henselae or B. quintana and usually occurs in AIDS patients and other immunocompromised hosts.55 Cutaneous lesions appear as painful,
dome-shaped vascular papules and nodules (often
resembling pyogenic granulomas). Disseminated
infection may occur and involve the liver, spleen, bone
marrow, and brain. Fever and lymphadenopathy may
be present. Patients often have a history of scratches or
bites by cats, the natural reservoir for B. henselae and
B. quintana. Diagnosis is made by demonstration of
pleomorphic bacilli in tissue specimens with Warthin
Starry silver stain. Preferred treatments include oral
erythromycin or azithromycin, or doxycycline.56
Chapter 29
are ubiquitous filamentous bacteria found in soil. While

N. asteroides was historically considered the most common species associated with human disease, the recent
availability of molecular diagnostics has allowed recategorization such that infections are now reported with
a variety of species, including N. farcinica, N. nova, N.
brasiliensis, N. asteroids sensu strictu, and N. cyriacigeorgica, among others.49 Species identification is important
as some show more virulence and antimicrobial resistance than others (e.g., N. farcinica), and infection patterns may differ (e.g., N. brasiliensis is often the cause
of primary cutaneous disease). Infection can be seen in
immunocompetent hosts, but the majority of infections
(60%) involve patients with immune compromise,
particularly those receiving long-term corticosteroid
therapy (the most important risk factor), solid organ
or bone marrow transplant recipients, cancer patients,
AIDS patients, intravenous drug users, and individuals with chronic pulmonary disease.50,51 Infections in
patients treated with rituximab and tumor necrosis
factor- inhibitors have also been reported. In transplant patients, the mean onset of infection is 9 months
after transplantation, although it can occur as early as
1 month afterward. Before the use of cyclosporine to
prevent rejection, infection rates were much higher in
transplant recipients, and this decline is attributed to
decreased use of corticosteroids.49
Most cases of nocardiosis in transplant patients
(approximately 80%) present as primary pulmonary
disease and dissemination occurs in up to 40% of
cases. The brain is commonly involved with disseminated infection, while approximately a third of cases
show cutaneous involvement. Rarely, the skin is the
primary location of infection.49 Several types of skin
lesions have been described, including lower extremity subcutaneous nodules with pustules (Fig. 29-7),
erythema nodosum-like disease, abscesses with sinus
tract formation, mycetoma, sporotrichoid nodules, and
cellulitis.8,52,53 Diagnosis is based on demonstration of
Gram-positive, partially acid-fast, branching bacilli
in tissue or tissue exudates, or is determined by tissue culture, although it often takes several weeks for
organisms to grow. Molecular techniques may now
aid in identification as well. The treatment of choice
remains trimethoprim-sulfamethoxazole (TMP-SMX);

however, the severely ill or those with cerebral or disseminated infection may benefit from the addition of
amikacin and/or imipenem. Numerous other antibiotics have been reported to be efficacious as well, such
as linezolid, minocycline, other carbapenems, and
third-generation cephalosporins. In addition, incision
and drainage of cutaneous abscesses should be performed.50 The duration of treatment and the use of
long-term prophylactic therapy to prevent primary or
recurrent disease in transplant patients or patients on
chronic corticosteroids are currently under debate. For
instance, breakthrough infections in solid organ and
hematopoietic transplant patients receiving traditional
thrice weekly doses of TMP-SMX have occurred, and
general resistance to sulfonamides is increasing.51,54
337
Section 4
::
338
Figure 29-8 Early (A) and late [after surgical debridement (B)] lesions of necrotizing fasciitis caused by Streptococcus
pyogenes in an intravenous drug abuser with underlying Job syndrome.
involvement include alcoholics, asplenic patients, and
those taking glucocorticosteroids. Skin lesions occur
commonly and include widespread macules, papules,
purpura, and gangrene. Septicemia carries a mortality
rate of 10%50%.61,62
In immunosuppressed patients, Salmonella species
have been associated with cutaneous abscesses and
necrotizing fasciitis of the head and neck.63
FUNGAL INFECTIONS
CANDIDIASIS. Although mucocutaneous candidiasis (see Chapter 189) is less serious than disseminated
Figure 29-9 Acute meningococcemia in a man with

acquired complement deficiency.
candidiasis in the setting of acute immunosuppression (as described earlier), it is a significant source of
morbidity in hosts with chronic cell-mediated immune
dysfunction. Studies in organ transplant recipients
suggest rates of oral candidiasis anywhere between
7% and 64%, depending on the type of transplant
and the location of the study population.41,64 Patients
with chronic mucocutaneous candidiasis have specific
underlying immune deficits in fighting candidal infections, including alterations in dendritic cells and the T
helper type 17 cells (Th17), and usually have chronic
widespread disease without systemic involvement.6567
Patients with oral mucosal candidiasis most commonly have pseudomembranous, white, friable
plaques that leave a raw, erythematous undersurface
when scraped. Less common oral lesions include erythematous or atrophic plaques as well as angular cheilitis. Esophageal involvement should be suspected in
any patient with oral candidiasis complaining of pain
or difficulty swallowing. Moist intertriginous areas are
common locations of cutaneous lesions and are characterized by tender erythematous papules and plaques,
often with satellite pustules. Onychomycosis and
paronychia caused by Candida species are common in
patients with chronic mucocutaneous candidiasis. For
mucocutaneous disease, topical therapy with nystatin
or clotrimazole and oral fluconazole are the treatments
of choice. Prophylactic treatment with fluconazole is
Figure 29-10 Vibrio vulnificus infection in an alcoholic

patient after minor trauma sustained while swimming in
the ocean.
superficial nail plate scrapings. These conditions should

prompt a search for underlying immune deficiency.31,69
DERMATOPHYTOSIS. Dermatophytoses (see Chapter 188) are common uncomplicated infections in normal hosts, but immunosuppressed patients may have
widespread, aggressive infection that can be resistant
to topical and systemic therapy.31,69 The overall incidence of dermatophyte infection is likely not higher
in immunocompromised patients compared to normal
hosts.70 Specific presentations seen in immunocompromised patients include multiple lesions, a wide distribution, tinea capitis in adults, and Majocchi granuloma.
Manifestations more suggestive of immunosuppression include both white superficial onychomycosis and
proximal subungual onychomycosis. In the former, the
surfaces of affected nails have a white, chalky appearance (Fig. 29-11), and hyphae are observed readily in
::
often recommended for patients at high risk for infection, such as those who have recently undergone organ
transplant surgery, although as noted before resistance
to this agent is increasing.68
Chapter 29
Figure 29-11 White superficial onychomycosis in a renal

transplant patient receiving cyclosporine.
CRYPTOCOCCOSIS. Cryptococcus neoformans

(see Chapter 190) is a yeast-like encapsulated fungus that is ubiquitous and is found commonly in soil
enriched with bird feces. Primary infection is almost
always via the respiratory tract by inhalation of
airborne spores and usually is asymptomatic in healthy
individuals. Organ transplant recipients are now the
population at highest risk of developing disseminated
disease, because improved antiretroviral agents have
decreased the incidence in those with HIV disease.71
Patients receiving high-dose systemic corticosteroids
are another group susceptible to hematogenous spread
and disseminated infection, while incidences in those
with diabetes mellitus, chronic lymphocytic leukemia,
chronic myeloid leukemia, multiple myeloma, and
Hodgkin disease are lower. Cryptococcal disease in
hematopoietic stem cell transplant recipients is very
rare.72 The central nervous system is most commonly
involved during dissemination, although infection
may occur in many organs including the lungs, bone
marrow, heart, liver, spleen, kidneys, thyroid, lymph
nodes, adrenal glands, and skin.
Cutaneous lesions occur in up to 20% of patients
with disseminated infection, however, skin lesions
may be present in two-thirds of organ transplant
patients receiving tacrolimus.73 In transplant patients,
erythematous, edematous, warm, painful plaques on
the extremities (clinically indistinguishable from bacterial cellulitis) have been reported most frequently
(Fig. 29-12A).74 Umbilicated papules (resembling molluscum contagiosum), nodules, pustules, vesicles, and
ulcers also may occur (Fig. 29-12B).75 Oral mucosal
cryptococcal nodules and ulcerations also have been
described. Lesions may be isolated or multiple and can
be quite painful.
Figure 29-12 Cellulitis and subsequent necrosis (A) and molluscum-like lesions (B) of cutaneous cryptococcosis. (Used
with permission from Jonathan Alexander, MD, Portland, OR and Yale Residents slide collection, respectively.)
339
Section 4
::
340
Although primary skin disease may occur in the

absence of pulmonary infection, diagnosis of cutaneous cryptococcosis always warrants an investigation
for systemic infection, especially because disseminated
disease may not always be evident clinically.76 Cerebrospinal fluid can be assessed for cryptococcal polysaccharide antigens. Budding encapsulated yeasts can
be identified readily in skin biopsy specimens as well
as in material obtained by a scraping of skin lesions.
The yeast stain red with periodic acid-Schiff and mucicarmine stains and black with methenamine silver
stain. India ink can be used to accentuate the capsule
in a skin scraping. Cryptococcus can be isolated in culture of cutaneous tissue. The treatment of choice for
cryptococcosis is a lipid formulation of amphotericin
B with or without flucytosine. Fluconazole is used as
alternative primary treatment and is the treatment of
choice for prophylaxis in individuals at high risk for
recurrent infection.77
HISTOPLASMOSIS. Histoplasma capsulatum (see

Chapter 190) is a dimorphic fungus found in soil
endemic to the central and eastern regions of the
United States. As with cryptococcosis, inhalation of
airborne spores causes primary pulmonary infection
that usually leads to self-limited disease in otherwise
healthy individuals. Disseminated disease is rare and
most often occurs in individuals with deficiencies
in cell-mediated immunity. In addition to pneumonia, immunosuppressed hosts may show fever, renal
failure, central nervous system involvement, hepatosplenomegaly, lymphadenopathy, and myelosuppression.78
Mucocutaneous lesions occur in 5%25% of patients
with disseminated infection and may be an initial sign
of disease. The head and neck region are favored and
the oropharynx is the most common site. Mucosal
lesions present with nodules or plaques that progress
to ulcers with indurated borders. Skin findings are
diverse and include molluscum-like papules, acneiform papules and pustules, and cellulitis.15,79 The
organism grows very slowly in culture so diagnosis is
best achieved by direct examination of tissue. Numerous small, oval, yeast-like fungi can be seen within the
cytoplasm of dermal macrophages. Antigen testing is
also available, but cross-reaction can occur with blastomycosis and other fungal infections (though not with
cryptococcus). The treatment of choice for disseminated histoplasmosis in an immunosuppressed host is
intravenous amphotericin B. For patients who are not
acutely ill, oral itraconazole may be used; itraconazole
is also recommended for immunosuppressed patients
to prevent recurrent disease.78
COCCIDIOIDOMYCOSIS. Coccidioides immitis (see
Chapter 190), the causative agent of coccidioidomycosis, is endemic to soil in the southwestern United
States, and infection is usually acquired through inhalation of spores, which causes pulmonary disease.78
Although progressive primary infection may occur in
immunosuppressed patients, reactivation of a prior,
clinically unapparent infection is more common. The
risks of dissemination and fatal infection are greater
among men, pregnant women, non-Caucasians, and

immunosuppressed patients with defects in cell-mediated immunity. Thus, disseminated coccidioidomycosis can occur in any immunocompromised patient who
lives or has lived previously in an endemic area.
Immunosuppressed patients with disseminated disease may have fever, pneumonia, bone involvement,
skin lesions, and/or meningitis. Mortality remains
high at around 30%, but has improved with targeted
prophylaxis in the organ transplant population.80 Primary cutaneous lesions of coccidioidomycosis are
extremely rare and usually resolve in healthy individuals, whereas lesions persist in immunocompromised patients. Morphologies are varied and include
multiple verrucous papules, abscesses, and ulcerated
papules and plaques. Nonspecific findings seen in systemic disease include erythema multiforme, urticaria,
a maculopapular rash, and erythema nodosum.15
Definitive diagnosis of coccidioidomycosis is made
by culture or demonstration of characteristic endosporulating spherules in smears or biopsy specimens.
Serologic studies may prove helpful, but may give
false-negative results in the immunocompromised. In
disseminated infections in immunosuppressed hosts,
treatments for life-threatening disease include amphotericin B until infection is controlled, followed by itraconazole or fluconazole. Immunosuppressed patients
with meningeal disease may require lifelong therapy.81
BLASTOMYCOSIS. Blastomyces dermatitidis (see

Chapter 190) is endemic to the soil of the Ohio and
Mississippi river valleys. Infection is acquired through
inhalation of spores. Immunosuppressed patients are
prone to disseminated disease involving the lungs,
bone, genital tract, and skin, although infection in this
population is still rare. Skin is the most common extrapulmonary site of involvement.15,78 Lesions appear as
verrucous or ulcerated plaques with serpiginous borders located on the head, neck, or distal extremities.
Ulcerative lesions begin as subcutaneous nodules and
pustules.82 Diagnosis is made on demonstration of
broad-based, budding, thick-walled yeasts in exudates
or skin scrapings from the edges of lesions or by tissue culture. In life-threatening disseminated infection,
intravenous amphotericin B is the treatment of choice,
whereas less severe disease is treated with oral itraconazole.83
OTHER FUNGAL INFECTIONS. Alternaria is a
common saprophytic fungus that can cause opportunistic infection in the setting of organ transplantation,
Cushing syndrome, autoimmune bullous disease, and
lymphoproliferative disorder. Over half of the patients
reported to have cutaneous alternariosis were taking
systemic corticosteroids, and secondary increased skin
fragility has been implicated as a risk factor. There
are two routes of infection: traumatic inoculation and
secondary colonization of a preexisting skin lesion.
Presentations include indurated plaques, ulcers, and
pustules.84,85
Penicillium marneffei is a dimorphic fungus that is
endemic to Southeast Asia (see Chapter 190). Most
infections are associated with HIV disease, but cases
in immunosuppressed patients residing or traveling

to endemic areas have occurred.86 Tinea versicolor and
folliculitis caused by Pityrosporum ovale (also known as
Malassezia furfur; see Chapter 189) may be more prevalent, widespread, and persistent in immunosuppressed
hosts. In addition, Pityrosporum has been reported
to cause indwelling catheter-associated fungemia in
immunosuppressed hosts, especially in those receiving parenteral lipid preparations.8
VIRAL INFECTIONS
Chapter 29
::
Figure 29-13 Severe chronic herpes simplex infection in

a patient receiving long-term, high-dose glucocorticoids
for autoimmune disease.
Figure 29-14 Severe recurrent varicella zoster virus infection in a child with acute lymphocytic leukemia.
HERPES VIRUS INFECTION. Herpes viruses (see

Chapters 193 and 194) include HSV-1, HSV-2, VZV,
CMV, EpsteinBarr virus (EBV), human herpes virus 6
(HHV-6), HHV-7, and Kaposi sarcoma-associated herpes virus (KSHV or HHV-8). Infections are most prevalent in patients with acquired defects in cell-mediated
immunity. Herpes viruses infect hosts for life and
remain dormant in the nuclei of latently infected cells.
Suppression of immunity often leads to reactivation
(i.e., a latent to lytic switch).
Recurrent HSV-1, HSV-2, and VZV infections are
common in cancer and posttransplant patients, with
the majority experiencing reactivation with at least
one of these three viruses. Clinically apparent HSV
outbreaks occur in up to 68% of organ transplant
patients not on prophylaxis.87 Herpes zoster (recurrent VZV infection) is most likely to occur during
the first year after transplantation with a 20100-fold
increased incidence in immunocompromised patients
(approximately 10% incidence).37,88 Although presentations can be identical to those in immunocompetent
hosts, lesions atypical in morphology and distribution
often occur. For example, in immunosuppressed hosts
recurrent lesions due to HSV or VZV may be isolated,
nondermatomal, disseminated, necrotic, ulcerative, or
verrucous (Figs. 29-13 and 29-14). In the mouth, chronic
recurrent HSV infection can form white plaques and
can be confused clinically with candidiasis. Lesions
can occur in atypical locations, such as the tongue.
Severe pain often is associated with both skin and oral
lesions, and postherpetic pain is common. Protracted
clinical courses of recurrent HSV or VZV infection are
also more common in the setting of immunosuppression. In short, any painful, eroded lesion in an immunocompromised patient, regardless of its distribution
or age, should be evaluated for both HSV and VZV by
Tzanck preparation, immunofluorescence testing for
viral antigen, polymerase chain reaction testing, and/
or viral culture. Importantly, systemic infection involving the lungs, central nervous system, liver, heart, and
gastrointestinal tract may occur. Treatment with systemic acyclovir or a related antiherpesviral drug is
always necessary. Prophylactic treatment to prevent
recurrent episodes should be considered for individual
patients if warranted. Foscarnet is the drug of choice
for acyclovir-resistant viruses.37
Reactivation and recurrent disease associated with
CMV are major causes of morbidity and mortality in
patients with marked immunosuppression, occurring in 20%60% of transplant recipients depending
341
Section 4
::
on the type of transplant and other risk factors.37,89

Disease is most commonly caused by reactivation of
preexisting CMV infection, although CMV may be
transmitted from donor to host in solid organ transplantation. CMV also exerts indirect effects in transplant patients, contributing to an increase in graft
loss and risk of other opportunistic infections. CMV
retinitis, gastroenteritis, hepatitis, and pneumonitis
are the most common clinical disease manifestations.
Cutaneous lesions can occur in 10%20% of patients
and are varied and nonspecific, including ulcers, papules, vesicles, petechiae, and morbilliform eruptions.
Oral ulcers caused by CMV, particularly on the lateral aspects of the tongue, are most common. Painful,
punched-out perianal ulcers have been reported and
coinfection with HSV can occur. Tzanck preparations
of specimens from the bases of ulcers may show multinucleated giant cells, and CMV-infected dermal endothelial cells may be seen in tissue sections by routine
microscopy, appearing as large cells with intranuclear
inclusions surrounded by clear halos (owl-eye nuclei).
In addition, CMV can be cultured from infected skin.
The treatment of choice for systemic CMV disease is
intravenous ganciclovir, although intravenous foscarnet, cidofovir, or CMV immunoglobulin also may be
effective.37,41 Prophylaxis of at-risk transplant patients
is routine.39
HHV-6 and HHV-7, herpes viruses closely related
to CMV, can also cause widespread multiorgan infection in immunosuppressed individuals. Disease itself
is usually mild, but indirect effects of viral reactivation
may allow other infections to occur and contribute to
allograft failure.90
Unlike the other herpes virus infections, EBV and
KSHV infections are associated with malignancies
in the setting of immunosuppression. Specifically,
chronic reactivated EBV infection is associated with
non-Hodgkin lymphoma and other lymphoproliferative disorders, whereas chronic KSHV infection is
associated with Kaposi sarcoma (KS), primary effusion
lymphoma, and the plasmablastic variant of Castleman disease. Their neoplastic potential is discussed
further later. Oral hairy leukoplakia is a unique presentation of EBV reactivation within oral mucosal epithelial cells, classically seen in patients with AIDS, but
also seen in other immunosuppressed individuals (see
Chapter 198).37 Lesions appear as adherent, white, corrugated plaques on the lateral aspects of the tongue.
Histologically, there is hyperkeratosis and vacuolated
suprabasal epithelial cells. Oral hairy leukoplakia may
respond to topical podophyllin or high-dose acyclovir, although it is usually asymptomatic and does not
require treatment. It has been regarded as a poor prognostic indicator in HIV-infected individuals, but the
clinical significance of oral hairy leukoplakia in transplant patients is not known.
HUMAN PAPILLOMAVIRUS INFECTION.
342
Warts
(see Chapter 196) caused by human papillomavirus (HPV) infection are a common problem in posttransplant patients and in others receiving long-term
immunosuppressive drug therapy. The prevalence of
warts increases with longer duration of immune com-
promise, with up to 95% of individuals affected 5 years

after transplant surgery.91 In this setting, lesions may
be numerous, persistent, and difficult to eradicate. The
morphology of the lesions may be typical or atypical.
Atypical lesions appear as scaly macules and plaques,
occur more commonly in sun-exposed areas, and are
associated with HPV types observed in patients with
epidermodysplasia verruciformis (e.g., HPV types 5
and 8). Several studies have reported that systemic
retinoids (i.e., isotretinoin or acitretin) can prevent or
decrease wart formation and prevent a variety of premalignant and malignant cutaneous lesions in posttransplant patients. In these patients, the association
between HPV infection and cutaneous genital and nongenital squamous cell carcinoma (SCC) is complex, as
discussed later.
HUMAN POLYOMAVIRUS INFECTION. Polyomaviruses are small double-stranded DNA viruses

found in a variety of species including humans. The
first two described, BK virus (BKV) and JC virus (JCV),
were identified in the 1970s and cause nephropathy in
kidney transplant patients and progressive multifocal leukoencephalopathy in immunosuppressed individuals, respectively. Neither produce skin lesions.92 In
2008, another polyomavirus was identified in tumors
from patients with the neuroendocrine tumor Merkel
cell carcinoma (MCC; see Chapter 120 and later in this
chapter), subsequently termed Merkel cell polyomavirus (MCPyV).93 MCPyV can be found in 24%89% of
MCC with the highest rates in North American and
European populations. Integration of the virus into
MCC tumor genomes suggests a direct oncogenic role
of MCPyV.94 Risk factors for MCC include advanced
age and excessive sun exposure, and the incidence is
greatly increased in the setting of immunosuppression,
especially in organ transplant recipients.95
PARASITIC INFESTATIONS:
CRUSTED SCABIES
Crusted (or Norwegian or keratotic) scabies infestation
(see Chapter 208) typically occurs in the settings of mental deficiency, malnutrition, or immunosuppression.
Clinically, patients present with multiple widespread,
thick, gray, or yellowish scaly plaques (eFig. 29-14.1 in
online edition), with numerous mites present within
lesions. Unlike in common scabies, pruritus may be
minimal. Several courses of treatment with topical permethrin, as well as keratolytics, may be necessary to cure
patients. Oral ivermectin is useful in these patients.96
CANCER
NONMELANOMA SKIN CANCER. Nonmelanoma skin cancer (NMSC; see Chapters 114 and 115)
is the most common malignancy in adult solid organ
transplant patients and causes significant morbidity
and mortality. The overwhelming majority of these
neoplasms are SCCs; however, the incidence of basal
cell carcinomas and other cutaneous malignancies is
Chapter 29
::
Figure 29-15 Caucasian renal transplant patient with

warts, actinic keratoses, and squamous cell carcinomas.
(Used with permission from Jonathan Alexander, MD,
Portland, OR.)
sis on monitoring of potentially premalignant lesions
(e.g., actinic keratoses, porokeratosis, leukoplakia)
for morphologic changes and initiation of treatment
as indicated. Ideally, patients would be treated for
precancerous lesions before transplant surgery. All
transplant patients should be advised to maximize
sun precautions.115 Oral retinoids, especially acitretin,
have been used successfully to decrease the occurrence of new SCCs and actinic keratoses in transplant
patients, but can be difficult to tolerate.116 A range of
dosages has been used, and good effects with minimal
side effects have been reported at daily dosages of 0.2
0.4 mg/kg/day.117 It is a common clinical observation
that when the medication is discontinued, numerous cancerous lesions arise (described as a rebound
effect).118 Thus, when retinoids are considered for prophylaxis of NMSC, they should be considered as a
long-term treatment.
Recent studies have demonstrated that voriconazole,
an oral broad-spectrum antifungal frequently used for
the long-term management of chronically immunosuppressed patients, is associated with photosensitivity, accelerated photoaging, pseudoporphyria cutanea
tarda, aggressive squamous cell carcinoma and melanoma. This accelerated cancer risk occurs in both children and adults. Thus, strict photoprotective measures
should be recommended when voriconazole is used
for prevention or treatment of fungal diseases.119,120
MELANOMA. The incidence of melanoma (see

Chapter 124) and widespread atypical melanocytic
nevi may be increased in transplant recipients and
in other immunosuppressed patients.97 In particular,
children who have had transplants appear to be at
higher risk for the development of melanoma (15% of
all skin cancers) compared with adults (6% of all skin
cancers).121 Most melanomas arise from precursor nevi
also increased.97 For SCC, the risk may be 200 times

higher in transplant patients than in the general population and increases exponentially with length of
immunosuppression.98,99 The cumulative incidence is a
staggering 80% after 20 years of immunosuppressive
therapy in renal transplant patients residing in Australia with its large amount of ultraviolet exposure.100
The incidence of other epithelial proliferative diseases,
including actinic keratoses, keratoacanthomas, porokeratosis, appendageal tumors, and sebaceous carcinomas, is greatly increased as well.
The pathogenesis of NMSC in posttransplant
patients is multifactorial and has been studied and
reviewed extensively.99,101103 Prior history of NMSC
was the most important predictor of risk in one comprehensive study.104 The distribution of lesions and
the populations at highest risk suggest that sun exposure is one of the most important risk factors.105 Risk
also increases with age and is greater for those with
fair skin type, those living near the equator, and those
with documented histories of significant sun exposure.
In addition, gene mutations in the tumor suppressor gene p53 characteristic of those caused by ultraviolet radiation are found within NMSC in transplant
patients.106,107 The commonly used immunosuppressive medications, including azathioprine and the calcineurin inhibitors cyclosporine and tacrolimus, are not
only directly carcinogenic, but their additional effects
on the immune system diminish immune surveillance
mechanisms that potentially serve to eradicate precancerous lesions. On the other hand, sirolimus which
blocks the mammalian target of rapamycin (m-TOR)
pathway, has chemoprotective effects, including blocking tumor growth and angiogenesis.108 Switching from
a calcineurin inhibitor to sirolimus-based therapy
reduces the rates of internal malignancies and skin
cancer in renal transplant patients.109
The role of HPV infection in organ transplant recipients is unclear. HPV is known to cause cervical and
anal SCC and can be detected in cutaneous cancers of
transplant patients (Fig. 29-15). Furthermore, epidermodysplasia verruciformis-associated HPV types (5,
8, and others) have been detected in cutaneous SCC,
and there is suspicion that infections by these viruses
may occur at an increased rate in immunosuppressed
patients. However, asymptomatic infection has been
identified in the general population, and thus it is
unclear whether these HPV types are transcriptionally
active and pathogenic in forming skin cancers in the
setting of immunosuppression.103,110112
Importantly, SCC in posttransplant patients can be
clinically aggressive leading to increased morbidity and
mortality than in the normal population. Local invasion,
recurrence after primary treatment, and distant metastases are not uncommon and are all associated with a higher
rate of mortality in organ transplant recipients.113,114 Oral
mucosal leukoplakia and oral SCC also occur more commonly in immunocompromised individuals.99 Lip lesions
are particularly common, which suggests a pathogenic
role for sunlight in lesion formation.
Careful and regular examination of skin and
oral mucosa by both patients and dermatologists is
required for all transplant patients, with an empha-
343
Section 4
::
344
in these patients. Melanomas have also been reported

to originate from donor organs causing metastatic disease in graft recipients.122
LYMPHOMA. Lymphoproliferative disorders (see

Chapter 145) are common devastating complications following transplantation and are often related
to EBV-mediated proliferation of B-cells. Extranodal
involvement is common, including involvement of
the gastrointestinal tract, lungs, central nervous system, the transplanted organ, and skin.4,123 Cutaneous
lesions present as violaceous macules to firm papules
and plaques, similar to presentation in immunocompetent individuals. Lymphoma with purely cutaneous involvement is rare after transplantation. Most
reported cases represent lymphomas of B-cell origin
and are occasionally CD30+. The presence of EBV is
often detected. Prognosis is generally better if there is
cutaneous involvement alone, perhaps due to the ease
of detection.37,124 Cutaneous T-cell lymphomas account
for 30% of cases of cutaneous lymphomas in transplant patients. EBV is not associated with development in these patients. Clinical presentation is similar
to that in nontransplant patients, except that there is
an increased incidence of erythroderma. Prognosis is
also worse than for cutaneous T-cell lymphoma in the
general population.125
KAPOSI SARCOMA. The occurrence of KS (see
Chapter 128) is increased in patients receiving immunosuppressive therapy after organ transplantation,
with an incidence of 0.5%5%. Risk factors in transplant recipients include male sex and Mediterranean,
Jewish, Arabic, Caribbean, or African descent, as in the
classic form of the disease.37,126 All cases of KS, regardless of clinical or geographic setting, are associated
with KSHV infection. The vast majority of patients
with posttransplant KS are KSHV seropositive before
transplantation. Rarely, posttransplant KS can occur
when KSHV-infected organs are transplanted into
KSHV seronegative recipients.126,127
Clinically, skin lesions of posttransplant KS are identical to other forms of KS. As in classic KS, transplantassociated disease is found most commonly on the
lower legs and feet, although the groin and oral cavity
are also common locations. Typically, early KS lesions
are deep red to violaceous macules or patches. With
time, lesions develop into papules, plaques, nodules,
or tumors. Visceral involvement occurs in 25% of renal
transplant patients and 50% of those with heart or
lung transplants.128 Reduction in immunosuppressive
treatment often causes disease regression, although
these patients remain at risk for developing KS at a
later time if immunosuppressive therapy is reinstituted. Recently, regression of KS lesions in transplant
patients after switching to a sirolimus-based regimen
have been reported.129 Additional treatments include
local excision or radiation therapy, intralesional therapy, and systemic chemotherapy.
MERKEL CELL CARCINOMA. MCC (see Chapter 120) is an unusual, aggressive skin cancer of neuroendocrine cells (Fig. 29-16). The incidence of MCC
Figure 29-16 Merkel cell carcinoma on the scalp of a

heart transplant patient. (Used with permission from
Jonathan Alexander, MD, Portland, OR.)
is increased and the cancer presents at a younger age
in transplant recipients.95 Sentinel lymph node biopsy
is becoming part of the standard of care in this population due to the high rate of lymph node metastases.
Wide surgical resection and adjuvant radiation is recommended. The mortality rate is high at 56% at 2 years
after diagnosis, which is nearly twice the rate for immunocompetent individuals. Less than 10% of individuals
with distant metastasis survive longer than 3 years.
There are early suggestions that MCC tumors positive
for MCPyV DNA convey a better disease course than
those lacking evidence of viral oncogenesis.92,130,131
KEY REFERENCES
4. Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357(25):2601-2614, 2007
7. Feld R: Bloodstream infections in cancer patients with
febrile neutropenia. Int J Antimicrob Agents 32(Suppl.
1):S30-S33, 2008
15. Lopez FA, Sanders CV: Dermatologic infections in the
immunocompromised (non-HIV) host. Infect Dis Clin
North Am 15(2):671-702, xi, 2001
18. Kubak BM, Huprikar SS: Emerging & rare fungal infections in solid organ transplant recipients. Am J Transplant
9(Suppl. 4):S208-S226, 2009
31. Mays SR, Bogle MA, Bodey GP: Cutaneous fungal infections in the oncology patient: Recognition and management. Am J Clin Dermatol 7(1):31-43, 2006
37. Tan HH, Goh CL: Viral infections affecting the skin in organ transplant recipients: Epidemiology and current management strategies. Am J Clin Dermatol 7(1):13-29, 2006
57. Wolfson JS, Sober AJ, Rubin RH: Dermatologic manifestations of infections in immunocompromised patients.
Medicine (Baltimore) 64(2):115-133, 1985
97. Vajdic CM, van Leeuwen MT: Cancer incidence and risk
factors after solid organ transplantation. Int J Cancer
125(8):1747-1754, 2009
114. Ulrich C et al: Skin cancer in organ transplant recipients
where do we stand today? Am J Transplant 8(11):21922198, 2008
128. Farge D: Kaposis sarcoma in organ transplant recipients.
The Collaborative Transplantation Research Group of Ile
de France. Eur J Med 2(6):339-343, 1993
Inflammatory Diseases Based on

Neutrophils and Eosinophils
Chapter 30 :: R
egulation of the Production and
Activation of Neutrophils

:: Steven M. Holland
REGULATION OF THE PRODUCTION
AND ACTIVATION OF NEUTROPHILS
AT A GLANCE
Human bone marrow commits enormous
resources to the creation of neutrophils,
producing approximately 1011 daily with a
circulating half-life of approximately
7.5 hours and tissue survival for 12 days.
Neutrophils are absolutely required for
the prevention of infection and are not yet
amenable to significant external replacement
therapy.
The neutrophil not only plays a central role
in host defense, it can be responsible for
significant tissue damage as well.
The pathophysiology of the neutrophil
indicates pathways, which can be exploited
to enhance protection from infection.
Selective abrogation of those pathways
that are injurious in certain settings is also
possible.
Regulation of neutrophil responses in the
skin is a major concern.
NEUTROPHILS
This section presents an overview of neutrophil biology and function and uses a few well-characterized
defects of myeloid function as illustrations.
ONTOGENY AND DEVELOPMENT

Similar to other components of the hematopoietic system, the neutrophil is ultimately derived from a pluripotent hematopoietic stem cell. The development of
the myeloid stem cell is largely determined by ambient

cytokines and reflected in its surface markers, morphology, and functional characteristics. The myeloblast is
fully committed to the neutrophil lineage and is the
first morphologically distinct cell in neutrophil development. Subsequent stages of neutrophil development
occur under the influence of granulocyte colony-stimulating factor (G-CSF) and granulocytemacrophage
colony-stimulating factor (GM-CSF). Four to six days
are required for maturation through the mitotic phase
to the myelocyte, and 57 days more for the myelocyte
to develop into a mature neutrophil, including the
metamyelocyte and band stages, before emerging as a
fully developed neutrophil. Development of neutrophils through the myelocyte stage normally occurs
exclusively in the bone marrow, which is composed
of approximately 60% developing neutrophils. The
mature neutrophil measures 1012 m and has a highly
condensed, segmented, multilobulated nucleus, usually with three to five lobes. Although 1011 neutrophils
are generated daily, this number can rise tenfold in the
setting of infection. The calculated circulating granulocyte pool is 0.3 109 cells/kg blood and the marginated
pool is 0.4 109 cells/kg blood, comprising only 3% and
4% of the total granulocyte pool, respectively. The bone
marrow releases 1.5 109 cells/kg blood/day to this
pool but keeps 8.8 109 cells/kg blood in the marrow in
reserve. An additional reserve of immature and less
competent neutrophils, 2.8 109 cells/kg blood, is also
available.
G-CSF is critically important for neutrophil production.1 Mice deficient in G-CSF show reduced neutrophil numbers and cannot upregulate neutrophil
numbers in response to infection. Interestingly, G-CSF
production is under the influence of IL-17, a cytokine
of importance in regulation of epithelial defenses.
BIOLOGIC FUNCTIONS
GRANULE CONTENT AND FUNCTION. (Table
30-1.) Neutrophils are characterized by cytoplasmic
granules and partially condensed nuclei. Granules
are first found at the promyelocyte stage.2 Primary
(azurophilic) granules are the first to arise, measure
TABLE 30-1
Human Neutrophil Components

Primary Granules
Secondary Granules
Other Cytoplasmic Organelles
Neutrophil
Galectin-10
Section 5
::
Inflammatory Diseases Based on Neutrophils and Eosinophils
346
Enzymes
Bactericidal/permeability-increasing
protein
Defensins
Lysozyme
Myeloperoxidase
Elastase
Cathepsin G
Proteinase 3
Azurocidin
Phospholipase A2
5-Lipoxygenase
Cyclooxygenase
Acid hydrolases
Cathepsin B
Cathepsin D
-Glycerophosphatase
-Glucuronidase
N-acetyl--glucosamine
-Mannosidase
p15s
Lysozyme
Proteinase 3
Cathepsin B
Cathepsin D
approximately 0.8 m in diameter, and contain numerous antimicrobial products including lysozyme, myeloperoxidase, and defensins.3 Primary granules are only
synthesized at the promyelocyte stage. The promyelocyte gives rise to the myelocyte, the last cell of the neutrophil lineage with proliferative potential. Therefore,
cytokines or agents that increase total neutrophil production must act at or before the myelocyte stage.
The smaller eosinophilic secondary (specific) granules
appear during the myelocyte stage. These granules
measure about 0.5 m in diameter and contain lactoferrin, collagenase, gelatinase, vitamin B12-binding protein, and complement receptor 3 (CR3; CD11b/CD18).
gp91phox and p22phox comprise the specific granule component cytochrome b558, defects in which cause chronic
granulomatous disease (CGD), characterized by infections with particular catalase-producing bacteria. Gelatinase also cleaves and potentiates the activity of the
chemokine interleukin-8 (IL-8). Because primary granules are synthesized early and distributed to daughter
cells during division, they are eventually outnumbered
by about 3:1 by the specific granules, which are produced throughout the myelocyte stage.
Granules fuse in a sequential fashion with incoming
phagocytic vacuoles, such as those containing ingested
bacteria. Secondary granules fuse to the phagosome
within the first 30 seconds after ingestion and release
their enzymes, many of which function best at neutral
or alkaline pH. By 3 minutes after ingestion, the primary
granules have fused to the phagolysosome leading to
rapid lowering of the intravacuolar pH. For objects too
Cathepsin B
Cathepsin D
-Glycerophosphatase
-Glucuronidase
N-acetyl--glucosamine
-Mannosidase
large to be ingested, or certain stimuli, degranulation to

the cell surface occurs with release of granule contents
into the surrounding environment. This can be inferred
by detection of lactoferrin levels in blood.
An example of disordered granule biogenesis is
ChdiakHigashi syndrome (CHS), a rare autosomal
recessive disorder with abnormal pigmentation due to
a generalized abnormality of primary granule and lysosome formation (see Chapter 143).
NEUTROPHIL-SPECIFIC GRANULE DEFICIENCY. Neutrophil-specific granule deficiency is a
rare, autosomal recessive condition clinically characterized by a profound susceptibility to bacterial infections.
There is a paucity or absence of neutrophil-specific granules, specific granule proteins (e.g., lactoferrin) and their
respective messenger RNAs, and very low levels of the
primary granule products defensins and their messenger RNAs. Specific granule deficiency is due to loss of
the transcriptional factor CCAAT/enhancer binding
protein e (CEBPe), which is essential in normal myeloid
development. Acquired abnormalities of neutrophil
granules are seen in some myeloid leukemias, in which
primary granule contents may be aberrantly accumulated (e.g., Auer rods in acute myelogenous leukemia).
TISSUE TRAFFICKING
CHEMOATTRACTANTS AND CHEMOTAXIS.
Metchnikoff discovered over a century ago that
ment of chemokine receptor blockers for treatment of

HIV infection (maraviroc and vicriviroc).
::
Regulation of the Production and Activation of Neutrophils
ADHESION. Neutrophils exist as free-flowing (those

which are sampled on blood drawing) and marginated
cells (those which are attached to the endothelium or
are traversing the lung, skin, or other tissues). Neutrophils rolling along the endothelium recognize sites of
activation (e.g., chemokine expression), adhere to
those sites, and traverse the endothelium to enter the
tissue and fight infection. Leukocyte physical interaction with endothelium and other leukocytes is mediated by integrins, selectins, and intercellular adhesion
molecules (ICAMs; Fig. 30-1).
Elaboration of chemoattractants or display of activation markers on endothelium triggers leukocyte high
affinity binding by 2 integrins, heterodimeric surface
molecules largely stored in the secondary granules of
neutrophils that are displayed on the cell surface upon
leukocyte activation. There are three 2 integrin heterodimers comprised of different chains, CD11a, -b,
and -c, and a common chain, CD18. Each CD11/
CD18 complex has separate and overlapping activities.
CD11a/CD18 [leukocyte function-associated molecule
1 (LFA-1)] binds to other leukocytes and mediates tight
adhesion to the endothelium through ICAM-1 and
ICAM-2. CD11b/CD18 (Mac-1, Mo-1, or CR3) binds to
the inactivated form of the third component of complement (C3bi) and thereby facilitates complement-mediated phagocytosis. CD11b/CD18 also binds to bacteria
directly, to fibrinogen, and to endothelium through
ICAM-1. The divalent cations Ca2+ and Mg2+/Mn2+
mediate adhesion through 2 integrin A domains
containing a metal ion-dependent adhesion site.
CD11b/CD18 may also induce the expression of the 1
integrin very late antigen 6 [VLA-6 (CD49f/CD29)],
derived from neutrophilic granules, to aid in tissue
infiltration. The integrin-associated protein (CD47),
expressed on neutrophils and endothelial and epithelial cells, is also involved in the transendothelial and
transepithelial migration of neutrophils.4 Metalloproteinases may be involved in cleavage of L-selectin,
allowing neutrophil migration through the basement
membrane.
Absence of CD18 causes lack of CD18/CD11 heterodimers and is called leukocyte adhesion deficiency
type 1 (LAD1). Neutrophils lacking CD18 roll normally along the endothelium but are unable to stick
to the vessel wall or exit the circulation after chemotactic stimulation. Absence of LFA-1 (CD11a/CD18)
makes neutrophils unable to bind tightly to and traverse activated endothelium to infected areas. Therefore, LAD1 patients have chronic neutrophil
leukocytosis, partly from inability of neutrophils to
bind tightly to endothelium and exit the circulation,
thus leading to a reduction in the marginated pool
and an increase in the circulating pool of neutrophils.
Poor neutrophil penetration to sites of bacterial invasion leads to necrotic ulcers that lack neutrophils on
biopsy. Absence of Mac-1 (CD18/CD11b or CR3)
leads to inability to perform complement-mediated
phagocytosis, although antibody-mediated phagocytosis remains intact.
Chapter 30
eutrophils move toward very slight gradients of

n
chemical signals, now termed chemoattraction. The
classic chemoattractants are N-formylmethionylleucyl-phenylalanine (fMLF), complement factor 5a
(C5a), leukotriene B4, and platelet-activating factor
(PAF). More recently, chemokines (chemoattractant
cytokines), a class of small (<10 kDa) extremely active
chemoattractant proteins have been identified (see
Chapter 12).
IL-8 is a potent chemoattractant and neutrophil activator (see Chapter 12). Its blockade by neutralizing
antibody in rabbit models of pulmonary inflammation
prevented neutrophil accumulation and reperfusion
injury, confirming its central role in neutrophil recruitment to sites of inflammation. Cellular sources for IL-8
include neutrophils, monocytes, T cells, B cells, natural
killer cells, basophils, eosinophils, fibroblasts, endothelial cells, keratinocytes, and smooth muscle. Exudative
neutrophils are particularly effective at synthesizing
IL-8, probably through a calcium-regulated mechanism.
Exuberant neutrophil function is implicated in Sweet
syndrome (acute febrile neutrophilic dermatosis) as
shown by the frequent association of the syndrome
with hematologic malignancies, dysmyelopoiesis, and
sometimes with the use of G-CSF (see Chapter 32).
The classic chemoattractants and chemokines use
similar receptors that have in common seven transmembrane regions, an extracellular amino terminal
domain, and transduce their signals through pertussis
toxin-sensitive heterotrimeric G proteins. These are the
same type of receptors through which light, neuropeptides, and neurotransmitters signal. Chemoattractant
receptor signaling entails exchange of bound guanine
diphosphate for guanine triphosphate by the subunit
of the heterotrimeric G protein, which in turn leads to
the dissociation of the subunit of the complex,
stimulation of phospholipase C, and generation of
inositol triphosphate and diacylglycerol from phosphatidylinositol bisphosphate. Inositol triphosphate
stimulates the release of calcium from intracellular
calciosomes, whereas diacylglycerol activates protein kinase C. Extracellular calcium also enters the cell,
preparing it for subsequent movement, generation of
oxidants, and secretion of vesicles.
Ras-related guanosine triphosphatases of the
superfamily are also involved in actin cytoskeletal regulation and adhesion. Phosphatidylinositol 3-kinase is
activated by rho and ras and is necessary for the neutrophilic respiratory burst, adhesion, endothelial transmigration, and chemotaxis. Mitogen-activated protein
(MAP) kinases are serine/threonine kinases that
include p38, Erk1, Erk2, and Jnk and are involved in
neutrophil signaling and adhesion. Inhibition of p38
impairs chemotaxis and tumor necrosis factor (TNF)-mediated superoxide production, adhesion, and
release of secondary granules. Erk activation is required
for neutrophil homotypic aggregation. Salicylates
inhibit neutrophil adhesion through Erk inhibition.
Several chemokine receptors also function as requisite human immunodeficiency virus (HIV) coreceptors. Mutations in the chemokine receptor CCR5 that
are protective against HIV infection led to develop-
347
Tissue trafficking of neutrophils

Systemic circulation/postcapillary venules
Free flowing
Tight adhesion
Rolling
Chemokine
other activators
Neutrophil
Fu
Fu
Fu
Section 5
CD15s
(Sialyl Lewisx)
Endothelium
CD62P
Fu
Fu
Fu
CD62E
CD62L
(L-selection)
CD34
CD11a
LFA-1
GlyCam-1
Mac-1
CD54
ICAM-1
::
348
CD18
CD11b
CD18
CD11c
CD18
CR4
CD102
ICAM-2
Tissue
Figure 30-1 Tissue trafficking of neutrophils. The interaction of selectins and integrins on the leukocyte surface with their
endothelial addressins is depicted (neutrophils on the top and eosinophils on the bottom). The leukocytes are in a laminar
flow pattern. Following tissue signals that activate endothelial selectins and glycoproteins, a subset of leukocytes begin to
roll along the vascular wall. For the neutrophil, this typically involves the interaction of CD15s with CD62P (P-selectin) and
CD62E (e-selectin) on the endothelial cell or CD62L (L-selectin) with CD34 or glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1) on the endothelial cell. Abnormalities in fucosylation of CD15s cause leukocyte adhesion deficiency 2
(LAD2). Activation of leukocytes by chemoattractants leads to the expression of integrins with higher avidity conformations. In the case of the neutrophil, the relevant integrins are the 2 family members [lymphocyte function-associated
antigen 1 (LFA-1), Mac-1, and CR4]; whereas eosinophils express a more limited number of 2 family members (LFA-1 and
Mac-1), but also express a 1 integrin VLA-4 and 7 integrin (47). The 2 integrins bind to ICAM-1 and ICAM-2, whereas
the 1 and 7 integrins bind VCAM-1 and mucosal addressin cell adhesion molecule-1 (MadCAM-1), respectively. Defects
in CD18, the chain of the 2 integrins, lead to the inability of neutrophils to exit the circulation at sites of infection and
is called leukocyte adhesion deficiency 1. Interestingly, eosinophils, monocytes, and lymphocytes are observed at sites
of infection in these patients, as these cells can use 1 integrins to mediate the firm adhesion step required for leukocyte
transendothelial migration. See figure in Chapter 31 for a similar analysis of eosinophil function.
LAD1 is diagnosed by fluorescent-activated cell

sorting (FACS), which shows levels of CD18 and its
coexpressed molecules CD11a, CD11b, and CD11c.
Severe LAD1 (<0.5% of normal protein expression) is
a disorder manifested by delayed umbilical stump
separation, umbilical stump infection, persistent
leukocytosis in the absence of active infection
(>15,000/L), and severe, destructive periodontitis
with the loss of teeth and alveolar bone. Recurrent
infections of the skin, upper and lower airway, bowel,
perirectal area, and septicemia are common and usually due to Staphylococcus aureus or Gram-negative
rods. Severe LAD1 patients should receive bone
marrow transplantation in early childhood. Moderate LAD1 (2.5%10.0% of normal protein expression)
patients tend to be diagnosed later in life and
have fewer life-threatening infections. Leukocytosis,
delayed wound healing, and periodontal disease are
still common.
Neutrophil rolling along the endothelium is

ediated through selectins, surface glycoproteins on
m
the endothelium, and sialyl-Lewis X (CD15s), a
surface glycoprotein on neutrophils (see Fig. 30-1).
Endothelial cells express e-selectin (CD62E) and
P-selectin (CD62P), whereas leukocytes express
L-selectin (CD62L). Although endothelial e-selectin
and P-selectin bind to the sialyl-Lewis X (CD15s) antigen on neutrophils, the neutrophil molecule L-selectin
probably binds to distinct antigens on endothelium,
including CD34, and is highly sensitive to glycosylation. L-selectin is shed by neutrophils on activation,
thereby allowing neutrophil migration into sites of
inflammation. Cross-linking of L-selectin on neutrophils results in superoxide generation and may result
in upregulation of TNF-, IL-8, and tyrosine phosphorylation and activation of MAP kinase. LAD2 is the
disease that occurs when CD15s is improperly fucosylated. These patients have neutrophilia, recurrent
MECHANISMS OF KILLING. Neutrophil granules contain enzymes and proteins for killing
ingested bacteria and fungi. Some of these bactericidal mechanisms are dependent on the generation
of oxygen metabolites for microbicidal activity, but
others are not. In addition to mobilizing their own
resources, neutrophils produce a multitude of cytokines that stimulate and attract other phagocytes as
well as lymphocytes.
Regulation of the Production and Activation of Neutrophils
OXYGEN-INDEPENDENT PATHWAYS. Bactericidal/permeability-increasing protein (BPI) is a highly

potent antibacterial granule protein synthesized and
stored in the primary granules. It is a highly basic (isoelectric point >9.6) protein of 452 amino acids and
approximately 58 kDa. Sequence homology to lipopolysaccharide (LPS)-binding protein, a critical endotoxin binding acute-phase reactant, suggests that it
acts by directly binding to LPS. BPI is cytotoxic to
Gram-negative bacteria at concentrations as low as 109
M, but much less effective against Gram-positive
organisms. Binding to LPS leads to insertion of BPI
into the outer membrane of the organism and eventual
insertion into the inner membrane. Arrest of bacterial
growth is solely dependent on the N-terminal half of
the molecule. The C-terminal fragment serves as an
anchor to the membrane. BPI appears to act inside the
phagolysosome. Not all Gram-negative rods are sensitive to BPI, especially Burkholderia (Pseudomonas) cepacia and Serratia marcescens, pathogens in patients who
lack oxidative killing.
Defensins are small (<4 kDa) cationic proteins in the
primary granules of neutrophils involved in killing
ingested Gram-positive and Gram-negative bacteria.
Defensins are synthesized during the promyelocyte/
myelocyte stage as prepropeptides, stored predominantly in a dense subset of the primary granules as
propeptides, and released during neutrophil degranulation. Defensins prefer an actively metabolizing target
and can kill transformed mammalian cells as well as
prokaryotes and yeasts. Defensins and BPI act synergistically against Gram-negative bacteria. Defensins
are reduced in CHS but absent in specific granule
deficiency.
Proteinase 3 is the antigen against which the antineutrophil cytoplasmic antibody is directed in Wegener
granulomatosis (see Chapter 164). It is found predominantly in primary granules but is also in secondary
and secretory granules. Synthesis and surface display
are upregulated by cytokines such as TNF-. Elastase
is a myeloid serine protease in primary granules that
has remarkable roles in host defense. Mice with elastase defects have decreased resistance to Gram-negative bacteria. However, human neutrophil elastase
deficiency causes the syndromes of severe congenital
neutropenia and cyclic neutropenia. Phospholipase A2
::
PHAGOCYTOSIS. Phagocytosis is the culmination

of object recognition, binding, signaling, adherence,
cytoskeletal remodeling, engulfment, and membrane
fusion. Two mechanisms are well characterized, one
mediated by immunoglobulin and the other mediated
by complement.
Receptors for the Fc portions of immunoglobulin G
[IgG (FcR)] are present on many components of the
cellular immune response, including neutrophils,
monocytes, macrophages, eosinophils, and basophils.
FcRI (CD64) is a receptor for IgG1 and IgG3 on
monocytes, macrophages, and eosinophils and is
upregulated on neutrophils after interferon- (IFN-)
stimulation. FcRII (CD32) binds IgG with rather low
affinity, and prefers IgG1 and IgG3. FcRIII (CD16)
binds IgG1 and IgG3 with intermediate affinity. Neutrophil FcRIIIB is bound to the membrane through a
glycan phosphatidyl inositol linkage, which is largely
cleavable by phosphatidyl inositol-specific phospholipase C. As FcRIIIB has no cytoplasmic domain, its
role in signal transduction may be through association with FcRII. Cross-linking of these receptors by
antibody leads to rapid engulfment of targets with
the release of granule contents and oxygen metabolites into the phagolysosome. If the target is too large,
degranulation occurs against the antibody-coated
surface.
The complement receptors CR1 and CR3 are
expressed on the surfaces of neutrophils, eosinophils,
and basophils. Complement receptor 1 is designated
CD35 and is found on many cell types. It binds C3b
and enhances its degradation to C3dg by factor I,
thereby removing that molecule from further activation of the alternative pathway. CR3, CD11b/CD18,
binds iC3b and fibrinogen as well as certain bacteria,

parasites, and fungi. CR1 and CR3 are not per se able
to stimulate phagocytosis, but in the presence of a second signal, such as one given through FcR or by cytokines, phagocytosis proceeds.
Chapter 30
ulmonary, periodontal, and cutaneous infections,

p
and abnormal chemotaxis. The defect is in the gene
SLC35C1, a GDP-fucose transporter. Because the disease affects sugar transport it is now classified as a
congenital disorder of glycosylation (CDG), and
known as CDG IIc. Interestingly, although infections
are common early in life, LAD2 (CDG IIc) patients
appear to improve with age. Administration of oral
fucose to some patients with LAD2 has been inconsistently therapeutic. Most patients also have mental
retardation, short stature, distinctive facies, and the
Bombay (hh) blood phenotype, indicating the multiple systems in which fucosylation is critical. LAD3
(previously known as LAD1 variant) is associated
with a syndrome like Glanzmanns thrombasthenia,
and is due to mutations in KINDLIN3 (FERMT3), a
molecule responsible for 1, 2, and 3 integrin activation in leukocytes and platelets leading to recurrent
infections and bleeding.
The CD18 integrin pathway is critical for inflammation in the skin, but not necessary for accumulation of
neutrophils in the lung or peritoneum. Therefore,
although CD18-dependent pathways are critical for
cutaneous inflammation, CD18-independent pathways exist for pulmonary and peritoneal inflammation. Further, in the setting of congenital absence of
CD18, compensatory pathways exist in the mouse to
respond to peritoneal inflammation.
349
Section 5
::
350
is also found in neutrophil granules, where its various

isoforms act both directly and synergistically with BPI
to kill intracellular bacteria.
Lactoferrin is an iron-binding protein present in specific granules and in mucosal secretions. When released
into the phagolysosome, lactoferrin binds iron and
inhibits the growth of phagocytosed bacteria and some
fungi. The mechanisms through which lactoferrin
exerts its antimicrobial action probably include the
depletion of iron from an organisms environment, but
iron binding-independent antimicrobial activities and
direct immunomodulatory effects are also reported.
Lactoferrin is readily released into the circulation after
burns and experimental endotoxemia, presumably
from neutrophil degranulation.
OXYGEN-DEPENDENT PATHWAYS. Neutrophils can produce toxic oxygen metabolites through

the reduced nicotinamide dehydrogenase phosphate
(NADPH) oxidase complex, which typically is assembled in the wall of the phagolysosome. The NADPH
oxidase catalyses the addition of an electron to molecular oxygen, leading to the formation of superoxide
anion. Superoxide in turn is converted to hydrogen
peroxide by superoxide dismutase. Inside the
phagolysosome, the primary granule component
myeloperoxidase converts hydrogen peroxide to
hypohalous acid by the addition of a halogen (chloride
in neutrophils forms bleach, bromide in eosinophils).
The NADPH oxidase is a multiprotein complex, which
is maintained in separate membrane-bound and cytosolic compartments. On cell activation, the cytosolic
components translocate to the phagolysosome membrane, resulting in an active NADPH oxidase, which
can produce the respiratory burst.
The components of the NADPH oxidase are named
phox (phagocyte oxidase) proteins. p22phox and gp91phox
are the and chains, respectively, of the cytochrome
b558 complex, which resides in the wall of the secondary granule. The cytosolic compartment contains three
factors, p47phox, p67phox, p40phox and the small guanine
nucleotide (guanine triphosphate) binding protein rac.
Assembly of the NADPH complex is caused by diverse
stimuli. p47phox and p67phox contain src-homology type
3 domains (SH3 boxes), which bind to proline-rich targets in themselves and in other members of the
NADPH complex. Stimulation leads to structural
changes in p47phox that promote its interaction with
p22phox through p47phox SH3 domains and p22phox C-terminal proline-rich sequences.
Pathologic mutations in the five required components impair the generation of phagocyte superoxide
and cause CGD, a disease characterized by recurrent
life-threatening infections with bacteria and fungi and
exuberant granuloma formation (see Chapter 143).5
PHARMACOLOGIC MANIPULATION
When neutrophils are overrecruited into neutrophilic
dermatoses, they can produce reactive oxygen intermediates, activate proteinases, and release chemotactic
cytokines, which can contribute to tissue injury and
inflammation. Therefore, it makes sense to aim treatment to suppress the generation of reactive oxygen
intermediates, to inhibit neutrophil adhesion and chemotaxis, and to suppress the release of lysosomal
enzymes and chemotactic factors.
Dapsone is often used for chronic neutrophilic dermatoses such as dermatitis herpetiformis, subcorneal
pustular dermatosis, or erythema elevatum diutinum
(see Chapter 225). Dapsone suppresses neutrophil
adherence and subsequent migration, is a successful
scavenger of reactive oxygen intermediates, and interferes with the myeloperoxidase-halide system and
leukocyte-mediated cytotoxicity. Thalidomide reduces
inflammation through inhibition of TNF- and subsequent neutrophilendothelial adhesion and reactive
oxidant generation (see Chapter 235). Dapsone and
thalidomide both inhibit the proinflammatory cytokine TNF-, which activates neutrophils through
upregulation of complement receptors (CR3, CR4)
and endothelial adhesion molecules, ICAM-1 and
e-selectin. Colchicine inhibits neutrophil chemotaxis,
release of lysosomal enzymes, and production of reactive oxidants and is therefore considered for Sweet
syndrome and neutrophilic bullous dermatoses. Antibiotics such as tetracyclines, macrolides, and metronidazole also have antioxidant properties and interfere
with neutrophil chemotaxis. In addition to its antioxidant activity, sulfasalazine induces neutrophil apoptosis and enhances adenosine release at sites of
inflammation, making it especially useful in pyoderma gangrenosum.
KEY REFERENCES
1. Nathan C: Neutrophils and immunity: Challenges and
opportunities. Nat Rev Immunol 6:173, 2006
2. Borreaard N, Srensen OE, Theilgaard-Mnch K: Neutrophil granules: A library of innate immunity proteins.
Trends Immunol 28:340, 2007
3. Heutinck KM et al: Serine proteases of the human immune
system in health and disease. Mol Immunol 47:1943, 2010
4. DiStasi MR, Ley K: Opening the flood-gates: How neutrophil-endothelial interactions regulate permeability. Trends
Immunol 30:547, 2009
5. Holland SM: Chronic granulomatous disease. Clin Rev
Allergy Immunol 38:3, 2010
Chapter 31 :: R
egulation of the Production
and Activation of Eosinophils

:: Kristin M. Leiferman, Lisa A. Beck, &
Gerald J. Gleich
EOSINOPHILS AT A GLANCE
Eosinophils play a role in innate and

adaptive immune responses, which
may explain why they are present in
normal, noninflamed tissues such as the
gastrointestinal tract and lymphoid tissues.
This section reviews the biologic actions of
eosinophils with particular focus on what
controls eosinophil production, activation,
and tissue trafficking.
Pharmacologic manipulation of eosinophil
inflammation is possible as new, more
specific strategies are emerging.
EOSINOPHILS
ONTOGENY AND DEVELOPMENT
Eosinophils develop in the bone marrow from multipotential, stem cell-derived CD34+ myeloid progenitor
cells in response to eosinophilopoietic cytokines and
growth factors (see Fig. 31-1). They are released into
the circulation as mature cells.13 Important stimulatory cytokines and growth factors for eosinophils
include interleukin (IL)-3, granulocyte macrophage
colony stimulating factor (GM-CSF), and IL-5. Activated T cells likely are the principal sources of IL-3,
INTERACTIONS OF EOSINOPHILIC
FACTORS AND CYTOKINES AND
INTRACELLULAR SIGNALING
The interactions of eosinophilopoietic factors with
their receptors stimulate a cascade of complex biochemical events through signal transduction. Signaling events progress in four steps: (1) juxtamembranous
signaling in which membrane-anchored tyrosine
kinases and lipid kinases are activated; (2) signal interfacing which serves to transduce juxtamembranous
signals to cytosolic signals; (3) mobile signaling in
which cytosolic signaling molecules translocate from
the receptor site to other cellular compartments including the nucleus, mitochondria, and cytoskeleton; and
(4) transcription activation resulting from nuclear
translocation and initiation of gene transcription. Studies have shown the pivotal role of IL-5 in immune
responses involving eosinophils through receptordriven signaling.20 IL-5 binds to the chain of the
IL-5R and induces recruitment of the common (c)
chain to IL-5R. Janus kinase (JAK)2 tyrosine kinase is
constitutively associated with IL-5R, and JAK1 tyrosine kinase with IL-5Rc; both are activated with IL-5
binding as part of the juxtamembranous step. Lyn and
Fes are other tyrosine kinases involved in the first
step; these tyrosine kinases also are activated by IL-3
and GM-CSF. Adaptor proteins, src homologues and
Regulation of the Production and Activation of Eosinophils
As proinflammatory cells, the presence

of eosinophils within most tissues is
associated with pathological states that
include infections, allergic reactions and
atopic diseases, fibrotic disorders, reactive
eosinophilias, and hypereosinophilic
syndromes.
::
Eosinophils primarily are tissue dwelling

cells, but only in certain tissues in humans,
with an average tissue life span of 25 days
that may be increased with eosinophil
survival factors for up to 14 days.
Chapter 31
Eosinophils are bone marrow-derived cells

that circulate transiently and normally
account for up to 6% (up to 400600 per
mm3) of circulating blood leukocytes.
GM-CSF, and IL-5 that induce eosinophil differentiation in bone marrow. However, depending on pathogenic stimuli, eosinophilopoietic cytokines may be
released by other cell types, including mast cells, macrophages, natural killer cells, endothelial cells, epithelial cells, fibroblasts, and even eosinophils, themselves.4
IL-3 and GM-CSF are pluripotent cytokines that have
effects on other hematopoietic lineages. IL-5 is the
most selective eosinophil-active cytokine, but it is relatively late acting. Although it is both necessary and
sufficient for eosinophil differentiation, IL-5 demonstrates maximum activity on the IL-5 receptor (IL-5R)positive eosinophil progenitor pool that first is
expanded by earlier acting pluripotent cytokines such
as IL-3 and GM-CSF4; expression of the high affinity
IL-5R is a prerequisite for eosinophil development.
Exodus from the bone marrow also is regulated by
IL-5. IL-3, GM-CSF, along with IL-5, promote survival,
activation, and chemotaxis of eosinophils through
binding to receptors that have a common chain
(CD131) with IL-5R, and unique chains. See eTable
31-0.1 in online edition for designations of many factors involved in eosinophil biology.
351
Eosinophils from undifferentialted hematopoietic cells to their fate in tissue

Transcription
factors
Differentiation in
bone marrow
Cytokines
IL-3
GM-CSF
IL-5
GATA-1
FOG-1
C/EBP
Pu.1
CD34+
IL5R+
CD34+
Section 5
IL5
CCL11
CD34
IL5R
CCR3
L-selectin
CD34+
IL5R+
CCR3
L-selectin
Release into
circulation
::
L-selectin
is shed
IL5R+
CCR3
Rolling
VLA4
Tethering
Flattening
Diapedesis
P-selectin
E-selectin
ICAM-1
Transmigration through
blood vessels into skin
VCAM-1
CCL24
CCL11
CCL26
LTB4
ExB4*
Fate in tissue
Degranulation:
Cytolytic
Piecemeal
Regulated
secretion/
exocytosis
FAS (CD95)
TGF
Siglec-8
CD30
Bcl-2
CD45
CD52
CD69
Dermal eosinophil
TNF
IFN
CD40
Leptin
Apoptosis
GM-CSF
IL-3
IL-5
Priming, activation
and survival
Figure 31-1 Eosinophils from undifferentiated hematopoietic cells to their fate in tissue. The images depict the eosinophils life from differentiation in the bone marrow to vascular transmigration to their fate in tissue with key factors noted.
ExB4 likely has activities comparable with those of LTB4.
352
MAMMALIAN STUDIES. In mammals, such as the

mouse and humans, the eosinophil is released as a
mature cell into the circulation from the bone marrow,
but is present in the blood only transiently, ranging
from 818 hours. Eosinophils comprise a small portion, normally 6% or less, of circulating leukocytes.
They are primarily tissue dwelling cells, but only in
certain tissues in humans, with an average tissue life
span of 25 days. This may be prolonged by cytokines
that increase eosinophil survival for up to 14 days.
Under normal circumstances, a balance exists between
bone marrow production and release of eosinophils,
their time in circulation, and their entrance into tissues.
Changes in any one of the compartments causes an
increase or decrease in circulating and tissue eosinophils. Eosinophilia in blood or tissue or both is associated with helminthiasis, allergic hypersensitivity, and
other pathological conditions. In humans, bone marrow, spleen, lymph node, thymus, and gastrointestinal
tract from the stomach through the colon, sparing the
esophagus, are the only tissues in which eosinophils
normally reside.38 Furthermore, the gastrointestinal
tract is the only organ other than bone marrow in
which extracellular eosinophil granule protein deposition is observed even under homeostatic conditions.
Eosinophils and their granule proteins are found in the
lamina propria in normal gastrointestinal tract and are
not found in Peyers patches or epithelium. Eosinophils may be important for thymocyte deletion based
on the localization of eosinophils within the thymus
and the timing of their migration during the neonatal
period.39 Murine observations indicate that eosinophils are also important for postnatal mammary gland
and uterine development, and their recruitment into
the uterus heralds estrus. Although eosinophils,
themselves, are not known to participate in human
reproduction, eosinophil proMBP-1 is expressed in
the uterus by placental X and giant cells during pregnancy, and its production peaks 23 weeks before
(See Fig. 31-2)

Mature eosinophils are 1217 m in diameter and,
therefore, slightly larger than neutrophils. They typically have a bilobed nucleus with highly condensed
peripheral chromatin. Eosinophils have distinctive
cytoplasmic granules, demonstrated by their staining
properties with acidic dyes such as eosin and by their
unique electron microscopic appearance. These specific or secondary granules are composed of an electron-dense core and a less electron dense matrix, the
core being a crystalline lattice by electron microscopy.
In cross section, the eosinophil contains approximately
30 of these membrane-bound, core-containing, secondary granules.1 Five highly basic proteins are found
within the granules: (1) major basic protein (MBP)-1,
(2) MBP-2, (3) eosinophil-derived neurotoxin (EDN)
also known as ribonuclease (RNase)2, (4) eosinophil
cationic protein (ECP) also known as RNase3, and (5)
eosinophil peroxidase (EPO). Several other types of
proteins are found in secondary granules and include
enzymes, cytokines, growth factors, and chemokines.
Eosinophils contain three other types of cytoplasmic
granules, referred to as (1) primary granules, (2) small
granules, and (3) secretory vesicles. Primary granules
are of variable size, round, uniformly dense, present in
13 per electron microscopic cross section, and more
common in immature eosinophilic promyelocytes.
BIOLOGIC FUNCTIONS
::
EOSINOPHIL ULTRASTRUCTURE
AND GRANULE CONTENT
These granules may contain CharcotLeyden crystal

protein (also known as galectin-10), which can be
31
found in neutrophils as well ; CharcotLeyden crystals (CLCs) are characteristically found in asthmatic
sputum and in feces from patients with helminth infections or eosinophilic gastroenteritis. Small granules
contain acid phosphatase and arylsulfatase and are
present at 28 per electron microscopic cross section.
Secretory vesicles, also referred to as tubulovesicular
structures or microgranules, are characterized by their
small, dumbbell-shaped appearance and their albumin
content. They are the most abundant granules in number, with approximately 160 per electron microscopic
cross section. Normal eosinophils contain varying
numbers of nonmembrane-bound lipid bodies, which
are the principal stores of arachidonic acid. Lipid bodies also contain the enzymes, cyclooxygenase, 5- and
15-lipoxygenase, which are required to synthesize
prostaglandins, leukotrienes (LTs), and eoxins (vide
infra), and are increased in activated eosinophils.1
Chapter 31
c ollagen (Shc), SH2-containing phosphatase-2 (SHP-2),

growth factor receptor-bound protein 2 (Grb2), Vav,
and lipid kinases, phosphatidylinositol 3-kinase (PI3K), function in the interfacing step. The activation of
JAK2 and signal transducer and activator of transcription (STAT) 5 is essential for IL-5 dependent signal
transduction. The Ras GTPase-extracellular signal-regulated kinase (Ras-ERK) and also known as Ras-mitogen-activated protein kinase (Ras-MAPK) pathway, in
addition to the JAK2-STAT5 pathway, is important in
IL-5 signaling in the mobile step. The JAK-STAT and
Ras-MAPK pathways converge at various levels in
IL-5 signaling of eosinophils. IL-5 induces the expression of cytokine-inducible SH2 protein (CIS) and JAKbinding protein (JAB), which is one of the negative
feedback loops in the regulation of IL-5 signaling. Multiple other interactive signal transduction pathways
induce and regulate gene expression for eosinophil
growth, development, activation, and survival.21,22
Much of the discovery in these pathways has been in
murine systems with presumed general applicability
to humans. However, at least part of the immune
response to IL-5 in mice is NOT part of the biological
effect in humans, i.e., in mice, IL-5 enhances several
functions of B cells, including immunoglobulin production, growth, and differentiation, whereas human
B-cells are influenced by IL-5 only in the presence of
specific cytokines and under certain conditions.20
However, human IL-5 does act on T cells by increasing
the expression of IL2R and augmenting cytotoxic T
cell generation.23
353
Products of eosinophils and localization of distinctive granule proteins

Reactive oxygen
intermediates
O2
H2O2
Hydroxyl radicals
Singlet oxygen
Miscellaneous
Lipid mediators
Galectin-10
(Charcot-Leyden
crystal protein)
Leukotriene C4/D4/E4
Eoxin C4/D4/E4
Prostaglandin E1/E2/F1
5-HETE
5,15- and 8,15-diHETE
Platelet activating factor (PAF)
Thromoxane B2
Enzymes
Section 5
::
354
-Glucuronidase
Arylsulfatase B
Acid phophatase
Catalase
Histaminase
Collagenase
Matrix metalloproteinase 9
-Mannosidase
Phospholipase A2
Cyclooxygenases
5-Lipoxygenase
15-Lipoxygenase
Leukotriene C4 synthase
Lysozyme
NADPH oxidase
Cytokines
GM-CSF, IFN, IL-1, IL-2, IL-3,
IL-4, IL-5, IL-6, CXCL8 (IL-8),
IL-10, IL-12, IL13, IL-16, TGF-,
TGF-1, fibroblast growth factor-2,
vascular endothelial growth factor,
nerve growth factor, TNF-,
MIP-1, PDGF, CCL3, CCL5,
CCL11, CXCL13
MBP-1
MBP-2
EDN
ECP EPO
Granule-derived proteins
Major basic protein (MBP)-1
Eosinophili peroxidase (EPO)
Eosinophil derived neurotoxin (EDN or RNase2)
Eosinophil cationic protein (ECP or RNase3)
MBP-2
Surface receptors
CCR3, CD4, LTB4, PAF, C3a, C5a, CR1, CR3,
IgA (CD89), IgG (CD16, CD32),
immunoglobulin-like, CD50 and CD54, CD62L,
VCAM-1 (CD106), cytokine receptors - IL-1, IL-2,
(CD25), IL-3 (CD123), IL-4 (CD124), IL-5 (CD 125),
IL-8, IL-9 (CD129), IL-13, IL-31, GM-CSF (CD116),
IFN- (CD119), TNF- (CD120), TGF-,
adhesion molecules - integrins, 1, 2, 7,
selectins, carbohydrates, enzymes, histamine,
stem cell factor, HLA-DR, adrenergic, PAR-2,
TLR-7, TLR-8, CD48, and apoptosis and
signaling factors, CD30, CD45, CD52, CD69, CD95
Figure 31-2 Products of eosinophils and localization of distinctive granule proteins. The eosinophil produces myriad
products, including toxic granule proteins, which implicate its role in disease pathogenesis. The characteristic eosinophil
granules are coarse and, as their name implies, eosinophilic upon staining with eosin. Distinctive granule proteins are
localized to core and matrix portions of the specific cytoplasmic granules. A. An intact dermal eosinophil with its distinctive granules and typical bilobed nucleus. B. Characteristic specific (secondary) eosinophil granule with electron dense
crystalline core and radiolucent matrix showing localization of distinctive granule proteins.
arturition.40,41 The recruitment of eosinophils to the

p
gastrointestinal, thymic, uterine, and mammary tissues
is under the control of the CC chemokine, CCL11.42,43
Once eosinophils enter tissues, most do not recirculate. Several possible mechanisms exist for removal of
tissue eosinophils. These include shedding of the cells
across mucosal surfaces into the lumen of the intestinal
or respiratory tract, engulfment of apoptotic eosinophils by macrophages, and lysis or degranulation with
cellular degeneration. In various inflammatory conditions, including those affecting the skin (Chapter 36),
striking numbers of free granules and/or eosinophil
granule protein deposition are present in the absence
of intact eosinophils.1 Studies recently have revealed
that isolated eosinophil granules express extracellular

domains for interferon (IFN)- receptor and CCR3 and,
upon stimulation, respond independently as organelles by releasing ECP.44
ROLE OF EOSINOPHILS IN
IMMUNE FUNCTION
Shortly after their discovery by Paul Ehrlich in 1879,
eosinophils were observed in association with helminth infections. Theories have been promulgated that
eosinophils are important for host defense against parasites spawning numerous studies.45 For example, in
The activities of eosinophil-derived products include

direct cytotoxic effects on structural cells and microbes,
increased vascular permeability, procoagulant effects,
innate immune responses to some parasites, viruses,
fungi and tumor cells, enhancement of leukocyte
migration, amplification of effector T-cell responses
and, possibly even mammary gland development.
Collectively, these varied biologic actions provide the
pathophysiological basis for the signs and symptoms
observed in eosinophil-associated diseases.
Eosinophils in lymph nodes and spleen are especially increased after allergen exposures or microbial
insults.61,62 Eosinophils have been found in several cancers, particularly in lymphomas, leukemias, and colon
cancer. Clinical studies indicate that certain tumors
associated with tissue and/or peripheral eosinophilia
have a more favorable prognosis,63 whereas in other
tumors, they are thought to confer a poor prognosis,
such as nodular sclerosing Hodgkin disease, Szary
syndrome, and gastric carcinomas. In Szary syndrome (see Chapter 145), the tumor cells produce IL-5
ROLE OF EOSINOPHILS IN DISEASE
::
Another protective function that eosinophils may

have is in viral infections. Eosinophils and their granule proteins are increased in the respiratory tracts of
patients with respiratory syncytial virus, an RNA-viral
infection. EDN (RNase2) and ECP (RNase3), eosinophil granule matrix proteins, are ribonucleases (vide
infra). Purified eosinophils, as well as EDN and ECP
individually, reduced viral titers when added to respiratory syncytial viral suspensions. In mice, at least 11
eosinophil-associated ribonucleases degrade single
stranded RNA containing viruses.51 Despite divergence of the coding regions, conserved eosinophil
ribonuclease activity across species suggests a strong
evolutionary pressure to preserve this critical enzymatic activity.51 In other studies, pretreatment of parainfluenza-infected guinea pigs with anti-IL-5, to reduce
numbers of eosinophils, strikingly increased viral load
in the airways. Viruses, including parainfluenza virus,
respiratory syncytial virus, and rhinovirus, induce the
release of another eosinophil granule protein, EPO,
when coincubated with antigen-presenting cells and T
cells.52 Paradoxically, eosinophils may be a potential
reservoir for the human immunodeficiency virus
(HIV)-1.53
Eosinophils may have other roles in immune
responses as well. Through MHC class II expression
and IL-1 production, they can function as antigenpresenting cells for a variety of viral, parasitic, and
microbial antigens, including staphylococcal superantigens, and allergens.54,55 Eosinophils are recruited to
secondary lymphoid structures to promote the proliferation of effector T cells although they are unable to
affect nave T cells.56 Eosinophils, as sources of cytokines, influence T cell-dependent responses.1 In keeping with the prominence of eosinophils in allergic
disorders, eosinophils are involved in T cell polarization favoring Th2 by promoting Th1 apoptosis in addition to their influence via cytokine expression.54,5760
Chapter 31
vitro studies demonstrated that eosinophils are cytotoxic to large nonphagocytosable organisms, such as
multicellular helminthic parasites. Eosinophils bind to
host-derived immunoglobulins and complement components on the surface of their targets (so-called antibody- or complement-) dependent cytotoxicity. They
also bind to carbohydrate ligands expressed on parasites, such as the Lewisx-related molecules, and cell
adhesion molecules similar to selectins. Eosinophils
are activated to release their granule products with
deposition of these biologically active proteins in and
around the parasites causing disruption of the parasites integument and, ultimately, death of the organism. The granule proteins have different effects. ECP
produces fragmentation and disruption whereas
MBP-1 produces a distinctive ballooning detachment
of the tegumental membrane, and EDN is active only
at high concentrations causing crinkling of the
tegumental membrane.46 However, in murine models
in which blood, marrow, and tissue eosinophilia is
largely abolished by neutralizing IL-5 activity, the
intensities of primary or secondary parasitic infection
are unchanged indicating that eosinophils have little
or no role in parasitic host defense in these models.1
The results must be interpreted cautiously because
mouse and human eosinophils have functional differences, and mice are not natural hosts of many of the
parasites tested experimentally.
Eosinophils also release cytotoxic granule proteins
onto the surface of fungal organisms and into the
extracellular milieu in fungal infections. Eosinophils
kill fungi in a contact-dependent manner. Eosinophils
adhere to the fungal cell wall component, -glucan, via
a 2-integrin surface molecule, CD11b.47 Eosinophils
do not express other common fungal receptors, such as
dectin-1 and lactosylceramide, and, specifically, do not
react with chitin. However, chitin, which is a polymer
that confers structural rigidity to fungi, helminths,
crustaceans, and insects, induces accumulation of
eosinophils in tissues through production of LT B4 in
mice.48 Eosinophils also are activated by fungal organisms that release proteases, such as Alternaria, through
protease-activated receptors (PARs). For example, fungal aspartate protease activates eosinophils through
PAR-2 and, thereby, mediates eosinophils innate
responses to certain fungi.49
As a granulocyte, the eosinophil is capable of phagocytosing and killing bacteria and other small microbes
in vitro, but eosinophils cannot effectively defend
against bacterial infections when neutrophil function is
deficient. Nevertheless, recent investigations reveal
that eosinophils may have a role in innate immunity
against bacteria using a unique mechanism, DNA
trap.50 Eosinophils rapidly release mitochondrial DNA
when exposed to bacteria, a complement component,
C5a, or CCR3 ligands. The traps contain eosinophil
granule proteins, ECP and MBP, and have antimicrobial
effects. In the extracellular space, the granule proteins
and mitochondrial DNA form structures that bind and
kill bacteria both in vitro and in vitro. Eosinophils,
unlike neutrophils, do not undergo cell death as part of
this process. This may be an important innate immune
response, particularly in mucosal epithelium.50
355
and, therefore, are responsible for the eosinophilia,

which is a reflection of tumor burden.64 Where eosinophilia is a good prognostic factor, eosinophils are considered to be part of an effective host response to the
tumor.65,66
EOSINOPHIL CONSTITUENTS AND

THEIR ACTIVITIES
Section 5
::
356
The eosinophil contains and produces a myriad of factors that implicate its role in inflammation and tissue
destruction and remodeling (see Fig. 31-2).70 Products
released by eosinophils include chemoattractants, colony-stimulating factors, and endothelial-activating
cytokines. In addition to toxic cationic proteins from
specific granules and oxidative products released into
tissues following activation, these factors include arachidonic acid-derived lipids, hydrolytic enzymes, neuropeptides, colony-stimulating factors, and cytokines/
chemokines that facilitate further leukocyte recruitment to sites of inflammation (see Fig. 31-2). Surface
molecule expression is important in all aspects of
eosinophil biology from promoting growth and differentiation to eosinophil trafficking into tissue to activation and/or priming of the cells to senescence.
Numerous membrane factors are expressed on eosinophils that further direct eosinophil biological effects.
(See eTable 31-0.1 in online edition for designations of
various eosinophil factors.)
EOSINOPHIL GRANULE PROTEINS. Among

the products of eosinophils that are most damaging to
the host are the specific granules cationic proteins.
Furthermore, the granule proteins are markers of
eosinophil activity because the eosinophil often loses
its characteristic morphology through cytolysis in tissues.71 Knowledge of their biological actions provides
insight into their functions in human disease. Once
deposited, the granule proteins persist in tissues for
extended timesEPO for 1 week, ECP for 2 weeks,
EDN for 2.5 weeks, and MBP-1 for 6 weeks.72 Each of
these proteins have been shown to induce direct tissue
damage to both host cells, including myocytes, endothelium, neurons, epithelium, and smooth muscle, and
to microbes (vide supra). For example, MBP-1, ECP, or
EPO application to airway epithelium in primates produces ciliostasis, desquamation, and hyperreactivity of
respiratory smooth muscle mimicking the pathology
of asthma.73,74 Damage to endothelium in eosinophilic
endomyocardial disease is thought to be the initiating
factor in the cardiomyopathy observed in the hypereosinophilic syndromes (see Chapter 36).75 All four of
the cationic granule proteins [(1) EPO, (2) ECP, (3)
EDN, and (4) MBP-1] likely contribute to the edema
observed in skin diseases due to their vasodilatory
effects with contribution from mast cells and basophil
histamine release by MBP-1.76 Eosinophil granule proteins stimulate various cells in addition to mast cells
and basophils, including neutrophils and platelets.
Nodules, eosinophilia, rheumatism, dermatitis and
swelling (NERDS), episodic angioedema with eosinophilia (Gleich syndrome), urticaria, eosinophilic cellu-
litis (Wells syndrome), and insect bite reactions

demonstrate variable degrees of edema that are probably explained, at least in part, by this mechanism (see
Chapter 36). Eosinophil granule proteins injected into
skin produce lesions including dose-dependent whealand-flare reactions by MBP and ulcerations by ECP
and EDN.77,78 Wound healing is delayed in the presence of eosinophils and eosinophil granule proteins.79,80
Eosinophils, through activities of granule proteins,
have procoagulant activity. Thromboses have developed in the hypereosinophilic syndromes, including
several case reports of hepatic vein obstruction (Budd
Chiari syndrome). The thromboses could be the result
of direct endothelial damage or due to the ability of
MBP and ECP to neutralize heparin. In addition, MBP
is a strong platelet agonist, and platelet-activating factor (PAF), which is released by eosinophils, causes
platelet aggregation.1
MAJOR BASIC PROTEIN

General Characteristics.
Major basic protein

(MBP) comprises the crystalloid core of the specific
eosinophil granule. It was so named because it
accounts for a major portion, about 55% (in guinea
pig), of the eosinophil granule protein, and has a high
isoelectric point, calculated at greater than pH 11, so
strongly basic that it cannot be measured accurately. It
is now known that MBP is expressed as two homologs,
MBP-1 and MBP-2, coded by different genes on chromosome 11.
Tissues Effects of Basic Proteins. MBP-1

directly damages helminths and also lethally damages
mammalian cells and tissues, examples of which are its
ability to cause exfoliation of bronchial epithelial cells
and to kill tumor cells. MBP-1 exerts its effects by
increasing cell membrane permeability through surface charge interactions leading to disruption of the
cell surface lipid bilayer.81 MBP-1 and MBP-2, but none
of the other eosinophil granule proteins, stimulate histamine and LTC4 release from human basophils.
Further, MBP-1 and MBP-2 stimulate neutrophils,
inducing release of superoxide, lysozyme, and IL-8.
MBP-1 and EPO are potent platelet agonists causing
release of 5-hydroxytryptamine and promoting
clotting.
EOSINOPHIL PEROXIDASE. Eosinophil peroxidase (EPO) is highly basic, pI 10.8, localized in the
matrix of the specific eosinophil granule and is a key
participant in generating reactive oxidants and free
radical species in activated eosinophils. EPO consists
of a heavy chain and a light chain encoded with a prosequence. The EPO gene is on chromosome 17 and
maps closely to myeloperoxidase and lactoperoxidase
genes, two other members of the mammalian peroxidase family found in neutrophils and mucosal glands,
respectively. Although MBP is present in the highest
molar concentration in eosinophil granules, EPO, by
weight, is the most abundant protein constituting
approximately 25% of the specific eosinophil granules
total protein mass. EPO catalyzes the oxidation of
CHARCOTLEYDEN CRYSTAL PROTEIN

General. Distinctive hexagonal, bipyramidal crys-
tals were initially described in 1853 in a patient with

leukemia and later, in 1872, in the sputa of asthmatic
patients. Since then, CLCs have been regarded as a
hallmark of eosinophilia. CLC protein is an abundant,
characteristic, although not unique, protein of eosinophils. It is also found in lesser amounts in basophils.
CLC mRNA and EDN mRNA are among the most
highly expressed mRNAs in mature peripheral blood
eosinophils suggesting de novo synthesis.1
CHARCOTLEYDEN CRYSTALS
REACTIVE OXYGEN METABOLITES. Reactive
oxygen species are important mediators of the tissue
injury caused by eosinophils. The reactive oxygen
intermediates produced by NADPH oxidase during
the respiratory burst initiated on eosinophil activation
include superoxide, hydroxyl radicals, and hydrogen
LIPID MEDIATORS
General. Lipid bodies in eosinophils are storage sites
for arachidonic acids. Eosinophils produce several arachidonic acid metabolites, including cysteinyl LTs from
the 5-lipoxygenase pathway (LTC4, LTD4, and LTE4)
and thromboxanes and prostaglandins from the cyclooxygenase pathway [thromboxane B2, prostaglandin
(PG) E2, and PGF1].99,100
CYTOKINES. Eosinophils are a considerable source

of growth factors and regulatory as well as proinflammatory cytokines and chemokines.1,103 The various
growth factors produced by eosinophils include transforming growth factor (TGF)-, TGF-, fibroblast
growth factor-2, vascular endothelial growth factor,
nerve growth factor, and platelet-derived growth
factor-. There is evidence that these growth factors
induce stromal fibrosis and basement membrane
thickening at sites of chronic eosinophilic inflammation including nasal polyps, asthmatic airways and,
likely, in certain skin disorders such as atopic dermatitis.1 The production and release of nerve growth factor
by eosinophils promotes neurites in nerve cells.104
Another group of cytokines produced by eosinophils
modulates other immune cells and includes tumor
necrosis factor (TNF)-, macrophage inflammatory
protein (MIP)-1 (CCL3), IL-1, IL-2, IL-3, IL-4, IL-5,
IL-6, CXCL8 (IL-8), IL-10, IL-12, IL-13, IL-16, GM-CSF,
and IFN-.103 Additional chemokines produced by
eosinophils are CXCL13 (B lymphocyte chemoattractant factor), CCL5 [regulated on activation, normal T
cells expressed and secreted (RANTES)], and CCL11,
in addition to CCL3 and CXCL8. CCL5 apparently is
stored in at least two intracellular compartments,
namely, (1) the matrix of specific eosinophil granules
and (2) small secretory vesicles. All of these cytokines
are constitutively produced in low levels in resting
eosinophils and induced in inflammatory conditions
with activation of eosinophils by engagement of
receptors (vide infra) with immunoglobulins, complement and cytokines, including those produced by
eosinophils, themselves, in an autocrine manner.
Notably, eosinophils produce the three principal cytokines involved in their own growth and differentiation(1) IL-3, (2) IL-5, and (3) GM-CSF, as well as
chemokines important in their own chemotaxis, CCL5
and CCL11. It is known that eosinophils synthesize
and secrete GM-CSF by a peptidyl-prolyl isomerase
(PIN1)-dependent mechanism.105 However, although
eosinophils produce quantities of certain cytokines
comparable to T cell production,106 the relative contributions of eosinophil-derived cytokines to inflammation remain to be determined. In summary, the
eosinophil-derived cytokines may function in both an
autocrine and paracrine fashion and likely have
pathophysiological relevance.
protein (ECP or RNase3) and eosinophil-derived neurotoxin (EDN or RNase2) are homologous proteins
with sequence identity in 37 of 55 amino acid residues
and are encoded on chromosome 14. ECP also has neurotoxic activity. ECP and EDN play a role in viral host
defense to RNA viruses.51,88,89 New roles for these proteins continue to be identified.90 EDN induces the
migration and maturation of dendritic cells.91 It also is
an endogenous ligand of Toll-like receptor 2 (TLR2)
and can activate myeloid dendritic cells by triggering
the TLR2-myeloid differentiation factor 88 (Myd88)
signaling pathway.60 Based on its ability to serve as a
chemoattractant and activator of dendritic cells along
with enhancing antigen-specific Th2-biased immune
responses, EDN functions as an alarmin alerting the
adaptive immune system to preferentially enhance
antigen-specific Th2 responses.60
::
EOSINOPHIL CATIONIC PROTEIN AND

EOSINOPHIL-DERIVED NEUROTOXIN
General Characteristics. Eosinophil cationic
peroxide. Hydrogen peroxide can generate hypohalous acids through the action of EPO, which are cytotoxic as well. Reactive oxygen species also can augment
the inflammatory response by inducing gene expression and T-cell proliferation.98
Chapter 31
halides, pseudohalides, and nitric oxide to form highly

reactive oxygen species (hypohalous acids), reactive
nitrogen metabolites (nitric dioxide), and other oxidants that then oxidize targets on proteins with oxidative stress and subsequent cell death by apoptosis and
necrosis. EPO kills numerous microorganisms in the
presence of hydrogen peroxide, generated by eosinophils and other phagocytes, and halide. This combination of products also initiates mast cell secretion. As
noted, both EPO and MBP induce noncytolytic, dosedependent 5-hydroxytryptamine release from platelets.82 Binding of EPO to neutrophils reversibly inhibits
EPO peroxidase activity but increases neutrophil
aggregation and adhesion to endothelial cells.83 EPO
binding to microbes, including Staphylococcus aureus,
greatly potentiates their killing by phagocytes. EPOcoated tumor cells are spontaneously lysed by activated macrophages.
357
Section 5
::
358
SURFACE EXPRESSION.
Eosinophils express
numerous receptors and other factors on their surface
membranes through which they communicate with
the extracellular environment, but no single surface
protein is uniquely expressed on eosinophils. These
receptors have been identified either by flow cytometry or by functional assays, and can be grouped as follows: chemotactic factor and complement receptors
including chemokine, LT and PAF; immunoglobulin
supergene family member receptors including immunoglobulins; cytokine receptors including those discussed above; adhesion molecule receptors; receptors
involved in apoptosis; and miscellaneous receptors
and surface factors. Eosinophil membrane proteins
are promising targets for therapeutic modulation of
eosinophil effects (see section Pharmacological
Manipulation).
CHEMOTACTIC FACTOR AND COMPLEMENT RECEPTORS. Chemotactic factors are
important in orchestrating cellular trafficking to sites

of inflammation as well as physiologic homing (e.g.,
eosinophils to gastrointestinal tract). The eosinophil
has receptors for many chemotactic agents such as
LTB4, PAF, bacterial products (N-formyl-methionylleucyl-phenylalanine), complement anaphylatoxins,
C3a and C5a. Eosinophils express complement receptor (CR)1 (CD35), a receptor for C1q that also binds
C4b, C3b, and iC3b, and CR3 (Mac-1, CD11b/CD18) in
addition to receptors for C3a and C5a. These are
important receptors in eosinophil effector functions.
The binding of chemokines to their respective receptors mediates many biological effects, which, in addition to cell shape change and migration, includes cell
activation, receptor internalization, induction of the
respiratory burst with generation of toxic oxygen
metabolites, and transient activation of integrin adhesiveness. PAF activity on eosinophils is mediated
through PAF receptors that have been cloned. PAF is
one of the most potent chemoattractants for eosinophils and selectively recruits eosinophils over neutrophils. PAF also induces release of granule proteins,
reactive oxygen species, and LTC4 from eosinophils.
LTB4 through its eosinophil receptor potently stimulates eosinophil chemotaxis and elicits arachidonic
acid metabolism and a respiratory burst. It does not
induce eosinophil degranulation. Eosinophils also
may have LTD4 receptors.1 The chemotaxins listed
above have potent effects on eosinophils but are nonselective in that they are active on other leukocytes.
Because many eosinophil-associated diseases are characterized by tissue eosinophil infiltration with little or
no neutrophil infiltration, the identification of the
CCR3 receptor and its ligands was an important breakthrough in discovering eosinophil-selective chemotaxins.107 Specific members of the chemokine family are
critical for the cellular trafficking of eosinophils. The
major ligands of CCR3, CCL5, CCL11, CCL13 (monocyte chemotactic protein-4), CCL24 (eotaxin-2), CCL26
(eotaxin-3), play a critical role in both the homeostatic
and inflammation-induced recruitment of eosinophils
to tissue sites.13,108 Not surprisingly, the most highly
expressed chemokine receptor on human eosinophils

is CCR3 (40,000400,000 receptors per cell). CCR3 is a
seven-transmembrane spanning G-protein coupled
receptor that can deliver both powerful positive and
negative signals depending on the interacting ligand.109
IMMUNOGLOBULIN SUPERGENE FAMILY

MEMBER RECEPTORS. Many of the studies of
eosinophil functions, including phagocytosis, antigendependent cytotoxicity, oxygen metabolism, LTC4 production, and eosinophil survival, have been performed
using IgG-coated targets. Among eosinophil surface
receptors for the immunoglobulin family members,
the most highly expressed receptor is FcRII (CD32),
which binds aggregated IgG, particularly of the subclasses IgG1 and IgG3. The binding of IgG to this receptor may be important in eosinophil degranulation in
parasitic and allergic diseases along with other eosinophil functions.1 Freshly isolated eosinophils express
only FcRII (CD32) of the IgG receptors, but eosinophils can be stimulated by cytokines, particularly IFN, to express FcRI (CD64) and FcRIII (CD16) and
augment FcRII (CD32) expression.
FcRI (CD89), the IgA receptor, is present on the surface of eosinophils. Eosinophils also possess a binding
site for secretory component that may account for the
finding that secretory IgA is the most potent immunoglobulin stimulant for eosinophil degranulation. The
interaction of eosinophils with IgA is enhanced by Th2
cytokines, IL-4 and IL-5. These observations, coupled
with the observation that many eosinophils are found
in epithelial tissues such as gastrointestinal tract, suggest that eosinophils and secretory IgA play an important role in mucosal immunity.
Members of the immunoglobulin superfamily are
type I transmembrane molecules that share common
structural characteristics of the globular domains
found in immunoglobulins. Intercellular adhesion
molecule (ICAM)-1 (CD54) and ICAM-3 (CD50) are
members of this superfamily expressed on eosinophils
and are likely important in leukocyteleukocyte and
leukocytetissue cell adhesion through leukocyte
function-associated antigen (LFA)-1 (L2; CD11a/
CD18) as its counterligand (see Fig. 31-1).
CYTOKINE RECEPTORS. Cytokine receptors are

present at low levels on the surfaces of eosinophils.
Receptors for IL-3 (CD123), IL-5 (CD125), and GM-CSF
(CD116) are readily detected and, as noted previously,
all share a common chain (CD132). Eosinophil activation has been observed by a variety of other cytokines
through presumed and/or detected receptors. These
include: stem cell factor (c-kit receptor; CD117), IFN-
(CD119), TNF- (CD120), IL-4 (CD124), IL-9 (CD129
and CD132), IL-13 (gp65), IL-2 (CD25), IL-31, and TGF receptors. Many of these receptors are for cytokines
that eosinophils produce providing further evidence
that they have autocrine functions.
ADHESION MOLECULE RECEPTORS. Adhesion molecule receptors are expressed on the eosinophil cell surface to mediate trafficking to and within
tissues, and for general cellcell interactions.112 These
The selective recruitment of eosinophils into sites of

inflammation results from interactions among eosinophil-activating cytokines, chemokine-inducing cytokines, and endothelial-activating cytokines (see
Fig. 31-1). Similar to other leukocytes, selectin, integrin, and immunoglobulin gene superfamily members
contribute to the signaling involved in eosinophil trafficking. In particular, eosinophils constitutively express
the integrin, VLA-4, which interacts with its ligand,
VCAM-1, induced on endothelial cells by cytokines,
especially Th2 cytokines (IL-4 and IL-13).125 After
movement through vessels, eosinophils adhere to
extracellular matrix proteins. Here, surface factors, b2
integrins such as CD11b/CD18 (Mac-1), bind to fibrous
proteins such as fibronectin, laminin, and collagen,
and, not only determine where eosinophils will reside,
but likely prolong their survival.126 In this regard,
CD11b/CD18 (Mac-1) integrin is also critical for eosinophil effector functions, including degranulation.127
FACTORS WORKING TOGETHER. The various

products elaborated by eosinophils in response to
receptor activation do not necessarily function independently but often act in concert to mediate their biological effects. For example, the release of TGF-,
TGF-, fibroblast growth factor-2, vascular endothelial
growth factor, MMP-9, and inhibitors of MMPs from
activated eosinophils collectively induce fibroblast
proliferation and extracellular matrix protein production. Eosinophils contribute factors of their own and
influence factor production from other cells, for example, eosinophil mediators induce platelet release of
TGF-. After intradermal eosinophil infiltration, there
is production of extracellular proteins, including
tenascin and procollagen 1, as well as myofibroblast
TISSUE TRAFFICKING
::
RECEPTORS INVOLVED IN APOPTOSIS. Eo

sinophils express several death receptors, that are
involved in apoptotic pathways, such as Fas receptor
(CD95), Siglec-8, CD30, CD45, Campath (CD52), and
CD69, along with important intracellular regulators of
eosinophil apoptosis such as the members of the B-cell
leukemia/lymphoma (Bcl)-2 and inhibitor of apoptosis families.113 Diseases characterized by eosinophilia
likely result, in part, from delayed or defective apoptotic pathways allowing accumulation and persistence
of eosinophils in blood and/or tissues.
formation.120 Eosinophil-induced fibrosis is observed

in the lungs and heart of patients with hypereosinophilic syndrome, in and around organs in other fibrosing/sclerosing disorders and in the skin of patients
with eosinophilic fasciitis (Shulman syndrome),
eosinophiliamyalgia syndrome, and toxic oil syndrome (see Chapter 36).121 Eosinophil granule proteins,
MBP-1 and EDN, along with other neuroactive mediators produced by eosinophils such as nerve growth
factor, vasoactive intestinal peptide, and substance P,
likely affect nerve physiology. In fact, eosinophils and
eosinophil granule proteins are often observed in close
proximity to nerve endings.122,123 Eosinophil-induced
nerve dysfunction is likely an important part of the
gastric dysmotility observed in subjects with food
allergies, the dysfunction of vagal muscarinic M2
receptors observed in asthmatics, and may also contribute to itch along with other physiological aberrations in atopic dermatitis and other cutaneous
diseases.123,124 Collectively, the eosinophils response
to surface factors determines its role in health and
disease.
Chapter 31
receptors fall into three groups: (1) immunoglobulin

superfamily (reviewed above), (2) selectins and their
glycoprotein counterligands, and (3) integrins. l-selectin (CD62L) and p-selectin glycoprotein ligand-1
(PSGL-1, CD162) are expressed at high levels on eosinophils, whereas e-selectin ligands, as an example,
sialyl-Lewis X (CD15s), are expressed at very low levels. p-selectin together with PSGL-1 is the most important selectin pair in eosinophil migration into tissues.
Eosinophils express a variety of integrins (1, 2, and
7) on their surface, which facilitate their adhesion to
extracellular matrix proteins, vascular cellular adhesion molecule (VCAM)-1 (CD106) on activated endothelium, or ICAM-1 present on resting or activated
epithelium and activated endothelium. Integrins are
composed of two subunits that exist as noncovalently
associated heterodimers, with and subunits. The 1
integrins expressed on eosinophils include 41 (very
late antigen-4 or VLA-4), which binds to VCAM-1
found on activated endothelium and the extracellular
matrix protein, fibronectin. Eosinophil adhesion to
fibronectin induces the autocrine production of eosinophil-activating survival cytokines, IL-3, IL-5, and
GM-CSF. The only other 1 integrin expressed on
eosinophils is 61, which mediates the binding to
another matrix protein, laminin. Four 2 integrins are
found on eosinophils: (1) L2 (LFA-1), (2) M2
(CD11b/CD18 or Mac-1), (3) X2, and (4) D2. These
integrins bind to ICAM-1, ICAM-2, ICAM-3, VCAM-1,
fibrinogen, and the complement fragment, C3bi. Lastly,
eosinophils also express 47, which is the ligand for
the gut mucosal addressin cell adhesion molecule-1
(MAdCAM-1), which is likely important in homing of
eosinophils to gastrointestinal mucosa; 47 also mediates adhesion to fibronectin and VCAM-1.
EOSINOPHIL-ACTIVATING CYTOKINES
GENERAL. Eosinophil-activating cytokines can be
produced by many cell types in addition to T cells and
mast cells, including keratinocytes, endothelial cells,
and monocytes, along with eosinophils, themselves. The
eosinophil-activating cytokines, IL-3, IL-5, GM-CSF, and
others, enhance chemotactic responses, in addition to
multiple other effects on eosinophils such as promoting
maturation, cell survival, and LT production.128
ENDOTHELIAL-ACTIVATING
CYTOKINES
(See Chapter 162)
359
Section 5
::
360
During eosinophil migration, at least three types

of endothelial activations occur. The first is the
expression of p-selectin, which occurs when Weibel
Palade bodies in endothelial cells are transported to
the cell surface rapidly after exposure to histamine,
LTs, and a host of other inflammatory mediators.
Expression of p-selectin on the endothelial-cell surface initiates leukocyte rolling, via CD162 (PSGL-1),
which is the important initial step before firm adhesion and transendothelial migration. A second type
of endothelial activation is that induced by nonspecific activators such as IL-1 and TNF-. These cytokines stimulate endothelial expression of e-selectin,
ICAM-1, and VCAM-1, to which eosinophils firmly
adhere, or tether. They also induce production of
chemokines by endothelial cells. The third type of
endothelial activation is that induced by IL-4 and
IL-13. These cytokines selectively induce VCAM-1,
which is centrally involved in the recruitment of
VLA-4-positive cells, including eosinophils, basophils, and lymphocytes into sites of allergic
inflammation.
CHEMOKINES
The transition from rolling to firm adherence is substantially increased by CCR3 ligands, the CC chemokines. Induction of the expression of chemokines by
activated endothelial cells results in higher levels of
chemokines on or near the endothelial surface,
which transiently affect 1 and 2 integrin avidity,
resulting in firm adhesion of the eosinophil to the
endothelial cell. However, chemokines produced by
structural cells such as fibroblasts, smooth muscle
cells, and epithelium probably are more important
in directing migration and activation of eosinophils
within tissues than those expressed on endothelial
cells.137
Tissue chemokine expression forms a gradient signal that guides eosinophils into tissue. CCL11 guides
eosinophils into tissue locations in which eosinophils
are normally present, thymus, uterus, mammary
gland, and gastrointestinal tract.143 In Th2 disorders,
Th2 cytokines induce chemokine expression. In lungs
affected by asthma and eosinophilic pneumonia,
CCL11, CCL24, and CCL26 are increased along with
other chemokines,144 such as LTB4 and galectin-9.145,146
In the intestinal tract, CCL26 plays a key role in eosinophilic esophagitis, whereas CCL11 is involved in
lower gastrointestinal eosinophil disorders. In skin,
IL-4, IL-13, and TNF- stimulate CCL11, CCL24, and
CCL26 production from mast cell and lymphocyte
sources as well as from fibroblasts (CCL11 and CCL26)
and keratinocytes (CCL26).147 As in eosinophilic
esophagitis, CCL26 may be important in atopic dermatitis in which serum CCL26 levels correlate with
disease activity.148
Arachidonic acid metabolites, particularly, the cysteinyl LTs, LTC4, LTD4 and LTE4, and PGD2, are
involved in eosinophil trafficking as evidenced by the
observations that LT receptor antagonists reduce
blood and lung eosinophilia and that mice, depleted
of LTB4 receptors, have markedly reduced lung

eosinophilia after allergen exposure. Eosinophil,
basophil, and Th2 cell recruitment occurs, to some
extent, through CRTH2 (CD294), the high affinity
PGD2 type 2 receptor. Other factors that contribute to
eosinophil trafficking are being identified. For example, eosinophils express high levels of histamine 4
receptors that mediate chemoattraction and activation.149 An extracellular matrix protein, periostin,
encoded by an IL-13 inducible gene, likely facilitates
eosinophil infiltration into tissues by directly affecting eosinophil adhesion; periostin is overexpressed in
eosinophilic esophagitis and correlates with eosinophil numbers in biopsies.150
ACTIVATION OF EOSINOPHILS
As reviewed previously, various inflammatory mediators activate eosinophils. In addition to cytokines,
TNF-, GM-CSF, IL-3, and IL-5, these include complement components, C3a and C5a, lipid mediators, LTC4
and PAF, chemokines, as well as engagement of IgA
and IgG Fc receptors. CD11b/CD18 (Mac-1)-dependent cellular adhesion is a critical component for
degranulation and superoxide production induced by
GM-CSF and PAF eosinophil activation and likely is an
in vitro mechanism that results from eosinophil contact with stromal cells and/or proteins.151 Members of
the CC chemokine subfamily, CCL5, CCL7 (MCP-3),
CCL11, CCL13 (MCP-4), CCL24 that bind to the chemokine receptor, CCR3, also potently activate eosinophils. Activated eosinophils develop a number of
phenotypic changes, including a reduction in granules,
vacuolization, and an expansion of their cytoplasm,
leading to a reduction in cell density and are referred
to as hypodense. The number of hypodense cells predicts allergic disease severity. A cell surface marker
that distinguishes hypodense from normodense eosinophils has not been identified, but there are several
surface markers with enhanced expression on in vitro
or in vitro activated or hypodense cells: M integrin
(CD11b), X integrin (CD11c), FcR111 (CD16), hyaluronic acid receptor (CD44), ICAM-1 (CD54), CD69,
and HLA-DR.152
Upon recruitment and activation in tissues, eosinophils have various effects as detailed in previous sections. In tissues, eosinophils release granule contents
into their extracellular space via three mechanisms:
(1) piecemeal degranulation, (2) regulated secretion
(also referred to as regulated exocytosis), and (3)
cytolytic degranulation. First, in piecemeal degranulation, eosinophils selectively release specific granule
components; as an example, IFN- activation promotes mobilization of granule-derived CCL5 to the
eosinophils surface without inducing cationic protein release.153155 Second, in regulated secretion, a
docking complex forms consisting of soluble N-ethylmaleimide-sensitive factor attachment protein
(SNAP) receptors (SNAREs) located on the vesicle
(vSNAREs) and the target membrane (tSNAREs).
Two types of SNAREs have been described based on
the presence of a conserved amino acid, arginine (R)
MANIPULATION.
::
PHARMACOLOGICAL
Eosinophil-associated disease is a term that, strictly

speaking, refers to diseases in which eosinophil numbers or eosinophil granule protein levels (or other
eosinophil products) are associated with disease
activity. This term encompasses multiple heterogeneous disorders, including skin diseases (see Chapter
36), in which targeting eosinophils and/or their products is a therapeutic goal. Many available treatments
reduce eosinophils numbers, thereby inhibiting
eosinophilic inflammation, including glucocorticoids,
calcineurin inhibitors, IFN-, IFN-, LT antagonists,
myelosuppressive/cytotoxic drugs, and, possibly,
even antihistamines. However, none is specific for
eosinophils. It is only in recent years that selective
and direct reduction of eosinophils has been achieved,
and these therapies have provided new insight into
disease pathogenesis.9
Among the nonselective drugs for eosinophil reduction, glucocorticoids generally are very effective. The
immediate (within 3 hours) reduction in circulating
eosinophils observed after systemic administration of
glucocorticoids likely occurs as a consequence of
sequestration into extramedullary organs (liver, spleen,
and lymph node), as has been shown in rodents. Glucocorticoids affect eosinophil infiltration into tissues
by four mechanisms: (1) sequestration into lymphoid
tissues, (2) induction of eosinophil apoptosis, (3)
reduction of eosinophil production by bone marrow,
and (4) alterations in the production of the cytokines/
chemokines important in eosinophil trafficking.158160
Glucocorticoids suppress the production of several
cytokines important for the induction of adhesion molecules on endothelial cells, including IL-1, TNF-, IL-4,
and IL-13, and the release of eosinophil-active chemokines, including CCL5, CCL7, and CCL11. Unfortu-
nately, steroid resistance develops in some patients,

and long-term administration of glucocorticoids is
associated with limiting side effects. The mechanism of
glucocorticoid resistance is unclear but, in part, may be
explained by decreased numbers of glucocorticoid
receptors, and polymorphisms and alterations in transcription factor activator protein-1 (AP-1).161 Patients
who have or who develop glucocorticoid resistance
require other therapies. Interestingly, lidocaine and
sulfonylureas (such as glyburide) also inhibit cytokineinduced eosinophil survival with glucocorticomimetic
effects and may have antieosinophilic effects clinically.162164
Calcineurin antagonists, such as cyclosporine, tacrolimus, and pimecrolimus, broadly inhibit T-cell cytokine release including those that specifically induce
eosinophilic inflammation (IL-4, IL-5, and GM-CSF).
They also decrease the expression of CCL5, CCL11,
and IL-5 with associated decreased tissue eosinophilia
as has been shown in atopic dermatitis.165 Mammalian
target of rapamycin (mTOR) inhibitors, including
rapamycin, have direct effects on eosinophils, decreasing eosinophil granule protein release after IL-5 activation.166 The use of these therapeutic agents are limited
by their side effects including immunosuppression, as
well as other metabolic effects that may be in part
genetically determined.167
Several myelosuppressive drugs, including hydroxyurea, vincristine sulfate, cyclophosphamide, methotrexate, 6-thioguanine, 2-chlorodeoxyadenosine and
cytarabine combination therapy, pulsed chlorambucil,
and etoposide, may be beneficial in eosinophil-associated disease alone or as steroid-sparing agents.
Hydroxyurea has been particularly effective in decreasing circulating eosinophil numbers.
In myeloproliferative hypereosinophilic syndrome
(chronic eosinophilic leukemia) with the FIP1L1-PDGFRA mutation that codes for a tyrosine kinase, imatinib
mesylate, a tyrosine kinase inhibitor, is approved for
the treatment of chronic myelogenous leukemia and
the hypereosinophilic syndrome and has produced
rapid, complete or near complete remissions.168
Patients who have features of myeloproliferative HES
but who lack FIP1L1-PDGFRA still may respond to
imatinib (see Chapter 36).169
Alemtuzumab is a monoclonal antibody to CD52
that is used to deplete CD52+ lymphocytes in the treatment of chronic (B-cell) lymphocytic leukemia and
T-cell lymphoma. Eosinophils, but not neutrophils,
also express CD52, and alemtuzumab has been useful
in treating patients with refractory hypereosinophilic
syndrome, including those with abnormal T cells,170172
but has serious limiting side effects from cytopenias,
infusion reactions and infections.
Interferons, both IFN- and IFN-, may be therapeutically beneficial in eosinophil-associated disease by
inhibiting eosinophil degranulation and inflammatory
mediator release. IFN- may be better tolerated
than IFN- and is used as a steroid-sparing agent predominantly in patients with lymphocytic variant
hypereosinophilic syndrome, but also may be useful
in myeloproliferative variant hypereosinophilic syndrome (see Chapter 36).173,174
Chapter 31
or glutamine (Q). Human eosinophils express the

R-SNARE, vesicle-associated membrane protein
(VAMP)-2 on cytoplasmic secretory vesicles, and the
Q-SNAREs, SNAP-23, and syntaxin-4, on the plasma
membrane.156 VAMP-7 also plays a critical role in
both eosinophil and neutrophil mediator release.157
The current understanding is that receptor-induced
eosinophil activation leads to rapid mobilization of
cytoplasmic vesicles to the plasma membrane, leading to the formation of a SNARE complex (VAMP-2,
-7/SNAP-23/syntaxin-4) and mediator release.
Third, cytolytic degranulation occurs in many
inflammatory diseases including skin disease, such
as atopic dermatitis, eosinophilic esophagitis, and
lesions found in affected organs with the hypereosinophilic syndromes. It is characterized by organelle
rupture, chromatolysis of nuclei with loss of morphologic integrity and identity of eosinophils, and
extensive deposition of eosinophil granules and
granule products in tissue.71 Therefore, it seems
somewhat paradoxical that eosinophils from atopic
dermatitis patients have prolonged eosinophil survival and yet exhibit such marked cytolytic degranulation in skin lesions. Clearly, there is much more to
learn about eosinophil biology and its relevance to
human diseases.
361
KEY REFERENCES
Section 5
1. Kita H, Adolphson CR, Gleich GJ: Biology of eosinophils.

In: Allergy: Principles and Practice, 6 edition, edited by NF
Jr. Adkinson, JW Yunginger, WW Busse, BS Bochner, ST
Holgate, FER Simons. Philadelphia, Mosby, 2003, pp.
305-332
2. Blanchard C, Rothenberg ME: Biology of the eosinophil.
Adv Immunol 101:81-121, 2009
3. Hogan SP et al: Eosinophils: Biological properties and
role in health and disease. Clin Exp Allergy 38(5):709-750,
2008
4. Ackerman SJ, Bochner BS: Mechanisms of eosinophilia in
the pathogenesis of hypereosinophilic disorders. Immu-
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9. Bochner BS, Gleich GJ: What targeting eosinophils has
taught us about their role in diseases. J Allergy Clin
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13. Rothenberg ME, Hogan SP: The eosinophil. Annu Rev
Immunol 24:147-174, 2006
61. Adamko D, Lacy P, Moqbel R: Eosinophil function in
allergic inflammation: From bone marrow to tissue
response. Curr Allergy Asthma Rep 4(2):149-158, 2004
103. Spencer LA et al: Human eosinophils constitutively
express multiple Th1, Th2, and immunoregulatory cytokines that are secreted rapidly and differentially. J Leukoc
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120. Munitz A, Levi-Schaffer F: Eosinophils: New roles for
old cells. Allergy 59(3):268-275, 2004
200. Takatsu K, Kouro T, Nagai Y: Interleukin 5 in the link
between the innate and acquired immune response. Adv
Immunol 101:191-236, 2009
::
Chapter 32 :: A
cute Febrile Neutrophilic Dermatosis
(Sweet Syndrome)

:: Philip R. Cohen, Herbert Honigsmann, &
Razelle Kurzrock
ACUTE FEBRILE NEUTROPHILIC DERMATOSIS (SWEET SYNDROME) AT A GLANCE
Acute febrile neutrophilic dermatosis (Sweet
syndrome) is characterized by a constellation
of symptoms and findings: the acute onset of
fever, neutrophilia, erythematous, and tender
skin lesions that typically show an upper dermal
infiltrate of mature neutrophils, and the prompt
improvement of both symptoms and lesions
after initiation of treatment with systemic
corticosteroids.
Cardiovascular, central nervous system,
gastrointestinal, hepatic, musculoskeletal,
ocular, oral, otic, pulmonary, renal, and splenic
organs can be involved by the extracutaneous
manifestations of Sweet syndrome.
Classical Sweet syndrome may be associated
with infection of the upper respiratory tract and/
or gastrointestinal tract, inflammatory bowel
disease, and pregnancy.
Malignancy-associated Sweet syndrome occurs
in individuals with previously undiagnosed or
relapsing hematologic malignancies and solid
362
tumors; in these patients, Sweet syndrome

appears as a cutaneous paraneoplastic syndrome.
Drug-induced Sweet syndrome describes
the onset of dermatosis in patients following
the initiation of certain medicationsmost
commonly granulocyte-colony stimulating factor.
Cytokinesdirectly or indirectlymay have an
important etiologic role in the pathogenesis of
this dermatosis.
The first-line oral systemic agents for treating
Sweet syndrome are corticosteroids, potassium
iodide, and colchicine.
The second-line oral systemic agents for treating
Sweet syndrome are indomethacin, clofazimine,
cyclosporine, and dapsone.
Topical application of high-potency
corticosteroids or intralesional corticosteroids
may be efficacious for treating localized Sweet
syndrome lesions.
HISTORY
EPIDEMIOLOGY
TABLE 32-1
Diagnostic Criteria for Classical Sweet Syndrome Versus Drug-Induced Sweet Syndrome
Classicala
Drug Inducedb
(1) Abrupt onset of painful erythematous plaques or nodules

(2)Histopathologic evidence of a dense neutrophilic infiltrate
without evidence of leukocytoclastic vasculitis
(3) Pyrexia >38C
(4)Association with an underlying hematologic (most
commonly acute myelogenous leukemia) or visceral
malignancy (most commonly carcinomas of the
genitourinary organs, breast, and gastrointestinal tract),
inflammatory disease (Crohns disease and ulcerative
colitis) or pregnancy, or preceded by an upper respiratory
(streptococcosis) or gastrointestinal (salmonellosis and
yersiniosis) infection or vaccination
(5)Excellent response to treatment with systemic
corticosteroids or potassium iodide
(6)Abnormal laboratory values at presentation (three of four):
erythrocyte sedimentation rate >20 mm/hour; positive
C-reactive protein; >8,000 leukocytes; >70% neutrophils
(A) Abrupt onset of painful erythematous plaques or nodules

(B)Histopathologic evidence of a dense neutrophilic infiltrate
without evidence of leukocytoclastic vasculitis
(C) Pyrexia >38C
(D)Temporal relationship between drug ingestion and clinical
presentation or temporally related recurrence after oral
challenge
Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome)
471,474,476,477,482,487, 489,490,492,493,505,506
::
More than 1,000 cases of Sweet syndrome have been

reported since Sweets original paper.1509 The distribution of Sweet syndrome cases is worldwide and there
is no racial predilection.1,2,12,1620,30,31 The dermatosis
presents in three clinical settings.13,15
Diagnostic criteria for classical or idiopathic Sweet
syndrome were proposed by Su and Liu in 1986 and
modified by von den Driesch in 1994 (Table 32-1).1114 It
may be associated with infection (upper respiratory tract
or gastrointestinal tract), inflammatory bowel disease, or
pregnancy.13,15 Two studies have noted a seasonal preference for the onset of Sweet syndrome for either autumn
or spring in 70% of 42 patients.416 or autumn.496
Chapter 32
Acute febrile neutrophilic dermatosis was originally

described by Dr. Robert Douglas Sweet in the August
September 1964 issue of the British Journal of Dermatology. The cardinal features of a distinctive and fairly
severe illness that had been encountered in eight
women during the 15-year period from 1949 to 1964
were summarized. Although the condition was originally known as the GommButton disease in eponymous honor of the first two patients with the disease
in Dr. Sweets department, Sweets syndrome has
become the established eponym for this acute febrile
neutrophilic dermatosis.110
Classical Sweet syndrome most commonly occurs in

women between the ages of 30 to 60 years. However,
classical Sweet syndrome also occurs in younger adults
and children.3248,405,415,445,447,453 The youngest Sweet syndrome patients are brothers who developed the dermatosis at 10 and 15 days of age.46
Several investigators consider it appropriate to distinguish between the classical form and the malignancyassociated form of this disease since the onset or
recurrence of many of the cases of Sweet syndrome are
temporally associated with the discovery or relapse of
cancer.15,4960 Recently, the investigators of a comprehensive review of 66 pediatric Sweet syndrome
patients observed that 44% of 30 children between
3 and 18 years of age had an associated hematologic malignancy.405,447 Malignancy-associated Sweet
syndrome in adults does not have a female predominance and is most often associated with acute myelogenous leukemia.61,62 In Sweet syndrome patients with
dermatosis-related solid tumors, carcinomas of the
genitourinary organs, breast, and gastrointestinal tract
are the most frequently occurring cancers.1,2,6366
Criteria for drug-induced Sweet syndrome were
established by Walker and Cohen in 1996 (Table 32-1).13
This variant of the dermatosis is most frequently
observed to occur in association with the administration of granulocyte-colony stimulating factor
(G-CSF).1,2,13,67,68 However, several other medications
have also been implicated in eliciting drug-induced
Sweet syndrome (eTable 32-1.1 in online edition).11,13,17,39,41,69124,401,402,422,427429,436,437,439,446,455,456,463,464,468,469
(E)Temporally related resolution of lesions after drug withdrawal

or treatment with systemic corticosteroids
The presence of both major criteria (1 and 2) and two of the four minor criteria (3, 4, 5, and 6) is required in order to establish the diagnosis
of classical Sweet syndrome; the patients with malignancy-associated Sweet syndrome are included with the patients with classical Sweet
syndrome in this list of diagnostic criteria.
b
All five criteria (A, B, C, D, and E) are required for the diagnosis of drug-induced Sweet syndrome.
Adapted with permission from Walker DC, Cohen PR: Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: Case
report and review of drug induced Sweet syndrome. J Am Acad Dermatol 34:918-923, 1996.
363
Section 5
::
364

The pathogenesis of Sweet syndrome may be multifactorial and remains to be definitively determined. A
condition, similar to Sweet syndrome, presenting as a
sterile neutrophilic dermatosis, has been described in a
female standard poodle dog after treatment with the
nonsteroidal anti-inflammatory drug firocoxib and in
multiple dogs temporally associated with the administration of carprofen.403
Sweet syndrome may result from a hypersensitivity
reaction to an eliciting bacterial, viral, or tumor antigen.2,127 A septic process is suggested by the accompanying fever and peripheral leukocytosis. Indeed, a febrile
upper respiratory tract bacterial infection or tonsillitis
may precede skin lesions by 13 weeks in patients with
classic Sweet syndrome. Also, patients with Yersinia
enterolitica intestinal infection-associated Sweet syndrome have improved with systemic antibiotics.2,77,125127
The systemic manifestations of Sweet syndrome
resemble those of familial Mediterranean fever.
Recently, the simultaneous occurrence of both conditions has been observed.421 Also, in a patient with
chronic myelogenous leukemia-associated Sweet syndrome, the causative gene mutation for familial
Mediterranean fever was detected.448 Hence, the pathogenesis for these conditions may be similar.
Leukotactic mechanisms, dermal dendrocytes, circulating autoantibodies, immune complexes, human
leukocyte antigen (HLA) serotypes, and cytokines
have all been postulated to contribute to the pathogenesis of Sweet syndrome. Complement does not appear
to be essential to the disease process. In some patients
antibodies to neutrophilic cytoplasmic antigens
(ANCAS) have been demonstrated;430 however, these
are likely to represent an epiphenomenon.2
Cytokinesdirectly and/or indirectlymay have
an etiologic role in the development of Sweet syndrome symptoms and lesions.2,2123 Elevated serum
levels of granulocyte-colony stimulating factor and
interleukin-6 were detected in a patient with myelodysplastic syndrome-associated Sweet syndrome who
was not receiving a drug.128 Detectable levels of intraarticular synovial fluid granulocyte macrophage-colony stimulating factor has also been observed in an
infant with classical Sweet syndrome.44 Another study
demonstrated that the serum G-CSF level was significantly higher in individuals with active Sweet syndrome than in dermatosis patients with inactive Sweet
syndrome.129 And, a recent study showed that the level
of endogenous G-CSF was closely associated with
Sweet syndrome disease activity in a patient with
acute myelogenous leukemia-associated Sweet syndrome and neutrophilic panniculitis.461
Significantly elevated levels of helper T-cell type 1
cytokines (interleukin-2 and interferon-) and normal
levels of a helper T-cell type 2 cytokine (interleukin-4)
have been seen in the sera of Sweet syndrome
patients.130 In a patient with neuro-Sweet disease presenting with recurrent encephalomeningitis, serial
measurements of cerebral spinal fluid interleukin-6,
interferon-, interleukin-8, and IP10 [which is also
referred to as the chemokine (CXC motif) ligand 10

(CXCL10)] were elevated as compared to levels in control subjects with neurologic disorders and also correlated with total cerebral spinal fluid cell counts; this
data suggests an important role of the helper T-cell
type 1 cell (whose cytokines include interferon- and
IP10) and interleukin-8 (a specific neutrophil chemoattractant) in the pathogenesis of neuro-Sweet disease.478
Other studies showed decreased epidermal staining
for interleukin-1 and interleukin-6 and postulated that
this was due to the release of these cytokines into the
dermis.131 In summary, G-CSF, granulocyte macrophage colony stimulating factor, interferon-, interleukin-1, interleukin-3, interleukin-6, and interleukin-8
are potential cytokine candidates in the pathogenesis
of Sweet syndrome.2,13,2123,44,128132
CLINICAL FINDINGS
HISTORY
Sweet syndrome patients may appear dramatically ill.
The skin eruption is usually accompanied by fever and
leukocytosis. However, the skin disease can follow the
fever by several days to weeks or be concurrently present with the fever for the entire episode of the dermatosis. Arthralgia, general malaise, headache, and
myalgia are other Sweet syndrome associated symptoms (Table 32-2).1,2,23
CUTANEOUS LESIONS
Skin lesions of Sweet syndrome typically appear as tender, red or purplered, papules or nodules. The eruption may present as a single lesion or multiple lesions
that are often distributed asymmetrically (Fig. 32-1).
Figure 32-1 Unilateral lesions of Sweet syndrome around

the eye and upper lip consisting of plaques and pseudovesicular papules suggesting herpes simplex.
TABLE 32-2
Clinical Features in Patients with Sweet Syndrome

Clinical Form
Characteristic
Epidemiology
Women
Prior upper respiratory tract
infection
Recurrencec
Drug Inducedb (%)
80
7590
50
16
59
20
71
21
30
69
41
67
8090
1256
88
26
79
34
100
21
1772
15
21
80
50
30
Infrequent
2
89
63
42
49
12
97
52
33
48
3
71
43
50
36
7
80
90
47
100
60
95
38
100
Infrequent
Infrequent
1150
82
68
15
83
50
7
100
50
0
Percentages for classical, hematologic malignancy, and solid tumor associated Sweets syndrome from Cohen PR, Kurzrock R: Sweets syndrome
and cancer. Clin Dermatol 11:149-157, 1993. Copyright 1993, Elsevier Science Publishing Co., Inc., New York, NY.
b
Percentages for drug-induced Sweets syndrome from Walker DC, Cohen PR: Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: Case report and review of drug induced Sweets syndrome. J Am Acad Dermatol 34:918-923, 1996. Copyright 1996, American
Academy of Dermatology, Inc., Mosby-Year Book, Inc., St. Louis, MO.
c
Recurrence following oral rechallenge testing in the patients with drug-induced Sweets syndrome.
d
Temperature greater than 38C.
e
Neutrophil count greater than 6000 cells/uL.
f
Erythrocyte sedimentation rate greater than 20 mm/hour.
g
Hemoglobin less than 13 g/dL in men and less than 12 g/dL in women.
h
Platelet count less than 150,000/uL or greater than 500,000/uL.
i
This includes hematuria, proteinuria, and renal insufficiency.
The pronounced edema in the upper dermis of the

lesions results in their transparent, vesicle-like appearance and has been described as an illusion of vesiculation (Fig. 32-2). In later stages, central clearing may lead
to annular or arcuate patterns. The lesions may appear
bullous, become ulcerated, and/or mimic the morphologic features of pyoderma gangrenosum in patients
with malignancy-associated Sweet syndrome.133,134 The
lesions enlarge over a period of days to weeks. Subsequently, they may coalesce and form irregular sharply
bordered plaques (Fig. 32-3). They usually resolve, spontaneously or after treatment, without scarring. Lesions
associated with recurrent episodes of Sweet syndrome
occur in one-third to two-thirds of patients.1,2,135,136
Cutaneous pathergy, also referred to as skin hypersensitivity, is a dermatosis-associated feature.1,2 It
occurs when Sweet syndrome skin lesions appear at
sites of cutaneous trauma.458,496 These include the locations where procedures have been performed such as
biopsies,20 injection sites,431 intravenous catheter placement,20 and venipuncture.12,17,20,37,137,138 They also
include sites of insect bites and cat scratches,20 areas
that have received radiation therapy,139141,138,484 and
places that have been contacted by sensitizing antigens.137,142,420 In addition, in some Sweet syndrome
patients, lesions have been photodistributed or localized to the site of a prior phototoxic reaction (sunburn).13,20,98,143145 Sweet syndrome lesions have also
rarely been located on the arm affected by postmastectomy lymphedema.100,146,419,505
Sweet syndrome can present as a pustular dermatosis.147 The lesions appear as tiny pustules on the tops of
the red papules or eythematous-based pustules. Some
of the patients previously described as having the
Laboratory findings
Neutrophiliae
Elevated erythrocyte
sedimentation ratef
Anemiag
Abnormal platelet counth
Abnormal renal functioni
Solid Tumora (%)
::
Lesion location
Upper extremities
Head and neck
Trunk and back
Lower extremities
Oral mucous membranes
Hematologic
Malignancya (%)
Chapter 32
Clinical symptoms
Feverd
Musculoskeletal
involvement
Ocular involvement
Classicala (%)
365
The cutaneous lesions of subcutaneous Sweet syndrome usually present as erythematous, tender dermal
nodules on the extremities.4,8,12,17,99,119,164185 When the
lesions are located on the legs, they often mimic erythema nodosum.170 Since Sweet syndrome can present
concurrently21,125,187189 or sequentially170 with erythema
nodosum,17,21,187,190,509 tissue evaluation of one or more
new dermal nodules may be necessary to establish the
correct diagnosiseven in a patient whose Sweet syndrome has previously been biopsy-confirmed.1,2,4

Section 5
::
Figure 32-2 Multiple confluent papules and plaques of

Sweet syndrome that at first sight give the illusion of vesiculation but are solid on palpation. (From Honigsmann
et al: Akute febrile neutrophile Dermatose. Wien Klin
Wochenschr 91:842, 1979, with permission.)
pustular eruption of ulcerative colitis are perhaps
more appropriately included in this clinical variant of
Sweet syndrome.1,148
Neutrophilic dermatosis of the dorsal hands or
pustular vasculitis of the dorsal hands refers to a
localized, pustular variant of Sweet syndrome when
the clinical lesions are predominantly restricted to the
dorsal aspect of the hands.3,149154 The lesions from this
latter group of individuals are similar to those of Sweet
syndrome in morphology and rapid resolution after
systemic corticosteroids and/or dapsone therapy was
initiated. In addition, many of the individuals with this
form of the disease also had concurrent lesions that
were located on their oral mucosa, arm, leg, back, and/
or face.3,155163,425,435,440,442,457,462,470,495,497
366
EXTRACUTANEOUS MANIFESTATIONS. (eTable

32-2.1 in online edition.) Extracutaneous manifestations of
Sweet syndrome may include the bones, central nervous
system, ears, eyes, kidneys, intestines, liver, heart, lung,
mouth, muscles, and spleen.12,16,17,20,25,26,32,33,44,73,75,101,117,138,139,
165,202,203,205,212257,407,408,410,433,444,450,452,459,465,468,475,478,481,486,599
The
incidence of ocular involvement (such as conjunctivitis)
is variable in classical Sweet syndrome and uncommon
in the malignancy-associated and drug-induced forms of
the dermatosis; however, it may be the presenting feature of the condition. Mucosal ulcers of the mouth occur
more frequently in Sweet syndrome patients with hematologic disorders and are uncommon in patients with
classical Sweet syndrome23,26,102,117,203,252; similar to extracutaneous manifestations of Sweet syndrome occurring
at other sites, the oral lesions typically resolve after initiation of treatment with systemic corticosteroids.1,2 In
children, dermatosis-related sterile osteomyelitis has
been reported.
ASSOCIATED DISEASES. (eTable 32-2.2 in online
edition.) Several conditions have been observed to occur
either before, concurrent with, or following the diagnosis of Sweet syndrome. Therefore, the development of
Sweet syndrome may be etiologically related to Behcets
disease, cancer, erythema nodosum, infections, inflammatory bowel disease, pregnancy, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid
Figure 32-3 Acute febrile neutrophilic dermatosis. Typical lesion consisting of coalescing, plaque-forming papules.
A. Bright-red lesions on the neck. B. Lesion on the dorsum of the right-hand exhibiting the relief of a mountain range
feature. (From Honigsmann H, Wolff K: Acute febrile neutrophilic dermatosis (Sweets syndrome). In: Major Problems in
Dermatology, vol 10, Vasculitis, edited by K Wolff, RK Winkelmann, consulting editor A Rook. London, Lloyd-Luke, 1980,
p. 307, with permission.)
disease. The association between Sweet syndrome and

the other conditions (eTable 32-2.2 in online edition)
remains to be established.1,2,5,1120,30,3643,69126,158161,164,166,
186190,195,214,231,236,259339,400,402,406,410,411,415,417,418,421424,426429,434,
436442,445,446,448,449,452456,459,460,463,464,466469,471477,479,480,482,483,487490,
492494,496,497,500,502504,508,509
ASSOCIATED NEUTROPHILIC DERMATOSES.
HISTOPATHOLOGY
Evaluation of a lesional skin biopsy is helpful when the
diagnosis of Sweet syndrome is suspected. Lesional
LABORATORY TESTS
tissue should also be submitted for bacterial, fungal,

mycobacterial, and possibly viral cultures since the
pathologic findings of Sweet syndrome are similar to
those observed in cutaneous lesions caused by infectious agents.1,2
A diffuse infiltrate of mature neutrophils is characteristically present in the papillary and upper reticular
dermis (Fig. 32-4); however, it can also involve the epidermis or adipose tissue. Histiocytoid Sweet syndrome refers to the setting in which the hematoxylin
and eosin-stained infiltrate of immature myeloid cells
are histiocytoid-appearing and are therefore initially
misinterpreted as histiocytes.201,412414,436,443,445,460,474
The dermal inflammation is usually dense and diffuse; however, it can also be perivascular or demonstrate secondary changes of leukocytoclastic vasculitis
believed to be occurring as an epiphenomenon and
not representative of a primary vasculitis,3,192,193 Neutrophilic spongiotic vesicles194 or subcorneal pustules12,80,167,195,196 result from exocytosis of neutrophils
into the epidermis.12,17,80,167,194,195,197 When the neutrophils
are located either entirely or only partially in the subcutaneous fat, the condition is referred to as subcutaneous Sweet syndrome.4,8,12,17,99,119,164184,451,461,493,497
Edema in the dermis, swollen endothelial cells,
dilated small blood vessels, and fragmented neutrophil nuclei (referred to as karyorrhexis or leukocytoclasia) may also be present (Fig. 32-5). Fibrin deposition
or neutrophils within the vessel walls (changes of primary leukocytoclastic vasculitis) are usually absent
and the overlying epidermis is normal.1,2,23,167,168 However, the spectrum of pathologic changes described in
cutaneous lesions of Sweet syndrome has expanded to
include concurrent leukemia cutis, vasculitis, and variability of the composition or the location of the inflammatory infiltrate.3,191,491,496
Lymphocytes or histiocytes may be present in
the inflammatory infiltrate of Sweet syndrome lesi
ons.11,104,167,168,198200,504 Eosinophils have also been noted
in the cutaneous lesions from some patients with either
idiopathic11,167,168,195,202204,212 or drug-induced84,107,110,111
::
CONCURRENT LEUKEMIA CUTIS. In patients

with hematologic disorders, Sweet syndrome may
present as a paraneoplastic syndrome (signaling the
initial discovery of an unsuspected malignancy), a
drug-induced dermatosis (following treatment with
either all-trans-retinoic acid, bortezomib, G-CSF, or
imatinib mesylate), or a condition whose skin lesions
concurrently demonstrate leukemia cutis.1 Acute leukemia (myelocytic and promyelocytic) is the most frequent hematologic dyscrasia associated with leukemia
cutis (characterized by abnormal neutrophils) and
Sweet syndrome (consisting of mature polymorphonuclear leukocytes) being present in the same skin
lesion.1,70,71,93,109,165,205211,497 Myelodysplastic syndrome
and myelogenous leukemia (either chronic or not otherwise specified) are the other associated hematologic
disorders that have been associated with concurrent
Sweet syndrome and leukemia cutis.109
Secondary leukemia cutis, in which the circulating immature myeloid precursor cells are innocent
bystanders that have been recruited to the skin as the
result of an inflammatory oncotactic phenomenon
stimulated by the Sweet syndrome lesions has been
suggested as one of the hypotheses to explain concurrent Sweet syndrome and leukemia cutis in the same
lesion.165,206,207 Alternatively, primary leukemia
cutis, in which the leukemic cells within the skin constitutes the bonified incipient presence of a specific
leukemic infiltrate is another possibility.207 Finally, it
is possible that the atypical cells of leukemia cutis
developed into mature neutrophils of Sweet syndrome as a result of G-CSF therapy-induced differentiation of the sequestered leukemia cells in patients
with primary leukemia cutis who were being
treated with this agent.205
Figure 32-4 Histopathologic presentation of acute febrile

neutrophilic dermatosis (Sweet syndrome) demonstrates
massive edema of the papillary dermis and a dense diffuse
infiltrate of mature neutrophils throughout the upper
dermis (hematoxylin and eosin stain). (From Cohen PR et
al: Sweets syndrome in patients with solid tumors. Cancer
72:2723-2731, 1993, with permission.)
Chapter 32
An inflammatory infiltrate of mature polymorphonuclear leukocytes is the unifying characteristic of

neutrophilic dermatoses of the skin and mucosa.
Concurrent or sequential occurrence of Sweet
syndrome with either erythema elevatum diutinum,340
neutrophilic eccrine hidradenitis,6 pyoderma gangrenosum,9,231,269,341,342,430,483,497 subcorneal pustular dermatosis,6,9 and/or vasculitis3,192,231 has been observed.
Although these conditions can display similar clinical
and pathologic features, the location of the neutrophilic
infiltrate helps to differentiate them.6,120,499
367
Section 5
::
Figure 32-5 Characteristic histopathologic features of Sweet syndrome are observed at low (A) and high (B)
magnification: papillary dermal edema, swollen endothelial cells, and a diffuse infiltrate of predominantly
neutrophils with leukocytoclasia, yet no evidence of vasculitis (hematoxylin and eosin stain). (From Cohen
PR et al: Concurrent Sweets syndrome and erythema nodosum: A report, world literature review and mechanism of pathogenesis. J Rheumatol 19:814-820, 1992, with permission.)
Sweet syndrome. Abnormal neutrophils (leukemia

cutis)in addition to mature neutrophilscomprise
the dermal infiltrate in occasional Sweet syndrome
patients with hematologic disorders.1,70,71,93,109,165,205211
Pathologic findings of Sweet syndrome can also
occur in extracutaneous sites. Often, these present as
sterile neutrophilic inflammation in the involved
organ. These changes have been described in the
bones, intestines, liver, aorta, lungs, and muscles of
patients with Sweet syndrome.2
OTHER LABORATORY TESTS
368
Peripheral leukocytosis with neutrophilia and an elevated erythrocyte sedimentation rate and are the most
consistent laboratory findings in Sweet syndrome.23
However, leukocytosis is not always present in patients
with biopsy-confirmed Sweet syndrome.26 For example, anemia, neutropenia, and/or abnormal platelet
counts may be observed in some of the patients with
malignancy-associated Sweet syndrome. Therefore, a
complete blood cell count with leukocyte differential
and platelet count, evaluation of acute phase reactants
(such as the erythrocyte sedimentation rate or C-reactive protein), serum chemistries (evaluating hepatic
function and renal function), and a urinalysis should
be performed. It is also reasonable to perform a serologic evaluation of thyroid function since there appears
to be a strong association between thyroid disease and

Sweet syndrome.1,2
SPECIAL TESTS
EVALUATION FOR EXTRACUTANEOUS
MANIFESTATIONS. Extracutaneous manifesta-
tions of Sweet syndrome may result in other laboratory

abnormalities. Patients with central nervous system
involvement may have abnormalities on brain SPECTs
(single photon emission computed tomography), computerized axial tomography, electroencephalograms,
magnetic resonance imaging, and cerebrospinal fluid
analysis. Patients with kidney and liver involvement
may demonstrate urinalysis abnormalities (hematuria
and proteinuria) and hepatic serum enzyme elevation.
And, patients with pulmonary involvement may
have pleural effusions and corticosteroid-responsive
culture-negative infiltrates on their chest roentgenograms.2,343
MALIGNANCY WORKUP. Recommendations for

the initial malignancy workup in newly diagnosed
Sweet syndrome patients without a prior cancer were
proposed by Cohen and Kurzrock in 1993.15 Their recommendations were based upon the age-related recommendations of the American Cancer Society for
early detection of cancer in asymptomatic persons and

the neoplasms that had concurrently been present or
subsequently developed in previously cancer-free
Sweet syndrome patients. The recommended evaluation included the following:
1. A detailed medical history
2. A complete physical examination, including:
(a) examination of the thyroid, lymph nodes, oral
cavity, and skin;
(b) digital rectal examination;

(c) breast, ovary, and pelvic examination in
women; and
(d) prostate and testicle examination in men.
Consider
Acral erythema
Erythema elevatum diutinum
Erythema multiforme
Halogenoderma
Lymphoma
Neutrophilic eccrine hidradenitis
Periarteritis nodosa
Urticaria
Viral exanthem
Always Rule Out
Bacterial sepsis
Behcets disease
Bowel bypass syndrome
Dermatomyositis
Familial Mediterranean fever
Granuloma faciale
Leprosy
Lupus erythematosus
Lymphangitis
Metastatic tumor
Rheumatoid neutrophilic dermatitis
Rosacea fulminans
Schnitzlers syndrome
Syphilis
Systemic mycosis
Thrombophlebitis
Tuberculosis
Adapted from Cohen PR, Kurzrock R: Sweets syndrome and cancer.
Clin Dermatol 11:149-157, 1993.
Since the initial appearance of dermatosis-related skin

lesions had been reported to precede the diagnosis of a
Sweet syndrome-associated hematologic malignancy
by as long as 11 years, they also suggested that it was
reasonable to check a complete blood cell count with
leukocyte differential and platelet count every 612
months.2,15
Most Likely
Drug eruptions
Cellulitis
Chloroma
Erysipelas
Erythema nodosum
Leukemia cutis
Panniculitis
::
(b) complete blood cell count with leukocyte

differential and platelet count;
(c) pap test in women;
(d) serum chemistries;
(e) stool guaiac slide test;
(f) urinalysis; and
(g) urine culture.
4. Other screening tests:
(a) chest roentgenograms;
(b) endometrial tissue sampling in either
menopausal women or women with a history
of abnormal uterine bleeding, estrogen
therapy, failure to ovulate, infertility, or
obesity; and
(c) sigmoidoscopy in patients over 50 years of
age.
Clinical Differential Diagnosis

of Sweet Syndrome
Chapter 32
3. Laboratory evaluation:
(a) carcinoembryonic antigen level;
TABLE 32-3
CLINICAL DIFFERENTIAL DIAGNOSIS

Sweet syndrome skin and mucosal lesions mimic those
of other conditions (Table 32-3.)2,15,23,148,165,202,220,344,345,409,
421,448,498
Therefore, infectious and inflammatory disorders, neoplastic conditions, reactive erythemas, vasculitis, other cutaneous conditions, and other systemic
diseases are included in the clinical differential diagnosis of Sweet syndrome.
HISTOLOGIC DIFFERENTIAL
DIAGNOSIS
The histologic differential diagnosis of Sweet syndrome
includes conditions microscopically characterized by
either neutrophilic dermatosis or neutrophilic panniculitis (eTable 32-3.1 in online edition).24,6,12,193,346353,432,451
The pathologic changes associated with Sweet syndrome are similar to those observed in an abscess or
cellulitis; therefore, culture of lesional tissue for bacteria, fungi, and mycobacteria should be considered to
rule out infection.23 Leukemia cutis not only mimics the
dermal changes of Sweet syndrome, but can potentially
occur within the same skin lesion as Sweet syndrome;
however, in contrast to the mature polymorphonuclear
neutrophils found in Sweet syndrome, the dermal infiltrate in leukemia cutis consists of malignant immature
leukocytes.354 The pathologic changes in the adipose
tissue of subcutaneous Sweet syndrome lesions can be
found in either the lobules, the septae, or both; therefore, conditions characterized by a neutrophilic lobular
panniculitis also need to always be considered and
ruled out.2,4
369
Section 5
::
370
COMPLICATIONS
Complications in patients with Sweet syndrome can be
directly related to the mucocutaneous lesions or indirectly related to the Sweet syndrome-associated conditions. Skin lesions may become secondarily infected
and antimicrobial therapy may be necessary. In
patients with malignancy-associated Sweet syndrome,
reappearance of the dermatosis may herald the unsuspected discovery that the cancer has recurred. Systemic manifestations of Sweet syndrome-related
conditionssuch as inflammatory bowel disease, sarcoidosis and thyroid diseasesmay warrant diseasespecific treatment.

COURSE
The symptoms and lesions of Sweet syndrome eventually resolved without any therapeutic intervention
in some patients with classical Sweet syndrome.
However, the lesions may persist for weeks to
months.10,23,254,355 In patients with malignancy-associated Sweet syndrome, successful management of the
cancer occasionally results in clearing of the related
dermatosis.13,15,23 Similarly, discontinuation of the associated medication in patients with drug-induced Sweet
syndrome is typically followed by spontaneous
improvement and subsequent resolution of the syndrome.13,15,23 Surgical intervention has also resulted in
the resolution of Sweet syndrome in some of the
patients who had associated tonsillitis, solid tumors, or
renal failure.1,2,19,315,356,357,507
Sweet syndrome may recur following either spontaneous remission or therapy-induced clinical resolution.10 The duration of remission between recurrent
episodes of the dermatosis is variable. Sweet syndrome recurrences are more common in cancer
patients; in this patient population, the reappearance
of dermatosis-associated symptoms and lesions may
represent a paraneoplastic syndrome that is signaling the return of the previously treated malignancy.1,2,15,135
Potassium iodide and colchicine are also first-line

systemic treatments for Sweet syndrome (eTable
32-3.2 in online edition).10,12,17,20,23,30,49,70,143,184,198,203,221,223,231,
240,245,250,259,261,281,284,294,296,329,359363,368384,468,496
Vasculitis and
hypothyroidism are potential drug-induced side effects
of potassium iodide.385 Gastrointestinal symptoms such
as diarrhea, abdominal pain, nausea, and vomiting are
potential adverse effects from colchicine which may
improve after lowering the daily dose of the drug.2
Second-line systemic agents for Sweet syndrome
include indomethacin,259,261,284,378,490 clofazimine,12,296,379
cyclosporine,12,30,231,294,380,381 and dapsone17,20,30,203,221,245,284,
372,382384,459,460,486
(eTable 32-3.2 in online edition). They
have all been used as monotherapy either in the initial
management of the patient or after first-line therapies
has failed. In addition, cyclosporine and dapsone
have been used in combination therapy either as a
corticosteroid-sparing agent or with other drugs.1,2,7,303
There are certain patients whose Sweet syndrome
lesions have improved after receiving systemic antibiotics7,412: individuals with Staphylococcus aureus secondarily impetiginized lesions treated with an
antimicrobial agent to which their bacterial strain is
susceptible,23 patients with inflammatory bowel disease treated with metronidazole,267,387 and persons
with dermatosis-related Yersinia125,126 or Chlamydia306,307
infection treated with either doxycycline,125,389 minocycline,30,126 or tetracycline.306,307,388
In addition, effective treatment of Sweet syndrome
has also been described, predominantly in case reports,
with other drugs: cytotoxic chemotherapies and
antimetabolites (chlorambucil and cyclophosphamide),30,39,148,200,251,360,390 danazol,9 etretinate,361 hepatitis
therapy,9 immunoglobulin,303 interferon ,202,366 and
tumor necrosis factor antagonists444 (adalimumab,501
etanercept,392,404 infliximab,264,265,278,266,501 and thalidomide5,393). Anakinra (an interleukin-1 receptor antagonist), in combination with oral prednisone, was promptly
effective in resolving the symptomsand subsequently
the clinical lesionsof Sweet syndrome in a patient with
long-standing disease that was refractory to other therapies.399 Pentoxifylline was hypothesized to be beneficial
for treating Sweet syndrome394,395; however, when used
as monotherapy, it was not found to be efficacious.1,2,7,295,362
KEY REFERENCES
TREATMENT
Systemic corticosteroids are the therapeutic mainstay

for Sweet syndrome (eTable 32-3.2 in online
edition).7,810,12,16,17,19,20,23,36,49,50,70,184,223,233,240,250,284,358361 Initiation of therapy promptly results in improvement of
the symptoms and resolution of the mucocutaneous
lesions. Daily pulse methylprednisolone administered
intravenously may be necessary in patients with
refractory disease. Topical (such as 0.05% clobetasol
propionate)13,1921,30,234,362365 or intralesional (such as triamcinolone acetonide at a dose between 3.0 and 10.0
mg/cc)362,366,367 corticosteroids may be effective for
treating localized Sweet syndrome lesions.1,2,7,9
1. Cohen PR, Kurzrock R: Sweets syndrome revisited: A

review of disease concepts. Int J Dermatol 42:761-778,
2003
2. Cohen PR: Sweets syndromeA comprehensive review
of an acute febrile neutrophilic dermatosis. Orphanet J
Rare Dis 2:34, 2007 (26 July (2007). http://www.ojrd.com/
contents/2/1/34
3. Cohen PR: Skin lesions of Sweet syndrome and its dorsal
hand variant contain vasculitis: An oxymoron or an epiphenomenon? Arch Dermatol 138:400-403, 2002
4. Cohen PR: Subcutaneous Sweets syndrome: A variant of
acute febrile neutrophilic dermatosis that is included in
the histologic differential diagnosis of neutrophilic panniculitis. J Am Acad Dermatol 52:927-928, 2005
5. Cohen PR: Sweets syndrome and relapsing polychondritis: Is their appearance in the same patient a coincidental
occurrence or a bonified association of these conditions?
Int J Dermatol 43:772-777, 2004
6. Cohen PR: Neutrophilic dermatoses occurring in oncology patients. Int J Dermatol 46:106-111, 2007
7. Cohen PR, Kurzrock R: Sweets syndrome: A review of
current treatment options. Am J Clin Dermatol 3:117-131,
2002
8. Cohen PR: Iotaderma #120 (Gomm-Button disease:
Sweets syndrome). J Am Acad Dermatol 50:100, 274,
2004
9. Cohen PR: Neutrophilic dermatoses: A review of current
treatment options. Am J Clin Dermatol 10:301-312, 2009
10. Cohen PR, Almeida L, Kurzrock R: Acute febrile neutrophilic dermatosis. Am Fam Physician 39(3):199-204, 1989
14. Cohen PR, Kurzrock R: Diagnosing the Sweet syndrome.
Ann Intern Med 110:573-574, 1989
15. Cohen PR, Kurzrock R: Sweets syndrome and cancer.
Clin Dermatol 11:149-157, 1993
22. Cohen PR, Kurzrock R: The pathogenesis of Sweets syndrome [letter]. J Am Acad Dermatol 25:734, 1991
23. Cohen PR, Kurzrock R: Sweets syndrome: A neutrophilic
dermatosis classically associated with acute onset and
fever. Clin Dermatol 18:265-282, 2000
26. Cohen PR, Talpaz M, Kurzrock R: Malignancy-associated
Sweets syndrome: Review of the world literature. J Clin
Oncol 6:1887-1897, 1988
PG is more frequent in female patients and

occurs at any age, but usually between 40 and
60 years.
The majority of patients with PG have
other systemic diseases (such as arthritis,
inflammatory bowel disease, hematological
dyscrasias, malignant disease, etc.), but PG
occurs independently of these disorders.
PG may present as ulcerative, bullous,
pustular, or vegetative variants. Clinical
features of different variants sometimes
overlap in individual patients but usually one
variant dominates the clinical picture.
EPIDEMIOLOGY
The prevalence of pyoderma gangrenosum (PG) is
unknown. Estimates have suggested that approximately three cases of PG per million of the population occur per year, with most large referral centers
seeing one to two cases per year.1 It has been reported
in all age groups but mainly affects adults between
There is no laboratory test or investigation that

establishes the diagnosis of PG with certainty. The
histopathological findings are not diagnostic but
can be supportive of the diagnosis of PG in the
appropriate clinical setting and are essential to
rule out alternative diagnoses.
Pyoderma Gangrenosum
Pyoderma gangrenosum (PG) is a rare

inflammatory disease of unknown etiology
characterized by sterile neutrophilic infiltration
of the skin. Similar neutrophilic infiltrations
may occur in other organs. It is considered
to be one of the groups of neutrophilic
dermatoses and clinical and histological
overlap with some of these may occur.
::
PYODERMA GANGRENOSUM AT A GLANCE
Chapter 33
Chapter 33 :: Pyoderma Gangrenosum

:: Frank C. Powell, Bridget C. Hackett, &
Daniel Wallach
Specified criteria (see below) suggest the

diagnosis of PG, but other conditions
(particularly infection, vascular disease, and
malignancy) must be excluded.
The mainstays of management are systemic
immunosuppressive agents together with
appropriate local and topical therapy.
Ulcerative PG is a chronic disease. Remission
usually requires months of treatment;
maintenance therapy is necessary in many and
relapses are common. Significant morbidity
and mortality are experienced by patients with
ulcerative and bullous PG.
the ages of 40 and 60 years.2 Most reported series of

patients with PG indicate a moderate preponderance
of females. PG often occurs in patients who have
other diseases (arthritis, inflammatory bowel disease, hematologic dyscrasias, etc.), but is not a manifestation or complication of these diseases and its
clinical course is usually unrelated to their severity
or activity.3
371
Approach to the patient with pyoderma gangrenosum
General examination
Detailed history
(includes drugs, trauma, systems review)
Detailed lesions:
location, type, size, outline, depth
Clinical impression of pyoderma gangrenosum
Investigations
Section 5
::
Routine tests:
Full blood count + differential
Erythrocyte sedimentation rate
Renal/liver/bone profiles
Serum iron
Autoantibody screen
Antineutrophilic cytoplasmic
antibody (pANCA, cANCA)
Anti-phospholipid antibody screen
Rheumatoid factor
Serum protein electrophoresis
Thyroid function tests
Chest x-ray, electrocardiogram
Swab for culture
Skin biopsies:
In formalin for histology (hematoxylin
and eosin, periodic acid-Schiff,
Giemsa, Fite, Gram stain, and other
stains)
Fresh tissue for culture (bacterial,
mycobacterial, atypical mycobacterial,
fungal)
Rule out differentials:

Vascular disease, infections,
malignancy, other neutrophilic
dermatoses, facticial disorder
Classify to subgroup
Ulcerative
Bullous
Pustular
Other tests as indicated:

1-antitrypsin level
Serum bromide/iodide
Blood cultures
Coagulation screen
Cryoglobulins, cryofibrinogens
Cold agglutinins
Serum B12/folate
Antistreptolysin 0 titer
Hepatitis/human immunodeficiency
virus screening
Syphilis serology screen
Midstream specimen of urine Bence-Jones protein
Computed tomography scan
(if deep accesses are likely)
Vascular studies
Endoscopy (upper and/or lower)
Bone marrow aspirate
Vegitative
Consider associated diseases
Frequent
Arthritis, inflammatory
bowel disease, monoclonal
gammopathy, malignancy
Frequent
Hematologic
dyscrasias/malignancy
Frequent
Inflammatory bowel
disease
Uncommon
Chronic renal impairment
Figure 33-1 Approach to the patient with pyoderma gangrenosum.
372
The etiology of PG is unknown, and its pathogenesis

poorly understood. Based on the presence of a lymphocytic infiltrate at the active advancing border of
PG lesions, it has been postulated that lymphocytic
antigen activation occurs with cytokine release and
neutrophil recruitment. This may take place not only
in the skin but also in other tissues such as the lung,
intestine, and joints. The predominance of the neutrophilic infiltrate in established lesions of PG have led to
its classification as one of the neutrophilic dermato-
ses.4 Clinical (and to an extent histologic) overlap

occurs with the other dermatoses in this category,
especially atypical or bullous forms of Sweet syndrome (see Chapter 32). Several of the neutrophilic
dermatoses (Sweet syndrome, erythema elevatum
diutinum, subcorneal pustular dermatosis, and PG)
share an association with immunoglobulin A monoclonal gammopathy, and diseases such as inflammatory bowel disease and hematologic disorders occur
more frequently than expected in these patients. The
recent description of the PAPA (Pyogenic Arthritis,
Pyoderma gangrenosum-Acne) syndrome,5 a disease
considered to be one of the autoinflammatory
iseases, raises the possibility that PG may lie within

d
this spectrum.
CLINICAL FINDINGS
Figure 33-2 Several pathergic pyoderma gangrenosum

lesions occurring along a thoracotomy scar site. Note
central ulceration, violaceous borders, and peripheral rim
of erythema.
PG is protean in its clinical expression with variable

presentation according to the variant and the stage of
disease. Lesions can be classified morphologically as
being (1) ulcerative (the commonest and originally
described variant), (2) bullous, (3) pustular, or (4) vegetative. Although some patients may show more than
one variant (e.g., isolated pustular lesions frequently
occur in patients with ulcerative PG), usually one variant of PG dominates the clinical picture and the patient
should be classified accordingly.
The most common initial clinical lesion in a patient
with ulcerative PG is an inflammatory pustule or nodular furuncle (these lesions are usually single but may be
multiple). They erupt on apparently normal skin (the
most common site being the leg), or sometimes at the
site of trauma or surgery (Fig. 33-2). The enlarging initial lesion develops a surrounding areola or zone of erythema that extends into the surrounding skin (Fig.
33-3). As it enlarges, the center degenerates, crusts, and
erodes, converting it into an eroding ulcer the development of which is accompanied by an alarming increase
in the severity of the pain. The ulcer often has a bluish/
violaceous edge (due to undermining by the necrotizing inflammatory process) and the base is covered with
purulent material. Ulcerative PG may erode deeply
with exposure of muscle or tendon in some cases.
Bullous PG (sometimes called atypical PG) presents
as a painful, rapidly expanding superficial inflammatory blister that quickly erodes. In the early acute stage,
the bullous nature of the lesion is evident, but because
the roof of the blister necroses rapidly, close inspection
of the border of established lesions is necessary to
reveal its bullous nature (Fig. 33-4). Bullous PG is commonly associated with hematologic disease and most
Figure 33-3 Established lesion of ulcerative pyoderma

gangrenosum showing well-defined ulceration with surrounding zone of erythema.
A patient with PG usually complains of severe pain

that is out of proportion to the clinical appearance of
the lesion. Approximately 25% of patients note the
onset of PG at sites of cutaneous trauma (needle stick,
inoculation site, insect bites, or surgical procedures).
This is called the pathergic phenomenon (Fig. 33-2).
Lesions progress rapidly (with the exception of vegetative PG) and cutaneous destruction evolves over
days rather than weeks. Special inquiry regarding
drug intake (especially iodides/bromides, hydroxyurea); exposure to and symptoms of infectious diseases (Box 33-1); symptoms relating to the
musculoskeletal system (joint pains, swelling, etc.),
the gastrointestinal tract (abdominal pain, diarrhea,
constipation, etc.), hematologic disease (tiredness,
anemia, bruising, blood clotting disorders, etc.),
respiratory disease, and nonspecific but potential
CUTANEOUS LESIONS: CLINICAL

VARIANTS OF PG
::
HISTORY
Chapter 33
The approach to an individual suspected of having PG

is outlined in the patient algorithm (Fig. 33-1). The
clinical presentation of PG may be diverse and there is
neither a diagnostic laboratory test nor pathognomonic histopathologic findings. Therefore, it is important to avoid misdiagnosing other diseases as PG.6 The
most important considerations are the exclusion of
infection (bacterial, viral, and deep fungal), vascular
disease (stasis, occlusion, and vasculitis), and malignancy in every patient. Close follow-up and reevaluation (with repeated skin biopsies, tissue and swab
cultures, and other tests as clinically indicated) is an
important part of the ongoing evaluation of patients
with suspected PG, particularly those who show a
poor response to therapy.
malignancy-related symptoms, such as weight loss

and fatigue, should be made.
373
BOX 33-1 Differential Diagnosis of Pyoderma Gangrenosum (PG)
Section 5
::
VARIANT SPECIFIC
Ulcerative PG
SITE SPECIFICa
Parastomal
Most Likely
Vascular
Venous stasis ulceration
Occlusive disease/Arteritis
Vasculitis
Antiphospholipidantibody syndrome
Malignancy
Primary or secondary
Infection
Bacterial
Mycobacterial/Atypical mycobacterial
Viral (herpes simplex)
Deep fungal infection (Sporotrichosis, Aspergillus,
Cryptococcus)
Other
Drugs (halogenoderma/hydroxyurea, etc.)
Consider
Infection
Necrotizing fasciitis
Syphilis/Amebiasis/Mucormycosis
Histoplasmosis/Rhizopus
Other
Dermatitis artefacta
Calciphylaxis/Insect bite (spider)
Most Likely
Dermatoses (extraintestinal Crohns)
Irritant/Allergic contact dermatitis
Other (e.g., psoriasis)
Infection
Bacterial (Staphylococcus/Streptococcus)/Cellulitis
Fungal (Candida)
Other
Extraintestinal inflammatory
Bowel disease
Malignancy
Bullous PG
Most Likely
Infection
Bacterial (cellulitis/impetigo)
Viral (in immunocompromised)
Fungal (mucormycosis in diabetics)
Other
Sweet syndrome/Behet disease
Consider
Bullous dermatoses
Erythema multiforme/Bullous pemphigoid
Other
Insect/Arthropod bite/Malignancy
Pustular PG
Most Likely
Infection
Bacterial/Viral/Fungal
Vasculitis
Pustular vasculitis
Consider
Other
Pustular psoriasis
SneddonWilkinson disease
Pustular drug eruption
Bowel bypass syndrome
Pyostomatitis vegetans
374
In Wounds
Most Likely
Infection
Bacterial/Cellulitis
Fungal (e.g., mucormycosis)
Breakdown
Suture allergy
Mechanical
Consider
Malignancy
Genital
Most Likely
Infection
Bacterial/Viral infection (herpes simplex virus,
EpsteinBarr virus, cytomegalovirus)
Tuberculosis/Tuberculide
Fournier gangrene
Malignancy
Squamous cell/Extramammary
Paget disease
Consider
Infection
Syphilis/Lymphogranuloma
Venereum/Histoplasmosis
Leishmaniasis/Granuloma inguinale
Other
Behet disease
Head and Neck
Most Likely
Infection
Dissecting cellulitis of the scalp
Malignancy
Squamous cell carcinoma
Consider
Vasculitis
Granulomatosis with polyangiitis (Wegeners)
Malignant pyoderma
(continued)
BOX 33-1 Differential Diagnosis of Pyoderma Gangrenosum (PG) (Continued)
SITE SPECIFICa
Other
The differential diagnosis of lower limb PG is essentially that delineated for variant-specific ulcerative PG.

The clinician should be aware that sterile neutrophilic
abscesses of internal organs (lung, bone joints, CNS,
CVS, intra-abdominal viscera, eye) can occur in association with or even precede the onset of cutaneous
PG.7 In the patient without cutaneous lesions surgical
procedures may be undertaken to establish the
Figure 33-5 Pustular pyoderma gangrenosum lesions of

the penis in a patient who also had ulcerative pyoderma
gangrenosum.
Figure 33-4 Bullous pyoderma gangrenosum lesion

showing collapsed roof of blister and superficial erosive
quality of the subsequent ulceration.
recently been reported as an autosomal dominant

condition classified as being one of the group of
autoinflammatory diseases.
::
often appears on the upper limbs.2 This variant of PG

may show clinical and histological overlap with Sweet
Syndrome (one of the neutrophilic dermatoses which
is itself often associated with hematologic disease).
Pustular PG (also called the pustular eruption of
inflammatory bowel disease) is a generalized eruption
that occurs almost exclusively in the setting of an exacerbation of acute inflammatory bowel disease (usually
ulcerative colitis). Its onset is dramatic, with the rapid
development of multiple, large, circular-to-oval, painful pustules on the trunk and, to a lesser extent, the
face and limbs (Fig. 33-5). Control of this eruption is
difficult without controlling the bowel disease, which
in some cases requires extensive resective surgery.
Vegetative PG (or superficial granulomatous pyoderma) usually presents as a single furunculoid nodule, abscess, plaque, or superficial ulcer, typically on
the trunk (Fig. 33-6). In contrast to other variants, it is
gradual in its onset, mild in the discomfort it generates,
and not usually associated with the presence of systemic disease. This form of PG is usually more responsive to localized or mild forms of systemic therapy
than the other variants.7
Postoperative and Peristomal PG are considered to be
examples of ulcerative PG demonstrating the pathergic phenomenon, while the PAPA syndrome has
Chapter 33
VARIANT SPECIFIC
Vegetative PG
Most Likely
Infection
Mycobacterial/Atypical mycobacterial
Leishmaniasis
Consider
Blastomycosis-like pyoderma
Dermatitis artefacta/Malignancy
Pyoderma vegetans
375
Section 5
::
376
Figure 33-7 Chest X-ray showing neutrophilic abscess in

the right upper lung with clear fluid level visible.
Figure 33-6 Vegetative pyoderma gangrenosuman
indolent area of chronic inflammation and ulceration that
was present for months.
iagnosis of the internal neutrophilic infiltration, the
d
wounds of which may subsequently break down and
present as postoperative PG. Because many patients
with PG also have diseases of other systems (more
than 70% of cases), a thorough physical examination is
mandatory with particular search for clinical and
biological markers of inflammatory bowel disease,
arthritis, vasculitis (leukocytoclastic/granulomatous/
cryoglobulinemic/Takayasu arteritis), hematologic
disease (monoclonal gammopathy and other dyscrasias), and internal malignancy.
LABORATORY TESTS
ROUTINE INVESTIGATIONS
(See Fig. 33-1)
All patients with PG should have the following tests
carried out: full blood cell count with differential white
cell count and erythrocyte sedimentation rate liver,
and bone profiles; autoantibody screen (including antiRo/La antibodies, antineutrophilic cytoplasmic antibodies, antiphospholipid antibodies, rheumatoid
factor); serum protein electrophoresis; thyroid function studies; chest X-ray (Fig. 33-7), electrocardiogram,
and midstream specimen of urine; and swabs from
lesions sent for bacterial, fungal, and viral cultures. An
incisional, wedge skin biopsy should be taken from the
edge of the lesion sampling a portion of normal skin
progressing through the border into the area of active
inflammation to allow the various histological patterns
to be discerned. The excised tissue should then be
divided with one section (fresh tissue) sent for bacterial, mycobacterial, and fungal culture, and another
portion sent in formalin for histological evaluation
requesting hematoxylin and eosin and periodic acidSchiff, Giemsa, Fite, Gram, and other stains considered
relevant. Although immunofluorescent studies may
show positive vascular staining in perilesional skin,
this is not essential for diagnostic purposes and can be
omitted unless vasculitis is suspected in the differential diagnosis.
HISTOPATHOLOGY
The histopathological changes in the skin are not diagnostic but can be highly suggestive of PG and require
experience to interpret. The inflammatory changes that
are seen depend on (1) the clinical variant of PG (ulcerative, bullous, pustular, or vegetative), (2) the timing of
the biopsy (early lesions show less marked changes
than established lesions), and (3) the site of the biopsy
relative to the inflammatory process.8 The site of the
biopsy is particularly important because biopsies
taken from the center of established ulcerative, bullous, or pustular PG lesions usually show marked neutrophilic infiltration with abscess formation in the mid
and deep dermis extending to the panniculus, whereas
those taken from peripheral areas (the ulcer edge or
inflammatory zone of erythema) show a mixed or predominantly lymphocytic inflammatory infiltrate.
A marked perivascular lymphocytic infiltration is
seen in biopsies taken from the zone or area of erythema which surrounds active lesions of ulcerative PG.
Lymphocytes may be seen to infiltrate vessel walls
with intramural and intravascular fibrin deposition
indicative of vascular damage (sometimes called lymphocytic vasculitis).9 Abscess formation with intense
dermal neutrophilic infiltration extending to the panniculus and areas of tissue necrosis dominates the histological findings in biopsies taken from central areas
of ulcerative PG lesions. Leukocytoclasis is not a prominent finding and although occasionally evidence of
leukocytoclastic vasculitis is seen close to the abscess
center, this is a minor feature and considered secondary to the intense inflammatory changes rather than
the primary event. Histological examination of lesional
skin from a patient with bullous PG shows a subepidermal or intraepidermal bulla with overlying epidermal necrosis and marked upper dermal edema with
prominence of neutrophils. Biopsy of pustular PG
shows a dense dermal neutrophilic infiltration (often
centered about a follicle) with subepidermal edema
and infiltration of neutrophils into the epidermis with
subcorneal aggregations. Vegetative PG is characterized histologically by the presence of pseudoepitheliomatous hyperplasia, sinus tract formation, and the
presence of palisading granulomas in the setting of
focal dermal neutrophilic abscesses.
SPECIAL INVESTIGATIONS
morphologic descriptions outlined above

(ulcerative, bullous, pustular, or vegetative)
in a (usually middle-aged) apyrexial patient
without significant toxemia or relevant drug
intake
(b) Histological evidence of marked
tissue neutrophilia in the absence of
significant leukocytoclastic vasculitis and
histopathological exclusion of malignancy
and of infective organisms by special studies
and negative tissue culture
(c) Exclusion of vascular stasis/occlusion/
vasculitis by appropriate studies
2. Minor criteria that are supportive of the diagnosis
are as follows:
(a) Localization of lesions at characteristic sites
(ulcerative PG on the legs, vegetative on
the trunk, bullous PG on the upper limb,
pustular PG on the trunk or face) or at a
site of cutaneous trauma (postoperative
ulcerative PG or peristomal PG).
(b) Rapid progression of the inflammatory
lesion with escalating pain severity (except
vegetative PG).
(c) Occurrence in an individual with systemic
disease, such as arthritis, inflammatory
bowel disease, or hematological dyscrasias
(except vegetative PG).
(d) Rapid reduction of pain and
inflammation on initiation of systemic
steroid therapy.
PROGNOSIS AND
CLINICAL COURSE
The prognosis depends on the PG variant; the age and
sex of the patient; presence of other systemic disease;
and the type, dosage, and duration of therapy required
to bring the disease under control. Patients with vegetative PG generally have a good prognosis and the skin
lesions often heal within 6 months of the initiation of
relatively mild forms of treatment.7 Peristomal PG similarly has a good prognosis often responding to topical
or intralesional therapy. Patients with pustular PG
often have complete remission of their cutaneous
lesions if the severe inflammatory bowel disease that
usually accompanies this variant is controlled. Ulcerative PG is a chronic recurrent disease with a significant
morbidity and mortality.2,10 Patients with this variant
older than 65 years of age and male patients seem to
have a worse prognosis. Patients with bullous PG who
have an associated hematological disorder also have a
poor prognosis. The onset of bullous PG in a patient
with stable polycythemia rubra vera appears to herald
the onset of leukemic change in some patients.11
1. Major criteria are as follows:

(a) Sudden onset of a painful lesion fitting the
Active or poorly controlled cutaneous PG causes significant morbidity (loss of mobility, pain, exposure to
secondary infection, anemia of chronic disease, etc.).
Lack of recognition of the neutrophilic infiltration of
internal organs in PG may lead to unnecessary surgical
procedures. Many of the treatments for PG must be
administered for many months and may have significant side effects. Frequent monitoring and follow-up
of patients are necessary. Elective surgery should be
undertaken with caution because of the possibility of
inducing new PG lesions.
::
The differential diagnosis to be considered in a patient

with PG is extensive.6 Different variants of PG (ulcerative, bullous, vegetative, pustular) suggest alternative
diagnoses and the occurrence of PG at certain cutaneous sites raises further diagnostic issues for the clinician, as shown in Box 33-1.
Because there is no confirmatory diagnostic test for
PG, the following major criteria are proposed which
make the diagnosis of PG likely:
Chapter 33
In some patients the following additional tests may be

warranted: endoscopy (upper and/or lower gastrointestinal); vascular studies; bone marrow aspirate
examination; ultrasound of abdomen (including liver/
spleen/aorta); computed tomography of the thorax,
abdomen, or brain; and other directed investigations
as outlined in Fig. 33-1.
COMPLICATIONS
TREATMENT
GENERAL MEASURES
The age, mobility, social support networks, pain
threshold, extent and severity of disease, and ability to
comply with therapeutic measures should be evaluated for each patient and the treatment adapted accordingly. The patient should be given realistic expectations
of the speed of recovery likely in this disease. Thus,
although lesions develop and evolve within days, the
healing process usually takes weeks or even months.
Adequate bed rest, efficient pain relief, correction of
anemia, and appropriate therapy of any associated disease are pivotal in the overall management strategy of
a patient with PG.12 If other systemic illnesses are present, cooperation with an internal medicine specialist is
important, and if surgery is anticipated appropriate
measures (such as the use of subcuticular sutures and
systemic steroid cover) should be adopted to avoid
precipitating new postoperative PG lesions.
377
The location, morphology, size, and outline of each

lesion should be recorded (by photography and by
using a calibrated transparent plastic sheet placed over
lesions on which the outline is traced) on presentation
and subsequent review.
WOUND CARE
Section 5
::
The cutaneous lesions of PG are usually extremely tender so cleansing should be carried out daily with tepid
sterile saline or a mild antiseptic solution. Potassium
permanganate solution diluted 1:2,000 is helpful if
there is marked exudation. Silver sulphadiazine 1%
cream is usually soothing when applied to the ulcerated lesions of PG and may facilitate granulation tissue
formation as well as inhibiting bacterial growth. A nonadhesive dressing should be applied over the lesion
and held in place with a crpe elasticized bandage
wound firmly, but not tightly, over it. Some patients,
particularly those with superficial lesions, obtain significant relief with the use of hydrocolloid dressings,
which can be left on for 23 days and melt into the
lesion. Careful instruction to the patient and nurse is
important to ensure compliance and to avoid the use of
irritants such as chemical desloughing agents, caustics
(such as silver nitrate), or dressings (such as gauze
impregnated with soft paraffin and/or antibacterial
agents which may adhere to the ulcer base) or pressure
dressings as are sometimes prescribed for patients with
ulcers due to venous insufficiency. A variety of bacteria
may be cultured from the wound surface, but these
usually represent contaminants and directed antibiotic
therapy is not required unless there are clinical signs of
incipient cellulitis around the wound.
TOPICAL TREATMENTS
Topical treatments are important adjuncts to the systemic treatment needed for the management of most
PG patients, and may be sufficient to bring the condition under control in those who have vegetative or
mild ulcerative PG. Potent topical corticosteroids
applied to the periphery of an active PG lesion can
reduce inflammation and may be sufficient to heal
vegetative or peristomal ulcerative PG.13 Although
topical disodium cromoglycate (with or without occlusion), benzoyl peroxide, nicotine cream or patches,
hyperbaric oxygen, and radiotherapy have all been
reported as being helpful in individual patients with
PG, their effectiveness has not been established. Clinical impression suggests that topical tacrolimus (with
or without occlusion) is particularly effective for isolated pustular lesions and for the superficial ulcerations of peristomal PG.
INTRALESIONAL TREATMENTS
378
Intralesional triamcinolone acetonide (510 mg/mL)

injected twice weekly into the border of a vegetative or
peristomal PG lesion may lead to healing and can also
be useful in a patient with ulcerative PG if one section

of the ulcer is proving recalcitrant to other therapies.
Intralesional cyclosporine and tacrolimus have also
been reported to be effective in some PG patients.
SYSTEMIC TREATMENTS
Because PG is a rare disease, most systemic treatment
recommendations are based on experience gained
from small series of patients studied.14 The main systemic treatments used for PG with their suggested dosages are listed in Box 33-2. As experience with newer
agents is gained, it is likely these recommendations
will change.15 The initiation of systemic therapy is
based on the variant of PG (ulcerative and bullous PG
usually require systemic therapy), the rapidity of its
evolution, the extent of cutaneous involvement, and
the general medical status of the patient.
Systemic corticosteroid treatment is probably the
initial treatment of choice for most patients with PG. It
is important to initiate systemic steroids at a sufficiently high dose to control the disease. Rapid diminution of pain is often recorded by the patient after
initiation of therapy and steroids should be continued
at this dosage until lesions show evidence of healing,
after which gradual tapering of the dose can be undertaken. A steroid-sparing agent should be added as
soon as possible, as well as bone protective measures
to diminish the risk of osteoporosis because prolonged
therapy can be anticipated in most patients. Intravenous corticosteroids in pulsed doses have been used to
induce PG remission, but serious potential adverse
effects limit their use to exceptional circumstances.
Dapsone has been traditionally used in the treatment
of PG and remains a useful drug, particularly when
used in conjunction with systemic corticosteroids.
Dapsone is generally well tolerated, but hematological
complications (including agranulocytosis, hemolysis,
hemolytic anemia, and methemoglobulinemia) as well
as other potentially serious side effects may occur.
Other antimicrobial agents reported as successful in
BOX 33-2 Systemic Treatments for

MEDICATION
DOSAGE
Prednisone
Methylprednisolone
(pulsed dose)
Dapsone
Clofazimine
Minocycline
Cyclosporine
Tacrolimus
Mycophenolate
mofetil
Infliximab
0.51.5 mg/kg/day PO
500 mg1 g IV
50200 mg/day PO
200400 mg/day PO
50100 mg twice daily PO
3 to 5 mgs/kg/day PO
0.10.3 mg/kg PO
500 mg1 g bid PO
5 mg/kg IV
donor sites, but cultured tissue allografts/autografts

and the use of bovine collagen matrix have been
reported to be useful in patients in whom the disease is
controlled but reepithelialization incomplete.23
The unpredictable nature of PG and its variable
aggressiveness in individual patients mean that a flexible approach to treatment is required and the use of
therapeutic agents have to be adapted to the patients
physiologic state (childhood, pregnancy, old age). By
whichever modality control of PG is achieved, maintenance therapy should be continued until there is complete wound healing. In addition, patients with
ulcerative PG have a significant risk of relapse, so longterm follow-up is required.
PREVENTION
::
A patient who has had a history of PG should be

advised to avoid trauma to the skin as there is the possibility of precipitating a new lesion (the pathergic
phenomenon). If such patients have to undergo surgery, they should have close supervision by a dermatologist of their postoperative course. Patients with a
history of aggressive PG may warrant a course of systemic steroids during and for a period (2 weeks or longer) postoperatively to prevent the development of
new PG lesions and subcuticular sutures should be
used where possible. Patients with a history of PG and
Crohns disease who are to have an ileostomy should
be warned about the possible development of peristomal PG lesions.
Chapter 33
the treatment of PG patients include rifampicin, tetracyclines, vancomycin, mezlocillin, clofazimine, and
minocycline. These have usually been prescribed in
combination with other systemic therapies and seem
to work in PG patients by mechanisms other than their
antibacterial properties. Most experience has been
with clofazimine and minocycline (100200 mg daily).
The latter agent is well tolerated and often allows for a
reduction in systemic corticosteroid dosage and
appears to prolong remission in some patients.
Cyclosporine is an alternative first-line therapy of
PG16 or may be used in combination with systemic corticosteroids to achieve rapid control of disease. Doses
of 3 to 5 mgs/kg/day have shown efficacy and continued treatment is usually required for 34 months. Less
risk of serious side effects (such as impairment of renal
function and hypertension) is seen at these low doses,
but careful monitoring of patients is required and
attention should paid to the possibility of other drugs
interacting with this medication.
Tacrolimus (FK-506) and mycophenolate mofetil
have also been used successfully in the treatment of PG
either as monotherapies or in combination with systemic corticosteroids or cyclosporine.17 Both drugs
cause significant immunosuppression with resultant
susceptibility of the patient to infection and malignant
disease and can have other potentially serious side
effects. Infliximab, an antitumor necrosis factor antibody, has been used successfully to treat patients with
inflammatory bowel disease and has been reported to
be effective in some patients with PG.18 Other similar
drugs that have been reported to be efficacious in the
treatment of patients with PG include etanercept and
adalimumab. The role of these agents in the management of PG has yet to be fully defined and susceptibility to reactivation of tuberculosis infection and other
significant side effects remain a concern. Anakinra, an
IL-1 receptor antagonist has been reported to be effective in treating PG of the PAPA syndrome and suggests
another possible treatment for this condition.5 The use
of thalidomide in the treatment of PG has probably
been superseded by the development of these other
agents. Other drugs which have been reported to be
helpful in the treatment of PG include azathioprine
(thiopurine methyl transferase levels should be
checked pretreatment), colchicine,19 cyclophosphamide, chlorambucil, and melphalan. These agents can
have toxic effects and evidence of their efficacy is
limited.
Other modalities which have been reported to be
useful in the management of individual patients or
small series of patients with PG include human intravenous immunoglobulin,20 interferon-, nicotine,21
potassium iodide, leukocytapheresis,22 and plasma
exchange. Skin grafting should be avoided if possible
because of the risk of inducing new PG lesions at the
KEY REFERENCES
1. Powell FC, Su WP, Perry HO: Pyoderma gangrenosum:
Classification and management. J Am Acad Dermatol 34:395,
1996
2. Bennett ML et al: Pyoderma gangrenosum. A comparison
of typical and atypical forms with an emphasis on time to
remission. Case review of 86 patients from 2 institutions.
Medicine (Baltimore) 79:37, 2000
3. Powell FC et al: Pyoderma gangrenosum: A review of 86
patients. Q J Med 55:173, 1985
4. Wallach D, Vignon-Pennamen MD: From acute febrile neutrophilic dermatoses to neutrophilic disease: Forty years of
clinical research. J Am Acad Dermatol 55:1066-1071, 2006
5. Brenner M et al: Treatment of pyoderma gangrenosum in
PAPA (pyogenic arthritis, pyoderma gangrenosum and
acne) syndrome with the recombinant human interleukin-1
receptor antagonist anakinra. Br J Dermatol 161:1199-1201,
2009
6. Weenig RH et al: Skin ulcers misdiagnosed as pyoderma
gangrenosum. N Engl J Med 347:1412, 2002
379
Chapter 34 :: Granuloma Faciale

:: David A. Mehregan & Darius R. Mehregan
GRANULOMA FACIALE AT A GLANCE
Granuloma faciale is an uncommon
inflammatory dermatosis characterized
clinically by reddish brown papules and
plaques primarily involving the face.
Section 5
The pathology shows changes of a chronic

leukocytoclastic vasculitis with a mixed
infiltrate containing eosinophils, extensive
perivascular fibrin deposition, and dermal
fibrosis.
::
Etiology is unknown.
CLINICAL FINDINGS
Granuloma faciale is characterized by solitary papules,

plaques, or nodules. The lesions are typically asymptomatic red, brown, or violaceous plaques that are soft,
smooth, and well circumscribed, often showing follicular accentuation and telangiectasia (Figs. 34-1 and
34-2). Ulceration is rare. Lesions are most common on
the face. Sites of predilection include the nose, preauricular area, cheeks, forehead, eyelids, and ears.4,12
Rarely, patients may present with multiple lesions or
lesions on the trunk or extremities. Extrafacial lesions
have been reported both as isolated findings and in
conjunction with facial lesions. Lesions may be present
for weeks or months and tend to follow a chronic
course. Lesions are typically asymptomatic; however,
patients may complain of tenderness, burning, or pruritus.4 Photoexacerbation of lesions has been reported.13
EPIDEMIOLOGY
LABORATORY FINDINGS
Early cases of granuloma faciale were reported as

eosinophilic granuloma of the skin. Weidman was
the first to separate three cases that had been previously reported in the literature as variants of erythema
elevatum diutinum.1 Lever and Leeper helped to differentiate the lesions from other eosinophil-rich diseases.2 Cobane, Straith, and Pinkus later stressed the
histologic resemblance to erythema elevatum diutinum (EED) and termed the lesions facial granulomas
with eosinophilia and later granuloma faciale.3 Granuloma faciale occurs predominantly in adult men and
women. There is a slight male predominance, and
mean age at presentation is 52 years.4,5 Granuloma
faciale can occur in individuals of any race; however,
it is more common in Caucasians. The disease presents most commonly with a single lesion on the face,
but extrafacial lesions have been described.6 Patients
with multiple lesions have also been reported.7 A rare
mucosal variant has been described as eosinophilic
angiocentric fibrosis, which typically involves the
upper respiratory tract.8
An extensive laboratory evaluation is not required.

Peripheral blood eosinophilia is occasionally detected.
The diagnosis may be established by a combination of
clinical findings and confirmatory tissue biopsy results.
A punch biopsy that includes the full thickness of the
dermis is recommended. Histologic examination shows
a normal-appearing epidermis, which may be separated
from the underlying inflammatory infiltrate by a narrow grenz zone (Fig. 34-3). Within the dermis is a dense
and diffuse infiltrate of lymphocytes, plasma cells,
eosinophils, and neutrophils with evidence of leukocytoclasis (Fig. 34-4). The inflammatory infiltrate surrounds the blood vessels, which show evidence of fibrin
deposition. In later stages, the perivascular fibrin
380
The etiology of granuloma faciale is unknown. The

disease can be considered a localized chronic fibrosing
vasculitis.9 Immunofluorescence studies have revealed
deposition of immunoglobulins and complement factors in the vessel walls consistent with a type III
immunologic response, marked by deposition of circulating immune complexes surrounding superficial
and deep blood vessels.10,11 However, other authors
have described negative results with immunofluorescence.12
Figure 34-1 Granuloma faciale. Raised edematous

plaques on cheek showing prominent follicular ostia.
Chapter 34
Figure 34-2 Granuloma faciale. Single plaque on the

temple showing prominent follicular ostia and central dell.
The clinical differential diagnosis for granuloma faciale

includes discoid lupus erythematosus, polymorphous
Figure 34-4 Granuloma faciale. This histologic section

shows perivascular deposition of fibrin and a mixed infiltrate of lymphocytes, neutrophils, and eosinophils.
light eruption, fixed drug eruption, benign lymphocytic
infiltrate of Jessner, lymphoma cutis, pseudolymphoma,
sarcoidosis, granuloma annulare, tinea faciei, insect bite
reaction, xanthogranuloma, mastocytoma, basal cell
Granuloma Faciale
::
deposition becomes extensive and dominates the histologic picture. Deposition of hemosiderin may contribute
to the brown color seen clinically. Electron microscopic
studies confirm the presence of an extensive eosinophilic infiltrate with CharcotLeyden crystals and
numerous histiocytes filled with lysosomal vesicles;
however, cases with few eosinophils in the infiltrate
have also been described.14 Immunoglobulins, fibrin,
and complement can be found deposited along the dermalepidermal junction in a granular pattern and
around blood vessels by direct immunofluorescence.10

of Granuloma Faciale
Most Likely
Face
Sarcoidosis
Benign lymphocytic infiltrate of Jessner
Rosacea
Extrafacial
Consider
Face
Discoid lupus erythematosus
Lymphoma cutis
Angiolymphoid hyperplasia with eosinophilia
Tinea faciei
Xanthogranuloma
Mastocytoma
Extrafacial
Granuloma annulare
Benign lymphocytic infiltrate of Jessner
Fixed drug eruption
Figure 34-3 Granuloma faciale. This low-power histologic

section shows a mixed infiltrate of lymphocytes, histiocytes, neutrophils, plasma cells, and eosinophils. There is
sparing of a narrow grenz zone between the inflammatory
infiltrate and the overlying epidermis.
Always Rule Out

Face
Trunk
381
BOX 34-2 Treatments for Granuloma Faciale

First-line therapy
TOPICAL
PHYSICAL
Cryotherapy
Pulsed dye laser
Second-line therapy
Topical tacrolimus ointment
Surgical excision
Section 5
::
carcinoma, Langerhans cell histiocytosis, and rosacea

(Box 34-1). The diagnosis can be reliably made by histologic examination. Absence of serologic evidence of
lupus erythematosus helps to differentiate these lesions
from the lesions of discoid lupus erythematosus.
The primary histologic differential diagnosis is EED.
Both diseases represent chronic forms of fibrosing
small vessel vasculitis and may be related. However,
there are several clinical and histologic differences.
EED is characterized by multiple lesions, primarily
located on extensor surfaces of the extremities in a
symmetric acral distribution. The trunk and face are
typically spared in EED. Histologically, both show a
chronic fibrosing vasculitis.15 However, a grenz zone of
normal collagen beneath the epidermis is not typical of
EED. Eosinophils and plasma cells are more prominent
in granuloma faciale while neutrophils are more frequently found in EED. EED may be associated with
systemic conditions, primarily monoclonal gammopathies, and shows an excellent response to dapsone.16,17
The histologic and clinical differential may also include
angiolymphoid hyperplasia with eosinophilia. However, the lesions of angiolymphoid hyperplasia with
eosinophilia contain blood vessels with prominent
hobnail endothelial cells that protrude into the vascular lumina rather than perivascular fibrin deposition. One case of tinea faciei caused by Trichophyton
rubrum has been described with clinical and histologic
changes consistent with granuloma faciale.18
COMPLICATIONS
Granuloma faciale is rarely associated with systemic
disease.19

COURSE
Lesions tend to be chronic and resistant to treatment.
TREATMENT
382
A variety of medical and surgical therapies have been

used in the treatment of granuloma faciale (Box 34-2).
Because of the small number of patients involved, randomized trials to evaluate these treatments are lacking.
Resistance to therapy and cosmetic complications should
be discussed with the patient before initiation of therapy.
SYSTEMIC
Dapsone, 50100 mg/day
Topical and intralesional steroids have been administered with modest improvement.4,20 Cryosurgery has
been applied with effective results.21,22 Because the disease is known to be a variant of chronic leukocytoclastic
vasculitis, dapsone 25 to 100 mg/day has been used with
benefit in a number of patients.23,24 Topical tacrolimus
ointment 0.1% also has been used with success.25
Surgical excision may be an option for small lesions.
Lesions of granuloma faciale have been treated with a
variety of medical lasers. In multiple studies utilizing
pulsed dye lasers at 585595 nm, clinical improvement
has been demonstrated.2630 A carbon dioxide laser has
also been applied with varying success.31 The use of an
argon laser resulted in total resolution of the granuloma faciale with subsequent scarring. The lesions in
two patients were reported to respond to the potassium-titanyl-phosphate 532-nm laser in combination
with tacrolimus ointment 0.1%.32 Case studies have
suggested a beneficial effect of tacrolimus ointment,33,34
as well as pimecrolimus cream 1%.34
KEY REFERENCES
3. Cobane JH, Straith CL, Pinkus H: Facial granulomas with
eosinophilia: Their relation to other eosinophilic granulomas of the skin and to reticulogranuloma. Arch Derm
Syphilol 61:442, 1950
4. Radin DA, Mehregan DR: Granuloma faciale: Distribution
of the lesions and review of the literature. Cutis 72:213,
2003
5. Marcoval J, Moreno A, Peyr J: Granuloma faciale: A
clinicopathological study of 11 cases. J Am Acad Dermatol
51:269, 2004
9. Carlson JA, LeBoit PE: Localized chronic fibrosing vasculitis of the skin: An inflammatory reaction that occurs
in settings other than erythema elevatum diutinum and
granuloma faciale. Am J Surg Pathol 21:698, 1997
10. Nieboer C, Kalsbeek GL: Immunofluorescence studies in
granuloma eosinophilicum faciale. J Cutan Pathol 5:68, 1978
11. Barnadas MA, Curell R, Alomar A: Direct immunofluorescence in granuloma faciale: A case report and review of
literature. J Cutan Pathol 33:508-511, 2006
12. Ortonne N et al: Granuloma faciale: A clinicopathologic
study of 66 patients. J Am Acad Dermatol 53:1002, 2005
17. Crowson AN, Mihm MC Jr, Magro CM: Cutaneous vasculitis: A review. J Cutan Pathol 30:161, 2003
19. Dowlati B, Firooz A, Dowlati Y: Granuloma faciale: Successful treatment of nine cases with a combination of
cryotherapy and intralesional corticosteroid injection. Int
J Dermatol 36:548, 1997
31. Ludwig E et al: New treatment modalities for granuloma
faciale. Br J Dermatol 149:634, 2003
Chapter 35 :: S
ubcorneal Pustular Dermatosis
(SneddonWilkinson Disease)

:: Franz Trautinger & Herbert Hnigsmann
SUBCORNEAL PUSTULAR
DERMATOSIS AT A GLANCE
A rare condition with worldwide occurrence.
Pathology: subcorneal pustules filled with

polymorphonuclear leukocytes.
Subcorneal pustular dermatosis (SPD) is a rare, chronic,

recurrent, pustular eruption characterized histopathologically by subcorneal pustules that contain abundant
neutrophils. The condition was originally described in
1956 by Sneddon and Wilkinson,1 who separated SPD
from other previously unclassified pustular eruptions.
Until 1966, when the first comprehensive review
appeared, more than 130 cases had been reported, but
not all fulfilled the clinical and histopathologic criteria
required for this diagnosis.2 A considerable number of
additional cases have since appeared in the literature,
and a subtype with intraepidermal deposits of immunoglobulin (Ig) A directed against desmocollin 1 has
been recognized.3 Today, these cases are usually classified as SPD-type IgA pemphigus and it is a matter of
debate whether the finding of epidermal IgA deposits
define a subset of SPD or a new pemphigus variant that
is otherwise indistinguishable from classic SPD.
EPIDEMIOLOGY
There is no racial predilection. Most of the reported
cases have been in whites, but the disease has also been
observed in Africans, Japanese, and Chinese. The condition is more common in women and in persons older
than 40 years of age, but SPD may occur at any age.2 A
pustular eruption that is clinically and histologically
similar to the human disease, which also responds to
dapsone treatment, has been observed in dogs.4
Subcorneal Pustular Dermatosis (SneddonWilkinson Disease)
Usually distributed symmetrically in the

axillae, groins, submammary, the flexor
aspects of the limbs, and on the abdomen.
The cause of SPD is unknown. Cultures of the pustules

consistently do not reveal bacterial growth. The role of
trigger mechanisms such as preceding or concomitant
infections, though repeatedly discussed, has remained
speculative. Immunologic mechanisms have been
implicated in the pathogenesis and in a subset of
patients, whose disease clinically resembled SPD,
intraepidermal IgA deposits have been detected. Some
of these patients also had circulating IgA antibodies
against the same sites within the epidermis. Desmocollin 1 and in a single case also desmocollins 2 and 3 have
been described as autoantigens in these cases and the
disease has been classified as a rare pemphigus variant
(SPD-type IgA pemphigus).3,57 The pathogenetic role
of these antibodies is still to be demonstrated.8
The occasional association of SPD with certain other
diseases may represent more than a mere coincidence.
Increased serum IgA has been detected in a number
of patients, and the disease has been reported to occur
in cases of IgA-paraproteinemia and IgA multiple
myeloma.912 In addition, SPD is associated with pyoderma gangrenosum,13,14 ulcerative colitis,15 and Crohn
disease.16 On the other hand, pyoderma gangrenosum
is not uncommon in patients with inflammatory bowel
disease, paraproteinemia, and myeloma (see Chapter
33). Whether or not the coexistence of these conditions
reflects common pathogenetic mechanisms remains to
be clarified, but an additional common denominator
linking these disorders is their response to sulfone and
sulfonamide therapy.
Further associations reported to date include IgG
paraproteinemia,17,18 CD30+ anaplastic large-cell lymphoma,19 marginal zone lymphoma,20 nonsmall cell
lung cancer,21 apudoma,22 rheumatoid arthritis,23,24 systemic lupus erythematodes,25 hyperthyroidism26 and
mycoplasma pneumoniae infection.27
::
Crops of flaccid, coalescing pustules; often in

annular or serpiginous patterns.
Chapter 35
A chronic recurrent disorder with a

benign course frequently associated with
various forms of immune dysfunction
[most commonly immunoglobulin (Ig) A
monoclonal gammopathy]. Occurrence of
intraepidermal deposits of IgA indicates a
relationship with IgA pemphigus.
CLINICAL FINDINGS
The primary lesions are small, discrete, flaccid pustules, or vesicles that rapidly turn pustular and usually
arise in crops within a few hours on clinically normal or
slightly erythematous skin (Fig. 35-1). In dependent
regions, pus characteristically accumulates in the lower
half of the pustule (see Fig. 35-1B); as the pustules usually have the tendency to coalesce, they often, but not
always, form annular, circinate, or bizarre serpiginous
patterns. After a few days, the pustules rupture and dry
up to form thin, superficial scales and crusts, closely
resembling impetigo. Peripheral spreading and central
healing leave polycyclic, erythematous areas in which
new pustules arise as others disappear (see Fig. 35-1A).
383
Section 5
::
Figure 35-1 Subcorneal pustular dermatosis. A. Typical distribution. Note accentuated involvement of groin and
abdomen. Hyperpigmented macules mark previously affected areas. B. Close-up showing coalescence of pustules, which
form annular and circinate patterns. Lesions of different developmental stages are seen side by side. At the lower right,
newly formed pustule with characteristic hypopyon formation.
There is no atrophy or scarring, but an occasional
brownish hyperpigmentation may mark previously
affected sites. Variable intervals of quiescence, lasting
from a few days to several weeks, may be followed by
the sudden development of new lesions. The eruptions
tend to occur symmetrically, affecting mainly the axillae, groin, abdomen, submammary areas, and the flexor
aspects of the limbs. In rare cases, the face,28 palms, and
soles29 may be involved. Scalp and mucous membranes
invariably remain free of lesions. Episodic itching and
burning represent subjective symptoms in a small
number of patients, but there are no systemic symptoms or abnormalities in routine laboratory parameters.
HISTOPATHOLOGY
The hallmark of the disease is a strictly subcorneal pustule filled with polymorphonuclear leukocytes,1 with
only an occasional eosinophils.2 Acantholysis is not
involved in pustule formation, but a few acantholytic
cells may be found in older lesions (secondary acantholysis). Surprisingly, the epidermal layers underlying the pustule exhibit little pathology, and, apart from
a variable number of migrating leukocytes, there is little evidence of spongiosis or cytolytic damage to the
epidermal cells. The dermis contains a perivascular
infiltrate composed of neutrophils and rarely mononuclear cells and eosinophils (Fig. 35-2).
BOX 35-1 Differential Diagnosis of

Subcorneal Pustular Dermatosis
384
Figure 35-2 Subcorneal pustular dermatosis. Strictly subcorneal pustule filled with polymorphonuclear leukocytes,
with the underlying epidermal layers exhibiting only slight
edema and some migrating leukocytes. There is a mild
inflammatory infiltrate around dermal blood vessels.
Bacterial impetigo
Pemphigus foliaceus
IgA pemphigus/intraepidermal IgA pustulosis
Pustular psoriasis
Necrolytic migratory erythema
Acute generalized exanthematous pustulosis
BOX 35-2 Treatments for Subcorneal Pustular Dermatosis

First line
Dapsone
Corticosteroids
Second line (anecdotally reported

beneficial responses)
Retinoids, photochemotherapy, ultraviolet B,

colchicine, cyclosporine, infliximab, etanercept

COURSE
SPD is a benign condition. Without treatment, attacks
recur over many years and remissions are variable,
lasting from a few days to several weeks. Despite the
protracted course the general health of the patient is
TREATMENT
The drug of choice is dapsone (Box 35-2) in a dose of 50
to 150 mg daily. The response is slower and less dramatic than in dermatitis herpetiformis, but complete
remission is most often obtained. In some patients, the
treatment may be withdrawn after several months,
although in others it may have to be continued for
years; the minimal effective dose to suppress disease
should be determined in these patients. Systemic corticosteroids are less effective, although they can suppress generalized flares when given in high doses.
Responses to retinoids, photochemotherapy, ultraviolet B, colchicine, cyclosporine, and topical tacalcitol
(1-24R-dihydroxyvitamin D3) have been anecdotally
reported.3134 More recently antitumor necrosis factor
therapy has been successfully used in single cases. Infliximab was described to induce rapid responses in
three recalcitrant cases, with one patient relapsing
despite continuing treatment.25,35,36 In two patients
etanercept was able to induce almost complete continuing remissions for 22 and 7 months, in one case
combined with acitretin.37
KEY REFERENCES
Subcorneal Pustular Dermatosis (SneddonWilkinson Disease)
(Box 35-1)
An early localized eruption of SPD may be clinically
and histologically indistinguishable from impetigo,
but the distribution pattern of the lesions, the absence
of bacteria in the pustules, and the ineffectiveness of
antibiotic therapy suggest the correct diagnosis. Dermatitis herpetiformis is highly pruritic, affects primarily the extensor surfaces, and has subepidermal
vesicles with granular IgA deposits in the dermal papillary tips. Pemphigus foliaceus has acantholysis and a
typical immunofluorescence pattern. Generalized pustular psoriasis (von Zumbuschs type) presents with
systemic symptoms (fever, malaise, leukocytosis), and
spongiform pustules within the epidermis. The necrolytic migratory eruption of glucagonoma syndrome
can be differentiated by its distribution, lack of actual
pustule formation, erosions of the lips and oral mucosa,
and, histologically, necrobiosis of the upper epidermis.
Biochemically, hyperglycemia and excess levels of glucagon are diagnostic. Acute generalized exanthematous pustulosis (AGEP) is widespread with an acute
febrile onset and histologically exhibits spongiform
subcorneal and intraepidermal pustules sometimes
with leukocytoclastic vasculitis.
usually not impaired. However, one of our own cases

who had SPD, pyoderma gangrenosum, and IgA paraproteinemia of more than 20 years duration died of
septicemia with staphylococcal abscesses in the lungs,
liver, and spleen.
::
50150 mg/day
As required
Chapter 35
In a subset of patients, direct immunofluorescence

reveals intraepidermal IgA deposits.17 In these
cases, IgA is usually present in a pemphigus-like
intercellular pattern, either in the entire epidermis or
confined to its upper layers. By indirect immunofluorescence, circulating IgA antibodies directed against
the intercellular substance of the epidermis were
detected in single cases. Today these cases are usually diagnosed as SPD-type IgA pemphigus (see
Chapter 54).
Ultrastructural examination of paralesional skin has
shown cytolysis of keratinocytes confined to the granular layer30; the formation of pustules has been
regarded as a secondary event caused by invasion and
subcorneal accumulation of leukocytes.

1. Sneddon IB, Wilkinson DS: Subcorneal pustular dermatosis. Br J Dermatol 68:385, 1956
3. Robinson ND et al: The new pemphigus variants. J Am
6. Ishii N et al: Immunolocalization of target autoantigens in
IgA pemphigus. Clin Exp Dermatol 29:62, 2004
8. Reed J, Wilkinson J: Subcorneal pustular dermatosis. Clin
Dermatol 18:301, 2000
36. Bonifati C et al: Early but not lasting improvement of
recalcitrant subcorneal pustular dermatosis (SneddonWilkinson disease) after infliximab therapy: Relationships
with variations in cytokine levels in suction blister fluids.
Clin Exp Dermatol 30:662, 2005
37. Berk DR: Sneddon-Wilkinson disease treated with etanercept: Report of two cases. Clin Exp Dermatol 34:347,
2009
385
Chapter 36 :: Eosinophils in Cutaneous Diseases

:: Kristin M. Leiferman & Margot S. Peters
EOSINOPHILS IN CUTANEOUS DISEASES AT A GLANCE
Eosinophils may be seen in skin biopsy
specimens from a broad range of cutaneous
diseases but are not pathognomonic for any
dermatosis.
Section 5
::
386
Eosinophils are an important component

of the characteristic histologic pattern in a
limited number of diseases, including the
following:
Angiolymphoid hyperplasia with
eosinophilia
Eosinophilic, polymorphic, and
pruritic eruption associated with
radiotherapy
Eosinophilic pustular folliculitis
Erythema toxicum neonatorum
Eosinophilic ulcer of the oral mucosa
Eosinophilic vasculitis
Hypereosinophilic syndromes
Incontinentia pigmenti
Kimura disease
Pachydermatous eosinophilic dermatitis
Wells syndrome (eosinophilic cellulitis)
Clinical reaction patterns with eosinophil
involvement include diseases in which
eosinophils probably play a pathogenic
role and are a component of the
histological pattern, but are not essential
for diagnosis.
Evidence for involvement of eosinophils in
cutaneous diseases is provided by observation
of intact eosinophils in lesional tissue sections
and/or by immunostains for their toxic
granule proteins, which are deposited in
tissues.
Granuloma faciale
Eosinophils have myriad phlogistic activities that

implicate them in disease.13 (See Chapter 31.) Peripheral blood eosinophilia and/or tissue infiltration by
eosinophils occur in a variety of common and unusual
diseases, including those of infectious, immunologic,
and neoplastic etiologies. Organ-specific eosinophil
disorders occur in the skin, lung, and gastrointestinal
tract.46 Eosinophils are conspicuous in tissue sections
stained with hematoxylin and eosin because of their
intense avidity for eosin dye. Common dermatoses
associated with eosinophils in lesional tissues include
arthropod bites and drug eruptions. Parasitic infections, especially those due to ectoparasites and helminthes, typically have a marked host response with
eosinophilia.7,8 Autoimmune blistering diseases, such
as bullous pemphigoid and the various forms of pemphigus, often have prominent eosinophil infiltration,
including histologic presentation as eosinophilic
spongiosis.9,10 Infiltration of eosinophils in the subcutaneous tissues, so-called eosinophilic panniculitis, is
not a specific diagnosis but rather is seen to a variable
degree in diverse entities.11,12 Eosinophils may be
found in Langerhans cell histiocytosis,13 cutaneous
epithelial neoplasms,14 and lymphoproliferative
disorders.15 Although eosinophils constitute one of the

histologic features in numerous cutaneous diseases,
eosinophil infiltration represents a criterion for histologic diagnosis in relatively few entities (Table 36-1).
The absence, presence or number of eosinophils in
skin biopsy specimens is often of limited value in reliably choosing among differential diagnoses with different and potentially important implications for
clinical management, such as drug reaction versus
acute graft-versus-host disease.16,17 Eosinophils play a
role in certain categories of clinical reactions, particularly those characterized by edema.18 The degree of
tissue eosinophil granule protein deposition in such
diseases, that exhibit relatively few or no intact eosinophils, suggests that the pathogenic influence of
eosinophils may be unrelated to their numbers in tissues. The degree of cutaneous eosinophil infiltration
should be taken in the context of other clinical features, other histological features, and knowledge that
its diagnostic power has limitations.19 However,
eosinophils do have potent biological activities, particularly imparted by their distinctive granules, and
eosinophils may play a pathogenic role in the absence
of identifiable cells in tissues.
TABLE 36-1
Eosinophils in Cutaneous Diseases
HYPEREOSINOPHILIC SYNDROMES
::
Parasitic diseases/infestations
Urticaria and angioedema
Vasculitis
Churg-Strauss syndrome
Eosinophilic vasculitis
Histological patterns defined by eosinophils
Eosinophilic spongiosis
Acute dermatitis
Arthropod bite
Immunobullous diseases
Pemphigoid
Pemphigus
Eosinophilic panniculitis
Arthropod bite
Erythema nodosum
Gnathostomiasis
Injection granuloma
Vasculitis
Wells syndrome
Eosinophils of doubtful, limited or no value in histological
diagnosis
Drug reaction versus graft-versus-host disease
Granuloma annulare
Interstitial granulomatous dermatitis
Neoplasms
Lymphoproliferative disorders (except HES types)
Keratoacanthoma
Chapter 36
Diseases characterized by tissue eosinophils

Eosinophilic, polymorphic, and pruritic eruption
associated with radiotherapy
Classical (Ofugi disease)
Infantile/neonatal
Human immunodeficiency virus-associated
Eosinophilic ulcer of oral mucosa
Granuloma faciale
Kimura disease
Pachydermatous eosinophilic dermatitis
Wells syndrome (eosinophilic cellulitis)
Diseases typically associated with tissue eosinophils
Arthropod bites and sting reactions
Bullous dermatoses
Pemphigoid
Pemphigus
Dermatoses of pregnancy
Drug reactions
DRESS (drug rash with eosinophilia and systemic
symptoms)/drug hypersensitivity syndrome
Interstitial granulomatous drug reaction
Histiocytic diseases
Juvenile xanthogranuloma
HYPEREOSINOPHILIC SYNDROMES AT A GLANCE

Spectrum of entities defined by criteria (Table 36-2).
Cutaneous lesions are common and may be
the presenting sign.
Two major hypereosinophilic syndromes
(HES) subtypes and several variants.
Lymphocytic HES characterized by T-cell
clones that produce interleukin 5.
Variant HES subtypes may evolve into
lymphocytic HES.
Organ-restricted.
Associated with specific disorders
such as ChurgStrauss syndrome.
Undefined with benign, complex, and
episodic presentations.
Myeloproliferative HES associated
with a deletion on chromosome 4 that
produces a tyrosine kinase fusion gene

Fip1-like 1/platelet-derived growth factor
receptor- or other mutation associated with
eosinophil clonality.
Responsive to imatinib.
Severely debilitating mucosal ulcers
portend a grim prognosis unless HES is
treated.
Overlap with mastocytosis.
Familial HES variant, family history of
documented persistent eosinophilia of
unknown cause.
Associated embolic events constitute a medical
emergency.
Eosinophilic endomyocardial disease occurs in
HES and in patients with prolonged peripheral
blood eosinophilia from any cause.
387
Section 5
::
388
EPIDEMIOLOGY
The hypereosinophilic syndromes (HES) consist of a
spectrum of disorders that occur worldwide and span
all age groups. Over 90% of patients with myeloproliferative HES and the mutant gene are men, but lymphocytic HES shows equal gender distribution. The
relative frequencies of these subtypes are unknown,
although up to 25% of HES patients may have lymphocytic HES. Rare familial cases have been reported.
A miniepidemic of eosinophilic esophagitis, a subtype of overlap HES with organ-restricted disease,
emerged over the last decade with prevalence estimates as high as 1:2,500 among children and 1:4,000
among adults.31,32
ETIOLOGY
Eosinophils are implicated as the cause of most endorgan damage in all HES subtypes.2,33 Clinical
improvement usually parallels a decrease in eosinophil count. Patients with lymphocytic HES have
abnormal T-cell clones with unusual surface phenotypes, including CD3+CD4CD8 and CD3CD4+.
These T cells display activation markers, such as
CD25, and secrete T helper 2 cytokines, including high
levels of interleukin 5 (IL-5).23,34 An 800-kilobase deletion on chromosome band 4q12 that codes for a tyrosine kinase has been found in myeloproliferative
HES.26 Patients with this FIP1L1-PDGFRA gene mutation form a distinct subset of HES, with cardiomyopathy and endomyocardial fibrosis, that responds to
imatinib. Patients in this HES subset have elevated
serum tryptase levels and increased atypical spindleshaped mast cells in bone marrow.27,28,35 Although they
do not have clinical manifestations of systemic mastocytosis or exhibit all its immunological markers, these
patients satisfy criteria for mastocytosis.36 The FIP1L1PDGFRA gene is detected in mast cells,37 eosinophils,
neutrophils, and mononuclear cells. Many HES
patients also have marked neutrophilia, likely due to
the aberrant gene in the neutrophil lineage. Thus,
alteration of several cell lines probably contributes to
the pathogenesis of myeloproliferative HES.38,39 Multiple other chromosomal abnormalities have been
identified in myeloproliferative HES, including translocations, partial and complete chromosomal deletions, and trisomies 8, 15, and 21. Myeloproliferative
HES with documented mutations also is known as
chronic eosinophilic leukemia. The World Health
Organization has an updated 2008 classification
scheme for myeloid disorders and eosinophilia.40,41
The etiology of the other HES variants is not well
understood, although patients in several HES subtypes, including with episodic angioedema and eosinophilia [Gleich syndrome42; see section Episodic
Angioedema Associated with Eosinophilia (Gleich
Syndrome)] and the nodules, eosinophilia, rheumatism, dermatitis, and swelling (NERDS) syndrome,43
have developed T-cell clones.30
TABLE 36-2
Revised Diagnostic Criteria for

Hypereosinophilic Syndromes30
1. Blood eosinophilia greater than 1500 eosinophils/mm3
on at least two separate determinations or evidence of
prominent tissue eosinophilia associated with symptoms
and marked blood eosinophilia
2. Exclusion of secondary causes of eosinophilia, such as
parasitic or viral infections, allergic diseases, drug- or
chemical-induced eosinophilia, hypoandrenalism, and
neoplasms
Original Criteria21
Peripheral blood eosinophilia of at least 1,500 eosinophils/
mm3
Longer than 6 months; or
Less than 6 months with evidence of organ damage.
Signs and symptoms of multiorgan involvement.
No evidence of parasitic or allergic disease or other known
causes of peripheral blood eosinophilia.
CLINICAL FINDINGS AND COURSE

Patients satisfying HES diagnostic criteria (Table 36-2)
present with signs and symptoms related to the organ
systems infiltrated by eosinophils.4446 HES often present with skin lesions47,48 that may be the only manifestations of HES.4951 Pruritic erythematous macules,
papules, plaques, wheals, or nodules are present in
over 50% of patients.52 Lesions may involve the head,
trunk, and extremities. Urticaria and angioedema
occur in all HES subtypes and are characteristic of certain variant subtypes. Erythema annulare centrifugum,5355 bullous pemphigoid,56 lymphomatoid
papulosis,57 livedo reticularis, purpura and/or other
signs of vasculitis,5861 Wells syndrome (eosinophilic
cellulitis),62,63 and multiple other mucocutaneous
manifestations48 may be found in patients with HES
(Table 36-3).
In myeloproliferative HES, the usual presenting
complex includes fever, weight loss, fatigue, malaise,
skin lesions, and hepatosplenomegaly.29,46,64,65 Mucosal
ulcers of the oropharynx or anogenital region (Fig.
36-1) portend an aggressive clinical course; death is
likely within 2 years of presentation if the disorder is
untreated.64,66 Cardiac disease occurs frequently.67
Eosinophils adhere to endocardium and release granule proteins onto endothelial cells, thrombus formation follows, and, finally, subendocardial fibrosis with
restrictive cardiomyopathy occurs. Mitral or tricuspid
valvular insufficiency results from tethering of chordae tendineae.67 Cardiac abnormalities that are essentially identical to those of HES but are confined to the
intramural regions can occur without appreciable
peripheral blood eosinophilia.68,69 Splinter hemorrhages and/or nail fold infarcts may herald the onset
of thromboembolic disease. The central and peripheral
nervous system, lungs, and, rarely, kidneys may be
affected.46 Patients with myeloproliferative HES frequently present with clinical features resembling those
of chronic myelogenous leukemia and, depending on
TABLE 36-3
Mucocutaneous Manifestations in
Hypereosinophilic Syndromes
(Modified from Leiferman KM, Gleich GJ, Peters MS: Dermatologic

manifestations of the hypereosinophilic syndromes. Immunol Allergy
Clin North Am 27(3):415-441, 2007 and Stetson CL., Leiferman, KM:
Chapter 26, Eosinophilic dermatoses. In: Dermatology, 2nd edition,
edited by JL Bolognia, J Jorizzo, RP Rapini, TD Horn, AJ Mancini, JM
Mascaro, SJ Salasche, J-H Saurat, G Stingl. Mosby, St. Louis 2008. pp.
369-378).
the classification, are regarded as having chronic eosinophilic leukemia. Although chromosomal abnormalities characterize this subtype and the disease may
evolve into definite leukemia, the relatively mature
nature of the eosinophils and lack of evidence for
clonal expansion may preclude such classification.
Lymphocytic HES commonly is associated with
severe pruritus, eczema, erythroderma, urticaria, and
A key criterion for diagnosis is marked peripheral

blood eosinophilia (see Table 36-2).44,7072 Other causes
of eosinophilia, including allergic and parasitic diseases, should be excluded. Tests to detect organ
involvement, particularly measurement of liver
enzyme levels, are important. Because eosinophilic
endomyocardial disease can develop in any patient
with prolonged peripheral blood eosinophilia, patients
should undergo periodic echocardiography along with
close observation for signs of thromboembolism.
Increased serum levels of immunoglobulin E (IgE) are
often present in lymphocytic HES, and levels of vitamin B12 and tryptase may be increased in myeloproliferative HES. The Chic2 fluorescent in situ hybridization
assay detects the deletion that produces the FIP1L1PDGFRA gene product and should be performed,
because patients with this mutation respond to treatment with imatinib.35,37 Alternatively, the mutant
gene can be detected by a polymerase chain reaction
assay. Both tests are available commercially. In patients
who lack the fusion gene, testing for other clonal
LABORATORY TESTS
::
Angioedema
Bullae (bullous pemphigoid)
Dermographism
Digital gangrene
Eczema
Eosinophilic cellulitis (Wells syndrome)
Erosions
Erythema
Erythema annulare centrifuge
Erythroderma
Excoriations
Livedo reticularis
Macules
Mucosal ulcers (oral and genital)
Nail fold infarctions
Necrosis
Nodules
Papules
Patches
Pruritus
Purpura
Raynaud phenomenon
Splinter hemorrhages
Ulcers
Urticaria
Vasculitis
Chapter 36
angioedema, as well as lymphadenopathy and, rarely,

endomyocardial fibrosis.34 In contrast to myeloproliferative HES, lymphocytic HES generally follows a
benign course, and T-cell clones can remain stable for
years. Patients should be observed closely and
regarded as having premalignant or malignant T-cell
proliferation, because the disease may evolve into lymphoma.
ChurgStrauss syndrome (see Chapter 164) is a variant HES subtype. Other variant HES subtypes include
Gleich syndrome42 [see section Episodic Angioedema
Associated with Eosinophilia (Gleich Syndrome)], in
which eosinophil counts fluctuate with extreme angioedema.
During the decade or more after diagnosis, HES may
evolve into acute leukemia and, less commonly, has
been associated with B-cell lymphomas. The overall
5-year survival rate for HES patients is 80%; congestive
heart failure from the restrictive cardiomyopathy of
eosinophilic endomyocardial disease is a major cause
of death, followed by sepsis.
Figure 36-1 Hypereosinophilic syndrome. Mucosal erosions and ulcers of the mouth (A) and glans penis (B); conjunctival
irritation (C).
389
Section 5
::
cytogenetic abnormalities or abnormal clonal T-cell

populations is warranted.27 Cytoflow of peripheral
blood lymphocytes and immunophenotyping of tissue
lymphocytes should be performed for the diagnosis of
lymphocytic HES and repeated periodically to detect
transformation from a variant HES type to lymphocytic HES or to T-cell lymphoma.34 An HES evaluation
assessment scheme for patients with eosinophilia is
presented in Table 36-4.
The cutaneous histopathological features of HES
vary with the type of lesion. Skin biopsy specimens
from urticarial lesions resemble idiopathic urticaria,
with generally mild, nonspecific perivascular and interstitial infiltration of lymphocytes, eosinophils, and,
occasionally, neutrophils. Immunostaining reveals
extensive deposition of eosinophil granule proteins, in
the absence of intact eosinophils, in episodic angioedema with eosinophilia,42 HES with mucosal ulcers,73
and in synovial tissues in NERDS.43 Other than in
ChurgStrauss syndrome, vasculitis only rarely has
been associated with HES.5860
(Box 36-1)
Clinically, parasitic infections and infestations may
closely resemble HES.74 A history of travel to endemic
areas or certain dietary exposure implicates helminthiasis. Along with eosinophilia, total serum IgE levels higher than 500 IU/mL commonly are found in
helminthic infections. Examination of stool samples
for ova and parasites and serologic testing for Strongyloides antibodies should be performed. In patients
with isolated urticarial plaques with or without
angioedema, the differential diagnosis includes common and persistent urticaria,75,76 but demonstration of
multiorgan involvement supports HES. HES with
episodic angioedema may resemble hereditary angioedema clinically, although patients with hereditary
angioedema often have a family history of the disease
rarely have the markedly elevated eosinophil counts
that characterize HES, and may be distinguished by
complement abnormalities. Pruritic eczematoid
lesions of lymphocytic HES may resemble those of
atopic dermatitis, contact dermatitis, drug reaction,
fungal infection, and T-cell lymphoma. There are
multiple diseases in the differential diagnosis of
patients with orogenital ulcers,64 including those
associated with thrombosis, such as Behet syndrome,
Crohn disease, ulcerative colitis, and Reiter syndrome. Others considerations are recurrent aphthous
stomatitis, immunobullous diseases, erythema multiforme, lichen planus, herpes simplex infection, and
syphilis.
TREATMENT
390
The goal of treatment is to relieve symptoms and

improve organ function while keeping peripheral
blood eosinophils at 1,000 to 2,000/mm3 and
TABLE 36-4
Evaluation of Patients with Eosinophilia

History
Attention to travel (parasite exposure)
Ingestants (drugs, health foods, food supplements, and
food allergy)
Close contacts with itch (ectoparasites)
Physical examination
Cutaneous features (see Table 36-3)
Cardiovascular signs
Murmur of mitral insufficiency
Nails for splinter hemorrhage (medical emergency)
Hepatosplenomegaly
Lymphadenopathy
Laboratory studies
Repeated complete blood counts with differentials
Cytogenetics for chromosomal abnormalities to include
FIP1L1-PDGFRA (CHIC2 gene) deletional mutation
T cell subsets for clonality by cytoflow/T cell receptor
gene rearrangement
B cell clonality analyses
Inflammatory and immunological markers
Erythrocyte sedimentation rate
C-reactive protein
Rheumatoid factor
Antiproteinase 3 and antimyeloperoxidase (c-ANCA
and p-ANCA)
IgE level
Strongyloides IgG antibody
Interleukin-5 serum level
Metabolic parameters
Liver function tests to include aspartate
aminotransferase and alanine aminotransferase
Renal function tests to include creatinine, blood
urea nitrogen and urinanalysis for protein and
sediment
Muscle enzymes to include creatine phosphokinase
and aldolase
B12 serum level
Mast cell/basophil tryptase (protryptase) level
Coagulation factors
Troponin (before initiation of imatinib treatment)
Serum protein analyses
Serum protein electrophoresis
Quantitative immunoglobulins
Immunofixation electrophoresis for monoclonal proteins
Imaging tests
Echocardiography
Computerized axiotomography of chest, abdomen, and
pelvis
Gastrointestinal endoscopy, as indicated
Pulmonary function tests, as indicated
Bone marrow aspirate and biopsy with staining for tryptase
and reticulum (myelofibrosis)
Tissue biopsy of skin and/or other accessible affected organs
Histological examination
Direct immunofluorescence for immunobullous disease
Immunostaining for eosinophil granule proteins
Modified from Gleich GJ, Leiferman KM: The hypereosinophilic
syndromes: Current concepts and treatments. Br J Haematol
145(3):271-285, 2009.

HYPEREOSINOPHILIC SYNDROMES
Behet syndrome
Crohn disease
Ulcerative colitis
Reiter syndrome
Recurrent apthous
stomatitis
Erythema multiforme
Lichen planus
Herpes simplex infection
Syphilis
WELLS SYNDROME
WELLS SYNDROME (EOSINOPHILIC
CELLULITIS) AT A GLANCE
Single or multiple lesions commonly located
on the extremities or trunk.
Lesions may be painful or pruritic.
Associated with general malaise but
uncommonly with fever.
Blisters may be a prominent feature.

Individual lesions persist for weeks and
gradually change from red to bluegray or
greenish gray, resembling morphea.
Multiple recurrences.
Peripheral blood eosinophilia common.
Histological pattern characterized by dermal
infiltration with eosinophils, and flame
figures surrounded by histiocytes.
Edematous and erythematous lesions evolve

into plaques with violaceous borders.
::
inimizing treatment side effects (Fig. 36-2). Recent

m
reviews have delineated evaluation and management
of HES.29,7072,77 Myeloproliferative HES is responsive to
imatinib.78 In patients with the mutant gene FIP1L1PDGFRA, administration of imatinib mesylate is indicated and usually induces hematologic remission, but
endomyocardial disease may worsen during the first
several days of treatment. Troponin levels should be
monitored before and during imatinib therapy.79,80 To
improve cardiac function, glucocorticoids should be
given before and with initiation of imatinib therapy.
Imatinib resistance can develop.8183 In the absence of
the gene mutation, after Strongyloides infection has
been excluded,84 first-line therapy is prednisone.
Approximately 70% of patients will respond, with
peripheral eosinophil counts returning to normal.
Patients for whom glucocorticoid monotherapy fails
have a worse prognosis generally; in such cases or
when long-term side effects become problematic, other
treatments should be used. Effective treatment of HES
in imatinib-responsive patients results in improvement of associated conditions including cardiac
involvement with endocarditis85 and myelofibrosis86
and skin disease with bullous pemphigoid.56 Patients
who have features of myeloproliferative HES but who
lack FIP1L1-PDGFRA still may respond to imatinib.25
Interferon (IFN)- has been beneficial in treating
myeloid and lymphocytic HES.87,88 In one patient, loss
of the FIP1L1-PDGFRA mutation after several years of
IFN- therapy was associated with complete remission.89 Extracorporeal photopheresis alone or in combination with IFN- or other therapies represent
additional therapeutic options. Other treatments for
HES with reported benefit include hydroxyurea, dapsone, vincristine sulfate, cyclophosphamide, methotrexate, 6-thioguanine, 2-chlorodeoxyadenosine and
cytarabine combination therapy, pulsed chlorambucil,
etoposide, cyclosporine, intravenous immunoglobulin, and psoralen plus ultraviolet A (UVA) phototherapy.90 Refractory disease may respond to infliximab
(antitumor necrosis factor-)91 or alemtuzumab (antiCD52),9294 as well as to bone marrow and peripheral
blood stem cell allogeneic transplantation.95,96 Two
monoclonal antibodies against human IL-5 have been
Chapter 36
Parasitic infection
Ectoparasitic infestation
Urticaria
Hereditary angioedema
Atopic dermatitis
Contact dermatitis
Drug reaction
Fungal infection
Mycosis fungoides
Szary syndrome
associated with clinical improvement and reductions

in peripheral blood and dermal eosinophils, particularly in patients with lymphocytic HES.97101 Treatments targeting IL-5 have provided new insights into
understanding eosinophil-associated disease.33
Systemic glucocorticoids usually therapeutic.

Cutaneous edema was the common clinical thread in
the first four cases reported by Wells.102 After prodromal burning or itching, lesions begin with erythema
and edema (Fig. 36-3A), sometimes in the form of
annular or arcuate plaques or nodules. Over a period
of days, they evolve into large edematous plaques with
violaceous borders. Bullae may develop.108,109,120,139
Individual lesions gradually change from bright red to
brownred and then to bluegray or greenish gray,
resembling morphea (Fig. 36-3B). Less common clinical presentations include papules, vesicles (Fig. 36-4),
and hemorrhagic bullae. The cutaneous lesions may be
single or multiple and may be located at any site, but
typically involve the extremities and, less often, the
trunk.137 The most frequent systemic complaint in
patients with Wells syndrome is malaise; fever occurs
in a minority of cases. Lesions resolve without scarring, usually within weeks to months, but multiple
recurrences are common.
391
Hypereosinophilic syndromes (HES): classification and treatment
FIP1L1-PDGFRA gene mutation

Myeloproliferative forms
Familial
Family members
with persistent
eosinophilia of
unknown cause
Negative
Lymphocytic forms
Positive
Chronic eosinophilic
leukemia
Clonal eosinophils or
Cytogenic abnormalities
and/or blasts
Section 5
::
392
Myeloproliferative HES
Etiology undetected 4 or
more of:
Dyplastic eosinophils
High serum B12
High serum tryptase
Anemia
Thrombocytopenia
Hepatosplenomegaly
Marrow hypercellularity
Spindle-shaped mast
cells and/or myelofibrosis
Imatinib alone (dose sufficient to eradicate

FIP1L1-PDGFRA, 100-400 mg/d) or with glucocorticoids
if cardiac involvement
Undefined
Benign,
no organ
involvement
Overlap
Associated with other
organ-restricted
eosinophilic disorders
Complex,
organ
dysfunction
but not
myeloproliferative or
lymphocytic
variant
Interferon alpha
Episodic,
cyclical
angioedema
and
eosinophilia
Treat
specific
disease
Monitor for development of T-cell clone

(or FIP1L1-PDGFRA)
Systemic glucocorticoids
0.5-1 mg/kg/d
Other tyrosine kinase inhibitors,

new agents in development
Associated
with Churg-Strauss,
inflammatory bowel
disease, sarcoidosis,
HIV and other
diseases
Monitor for cardiac disease
Consider trial of imatinib therapy

(up to 50% of responsive patients
do not have FIP1L1-PDGFRA mutation)
One or combinations of the following agents:

Hydroxyurea
Extracorporeal photopheresis
PUVA
Dapsone
Methotrexate
Vincristine sulfate
Cyclophosphamide
6-thioguanine
2-chlorodeoxydenosine and cytarabine
Pulsed chlorambucil
Etoposide
Cyclosporine
Intravenous immunoglobulin
Alemtuzumab
IL-5 monoclonal antibody (currently only in clinical trials)
Bone marrow transplantation (only after failure of above)
Figure 36-2 Hypereosinophilic syndromes (HES): classification and treatment. Provisional classification consists of myeloproliferative, lymphocytic and familial forms of HES. Chronic eosinophilic leukemia with clonal eosinophilia and myeloproliferative HES with features of the disease but without proof of clonality are included in the myeloproliferative forms
of HES; HES with eosinophil hematopoietin-producing T-cells with or without a documented T-cell clone constitute the
lymphocytic forms of HES. Further HES classification refinement expected in near future from a multidisciplinary consensus compendium in preparation. FIP1L1-PDGFRA, Fip1-like 1/platelet-derived growth factor receptor-; HIV, human
immunodeficiency virus; IL-5, interleukin 5; PUVA, psoralen plus ultraviolet A phototherapy. Further classification revisions likely in near future. (Information from Roufosse F, Weller PF: Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol 126(1):39-44, 2010; Klion AD: Approach to the therapy of hypereosinophilic syndromes.
Immunol Allergy Clin North Am 27(3):551-560, 2007; and Stetson CL, Leiferman KM: Chapter 26: Eosinophilic dermatoses.
In: Dermatology, 2nd edition, edited by JL Bolognia, J Jorizzo, RP Rapini, TD Horn, AJ Mancini, JM Mascaro, SJ Salasche,
J-H Saurat, G Stingl. Mosby, St. Louis, 2008. pp. 369-378.)
Peripheral blood eosinophilia is observed in approximately 50% of patients. Skin lesions histologically are
characterized by diffuse dermal infiltration with
eosinophils, histiocytes, and foci of amorphous and/
or granular material associated with connective tissue
fibers, which Wells termed flame figures.102 In the early
stages, there also is dermal edema. Later, histiocytes
palisade around flame figures. In addition to eight
patients with the syndrome, the 1979 report of Wells
and Smith includes nine patients with the typical histologic features of eosinophilic cellulitis but in association with a variety of clinical diagnoses, including
pemphigoid, eczema, and tinea.103 This and subsequent reports of flame figures in lesions from patients
with a wide spectrum of diseases (see Table 36-5 and
Figure 36-4 Familial Wells syndrome. Plaques with erythema, edema, vesicles, and bullae resembling acute
dermatitis or pemphigoid. (From Davis MD et al: Familial
eosinophilic cellulitis, dysmorphic habitus, and mental retardation. J Am Acad Dermatol 38:919, 1998, with permission.)
referenced above) indicate that the flame figure is

characteristic for, but not diagnostic of, Wells syndrome.105 When examined for eosinophil granule
major basic protein by immunofluorescence, flame figures show bright extracellular staining (Fig. 36-5),
indicating that extensive eosinophil degranulation
has occurred.113
TABLE 36-5
LABORATORY TESTS AND

HISTOPATHOLOGY
::
Figure 36-3 Wells syndrome. A. Early lesion with erythema and edema. B. Late lesion resembling morphea.
Chapter 36
Conditions Associated with Wells Syndrome

and/or Flame Figures
Arthropod bite
Ascariasis
Bronchogenic carcinoma
ChurgStrauss syndrome
Colonic adenocarcinoma
Dental abscess
Dermographism
Drug reaction
Eczema
Herpes gestationis
Hymenoptera sting
Mastocytoma
Molluscum contagiosum
Myeloproliferative diseases
Onchocerciasis
Vaccinations
Tinea
Toxocariasis
Urticaria
Ulcerative colitis
Varicella
393
Section 5
Figure 36-5 Flame figure in familial Wells syndrome. A. Hematoxylin- and eosin-stained section. B. Eosinophil granule
major basic protein immunostain (of serial section to A) shows extensive granule protein deposition localized to the flame
figure. (Original magnification 400.)
::
(Box 36-2)
Urticaria, erysipelas, and acute cellulitis should be
considered in the differential diagnosis of the early
stages of Wells syndrome (see Fig. 36-3A). Later,
plaques may resemble morphea (see Fig. 36-3B). The
presence of blisters may suggest pemphigoid (see Fig.
36-4). Flame figures are the hallmark of Wells syndrome, but, because they have been identified in biopsy
specimens from other dermatoses (Table 36-5), they are
not alone sufficient for the diagnosis. However, a diagnosis of Wells syndrome in the absence of flame figures
should be met with skepticism, even in the presence of
dermal infiltration with eosinophils and histiocytes.105
EPIDEMIOLOGY
Angiolymphoid hyperplasia with eosinophilia (ALHE)
occurs in both males and females, but there is a slight
female predominance. Patients are generally in the
third to fifth decade of life. In contrast to Kimura disease (KD), which develops mainly in patients from
Asia, ALHE has no racial predilection.
ETIOLOGY
TREATMENT
Wells syndrome usually improves dramatically after
administration of systemic glucocorticoids, and tapering of steroid dose over 1 month is well tolerated in
most patients. Recurrences may be treated with additional courses of systemic glucocorticoids. For patients
who fail to respond, or who experience relapse often
enough to raise concerns about the long-term side
effects of systemic glucocorticoid therapy, other options
such as minocycline, dapsone, griseofulvin, and antihistamines may be beneficial. Cyclosporine and IFN-
also have been used with success. For treatment of mild
disease, topical glucocorticoids may be sufficient.

WELLS SYNDROME
394
ANGIOLYMPHOID HYPERPLASIA
WITH EOSINOPHILIA (EPITHELIOID
HEMANGIOMA)
Urticaria
Erysipelas
Acute cellulitis
Pemphigoid
Morphea
The pathogenesis of ALHE is unknown, but it has been

considered a vascular proliferation arising in response
to or in association with underlying vascular malformation. There is a history of trauma in some cases.
ALHE has been reported to occur in pregnancy, which
implies that sex hormones may be a factor in its development.145 ALHE also has developed in patients with
T-cell clonality, which suggests that it may be an early
or low-grade T-cell lymphoma and further highlights a
relationship between T-cells and eosinophils, particularly T-cells with the TH2 phenotype.146,147

ALHE shows a predilection for the head and neck
area, including the ears,148 and is characterized by solitary, few, or multiple, sometimes grouped, erythematous, violaceous or brown papules, plaques, or
nodules of the dermis and/or subcutaneous tissues
(see Chapter 146). Lesions may be associated with
pruritus or pain, or may pulsate. Although they are
confined to the skin in most patients, mucosal involvement may occur.149 ALHE tends to be chronic and nonremitting over months to years.
ANGIOLYMPHOID HYPERPLASIA
WITH EOSINOPHILIA (EPITHELIOID
HEMANGIOMA) AND KIMURA
DISEASE AT A GLANCE
Kimura disease (KD) occurs mainly in Asian
males; angiolymphoid hyperplasia with
eosinophilia (ALHE) occurs in all races, with
a female predominance.
KD is found in a younger age group than
ALHE.
Chapter 36
Characterized by recurrent dermal and/or

subcutaneous lesions, primarily of the head
and neck area.
A
::
ALHE lesions tend to be smaller, more

superficial, and more numerous than
those of KD.
KD tends to involve subcutaneous tissues,
regional lymph nodes, and salivary glands.
ALHE may be painful, pruritic, or pulsatile,
whereas KD is generally asymptomatic.
Peripheral blood eosinophilia present in both
diseases.
Increased immunoglobulin E levels are
found only in KD.
Renal disease is associated only with KD
(reported incidence of 10% to 20%).
Histopathological features:
Dominant feature of KD is lymphoid
proliferation, often with germinal centers,
whereas ALHE is characterized by
vascular proliferation with numerous large
epithelioid or histiocytoid endothelial cells.
Fibrosis is characteristic of KD and is
limited or absent in ALHE.
Inconspicuous to numerous eosinophils in
ALHE.
Eosinophil abscesses may occur in KD.

HISTOPATHOLOGY
Approximately 20% of patients have peripheral
blood eosinophilia; IgE levels are unremarkable.
There is no association with renal disease. The dominant histological feature is a well-defined area, in the
Figure 36-6 Angiolymphoid hyperplasia with eosinophilia. A. Forehead nodule. B. Recurrence of lesions in skin
graft and adjacent sites 6 years after surgical removal of
lesion in A.
dermis and/or subcutis, of prominent vascular proliferation with large epithelioid or histiocytoid endothelial cells that contain abundant eosinophilic
cytoplasm, often with cytoplasmic vacuoles (see
Chapter 147). There are variable numbers of eosinophils and lymphocytes,150 with an occasional finding
of lymphoid nodules. In their report of 116 patients
with ALHE, Olsen and Helwig found 53 cases in
which an arterial structure appeared to be associated with venules or was the area of endothelial
proliferation, which provided evidence that these
lesions may represent a form of arteriovenous
shunt.151 The stroma typically is myxoid, and fibrosis
is minimal or absent. Mast cells may be a component
of the histologic picture.
395

ANGIOLYMPHOID HYPERPLASIA WITH
EOSINOPHILIA
Kimura disease
Pyogenic granuloma
Epithelioid hemangioendothelioma
Epithelioid angiosarcoma
Kaposi sarcoma
Section 5
::
396
(Box 36-3)
Lesions of ALHE generally are smaller, more superficial, and more numerous than those of KD, and often
are symptomatic. Although lymphoid follicles may
occur in ALHE, they represent the dominant characteristic of KD (Table 36-6), and although KD may exhibit
some vascularity, it lacks the large epithelioid endothelial cells that are a key feature of ALHE (see Table 36-6).
ALHE should be distinguished from a variety of
benign and malignant vascular proliferations, including pyogenic granuloma, epithelioid hemangioendothelioma, and Kaposi sarcomaall of which lack a
noticeable eosinophil infiltrate.
TREATMENT
Intervention is dictated in part by the number, location, size of lesions, and the patients general health.152
Patients with solitary or a few small lesions may benefit from excision or Mohs surgery, 153 but there may be
recurrence at the surgical site (see Fig. 36-6). A variety
of other treatment modalities have been used with success, including systemic and intralesional glucocorti-

KIMURA DISEASE
Lymphoma
coid administration, INF- therapy,154 cryotherapy,155
laser therapy,156 and topical application of tacrolimus.157
KIMURA DISEASE
(Box 36-4)
TREATMENT
Surgical excision is the treatment of choice when feasible in patients with a single or a limited number of
nodules, but lesions may recur.167,168 Other therapeutic
options include systemic glucocorticoids, cyclosporine, and radiation therapy.169,170 The presence of renal
disease may influence or dictate the therapeutic regimen. The finding of platelet-derived growth factor-
and c-kit in tissues from KD patients suggests that imatinib or another tyrosine kinase inhibitor may be effective in the disease.171
EOSINOPHILIC PUSTULAR
FOLLICULITIS
Classical EPF presents as recurrent crops or clusters of
follicular papules and pustules, which may form an
TABLE 36-6
Comparison of Angiolymphoid Hyperplasia with Eosinophilia (ALHE) and Kimura Disease (KD)
ALHE
KD
Gender
Typically middle-aged females
Predominantly young adult males
Symptoms
Pruritus, pain, pulsation
Asymptomatic
Lesion type and location
Small and superficial, with overlying erythema;

head and neck region
Large, mainly subcutaneous; overlying skin

normal; head and neck region; may involve
regional lymph nodes and salivary glands
Lymphoid follicles
Uncommon
Prominent lymphoid follicles with germinal

centers
Vascular proliferation
Prominent vascular proliferation with large

epithelioid/histiocytoid endothelial cells;
evidence of underlying vascular malformation
may be evident
Some stromal vascularity with unremarkable

endothelial cells
Fibrosis
Absent or limited
Prominent
Serum immunoglobulin E level
Normal
Increased
Nephropathy
Absent
Present in up to 20% of patients
EOSINOPHILIC PUSTULAR
FOLLICULITIS AT A GLANCE
Three clinical types, characterized by
follicular papules and pustules that may
involve the head, trunk, and extremities
Classic eosinophilic pustular folliculitis
(Ofuji disease)

associated with immunosuppression
Follicular pustules of the scalp

Tendency for recurrences and chronicity
(except eosinophilic pustular folliculitis of
infancy)
Characterized by follicular and perifollicular
eosinophil infiltration
Associated with peripheral blood
eosinophilia
annular pattern and usually resolve in 7 to 10 days.

Lesions predominantly involve the face and trunk but
also may affect the extremities, with involvement of
the palms and soles in approximately 20% of patients.177
In EPF of infancy, lesions typically are located on the
scalp but also may be found on the face and extremities. In some neonates who have pustular eruptions
that clinically resemble EPF and typically have peripheral blood eosinophilia, the disorder may be classified
more appropriately under the term eosinophilic pustulosis because the cutaneous infiltrates are not folliculocentric (see Chapter 107).202 In contrast, HIV-associated
EPF tends to manifest as extremely pruritic discrete
follicular papules, typically involving the head and
neck and often the proximal extremities (see Fig. 198-3,
Chapter 198). Rosenthal et al emphasized the urticarial
quality of such lesions.178 EPF of infancy has a good
prognosis, whereas classical and HIV-associated EPF
are characterized by recurrences. Postinflammatory
pigmentation may be seen as lesions resolve, but scarring does not occur.
(Box 36-5)
Folliculitis secondary to bacterial or fungal infection
must be kept in mind, particularly in immunosuppressed patients. Based on the distribution of lesions,
seborrheic dermatitis should be considered, when
there is head and neck involvement, and palmar
plantar pustular psoriasis may also be included in the
differential diagnosis when there is hand and foot
involvement. Acneiform eruptions may resemble EPF.
Erythema toxicum neonatorum, acropustulosis, and
acne neonatorum also should be considered in infants.
Follicular mucinosis usually is clinically and histologically distinguishable from EPF.
Eosinophilic pustular folliculitis of

infancy/neonatal period
::
Most often occurs in patients with

human immunodeficiency virus
infection, who have severely pruritic
papules of the face and upper trunk
Patients suspected of having EPF should be evaluated

for underlying immune deficiency, particularly HIV
infection. Peripheral blood eosinophilia is a component of all three types of EPF. Although patients with
classical EPF usually have eosinophilia with leukocytosis, HIV-positive patients often exhibit eosinophilia
with lymphopenia. Low CD4 cell counts and high IgE
levels are typical of HIV-associated EPF.178 Histologically, the most striking feature is the infiltration of
eosinophils into hair follicles and perifollicular areas
(see eFig. 36-6.2 in online edition), sometimes with follicular damage. The infiltrates also may contain lymphocytes and neutrophils, and may be perivascular as
well as follicular.203 Follicular mucinosis (see Chapter
145) has been noted in association with EPF204; however, T-cell clonality is not observed in EPF-associated
follicular mucinosis.205
Chapter 36
Typically occurs in Japanese patients,

who have chronic, recurrent follicular
pustules, with a tendency to form
circinate plaques, in a seborrheic
distribution

HISTOPATHOLOGY
TREATMENT
Topical glucocorticoids and topical calcineurin inhibitors generally are the first approach to the treatment of
all types of EPF. Topical tacrolimus is helpful for facial
lesions.206 Nonsteroidal anti-inflammatory drugs, particularly indomethacin, also are recommended as firstline therapy; clinical improvement may be observed
within 2 weeks and is associated with a decrease in
peripheral blood eosinophil counts.207209 A mechanism

EOSINOPHILIC PUSTULAR FOLLICULITIS
Folliculitis, bacterial or fungal
Palmarplantar pustular psoriasis
Acne, including acne neonatorum
Acropustulosis
Follicular mucinosis
397
for this has been proposed based on the observation

that indomethacin, not only inhibits cyclooxygenases
and subsequent prostaglandin D2 synthesis, but also is
associated with reduction in the prostaglandin D2
receptor (chemoattractant receptor homologous molecule expressed on TH2 cells, CRTH2) on eosinophils
and lymphocytes.210 UV light therapy (UVB or psoralen and UVA) may be beneficial. Topical permethrin,
systemic retinoids, systemic glucocorticoids, cyclosporine, itraconazole, metronidazole, cetirizine, minocycline, dapsone, and IFNs have been tried with
success.207,208 Antiretroviral treatment that results in
increased CD4 cell counts often is associated with
improvement in HIV-associated EPF.
Section 5
::
CLINICAL REACTION PATTERNS

WITH EOSINOPHIL INVOLVEMENT
There are a variety of diseases in which eosinophils

may be present in cutaneous lesions, with or without
associated peripheral blood eosinophilia, but either
the histologic pattern is unremarkable or eosinophils
are not critical for the histological diagnosis of the
given entity (see Table 36-1). In many of these dermatoses, the eosinophil loses its morphologic integrity
after disruption through cytolysis and is not identifiable histologically.216 However, toxic granule proteins
and other phlogistic eosinophil products are deposited
in skin, persist for extended periods of time, and cause
tissue effects.73,217
EDEMA
Prominent among the eosinophil-associated skin reactions are those manifesting edema, including urticarias.218221 In addition to the presence of distinctive, toxic
eosinophil cationic granule proteins in lesions, the
ability of eosinophils to elaborate vasoactive mediators, induce histamine release from mast cells and
basophils, and elicit a cutaneous wheal-and-flare reac-
398
tion supports a role for the eosinophil as a primary

participant in the edema associated with certain cutaneous diseases (see Chapter 31).2,18
EPISODIC ANGIOEDEMA ASSOCIATED

WITH EOSINOPHILIA (GLEICH SYNDROME).
Episodic angioedema associated with eosinophilia is

characterized by recurrent angioedema (with up to
30% increase in body weight), urticaria, fever, increased
serum IgM levels, and leukocytosis as high as 100,000
cells/mm3 with up to 90% eosinophils; disease activity
fluctuates with the peripheral eosinophil count.42,222
Skin biopsy specimens from this disorder42 and its
localized variant, recurrent facial edema with eosinophilia,223 show few eosinophils, but immunofluorescence staining reveals extracellular deposition of
eosinophil granule proteins around collagen bundles
and blood vessels. The syndrome is associated with a
number of immunologic abnormalities, including
increased activated T cells224,225 and increased serum
IL-5 levels.226,227 Capillary leak syndromes, due to
administration of IL-2228 and granulocyte-macrophage
colony-stimulating factor,229 also are associated with
peripheral blood eosinophilia, increased serum IL-5
levels, and eosinophil degranulation.
CHRONIC DERMATITIS/PRURITUS
Although infestations typically are associated with
eosinophils, the histologic pattern is nondiagnostic
unless a specific organism is identified in tissue sections.8,230 Infection with Onchocerca volvulus causes a
pruritic dermatitis with lichenification, associated with
slight cutaneous eosinophil infiltration but extensive
deposition of eosinophil granule proteins throughout
the dermis231; after treatment, extracellular deposition
of eosinophil granule proteins is located around
degenerating microfilaria.230,232 Although eosinophils
are rarely a prominent histological feature of atopic
dermatitis, extensive dermal deposition of eosinophil
granule proteins is seen in lesions (Fig. 36-7) but not
in normal-appearing skin.231,233 A link between
Figure 36-7 Involved skin from a patient with atopic dermatitis. A. Eosinophil granule major basic protein immunostain
shows extensive extracellular granule protein deposition in the presence of only three intact eosinophils (brightly fluorescent ovals). B. Hematoxylin and eosin counterstain of A shows minimal nonspecific chronic inflammation. (A and B 400,
original magnification) (From Leiferman KM et al: Dermal deposition of eosinophil-granule major basic protein in atopic
dermatitis. Comparison with onchocerciasis. N Engl J Med 313:282, 1985, with permission).
Figure 36-8 Eosinophilic spongiosis. There are eosinophils and intercellular edema within the epidermis. (Hematoxylin and eosin 400, original magnification)
BLISTERS
Autoimmune blistering diseases (see Chapters 54 and
56) often are associated with prominent infiltration of
eosinophils, including presentation as eosinophilic
spongiosis (Fig 36-8), and extracellular deposition of
eosinophil granule proteins. IL-5 and eotaxin are present in pemphigoid blister fluid, and eosinophil-derived
matrix metalloproteinase 9 that likely cleaves basement membrane zone.247,248, 249
In addition to pemphigoid gestationis (which may
exhibit eosinophilic spongiosis),250 other pruritic dermatoses of pregnancy (see Chapter 108) may demonstrate tissue eosinophilia.251253
EOSINOPHILIC FASCIITIS. Eosinophilic fasciitis

usually presents with pain, erythema, edema, and
induration of the extremities, as well as peripheral
blood eosinophilia and hypergammaglobulinemia.256
Contractures and rippling of the skin may develop
(Fig. 36-9). There is infiltration of lymphocytes, plasma
cells, mast cells, and eosinophils, as well as increased
thickness of the fascia.
EOSINOPHILIAMYALGIA
SYNDROME.
Eosinophiliamyalgia syndrome (EMS), historically

related to ingestion of certain lots of l-tryptophan,257
is characterized by marked peripheral eosinophilia,
disabling generalized myalgias, pneumonitis, myocarditis, neuropathy, encephalopathy, and fibrosis,258 a constellation of features that are similar to
but distinguishable from eosinophilic fasciitis.259,260
Cutaneous abnormalities of EMS include edema,
pruritus, a faint erythematous rash, hair loss, and
peau dorange or morphea-like skin lesions.261 Lungs,
heart, and nervous system may be affected.262 There
Eosinophils are found in all types of drug reactions.

There is evidence that, when eosinophils are part of the
histologic pattern in leukocytoclastic vasculitis, the
eruption is probably drug-induced243 (see Chapter 41).
The drug reaction with eosinophilia and systemic
symptoms syndrome, so-called DRESS and also known
as drug hypersensitivity syndrome, is a serious multiorgan disorder. Many drugs induce DRESS, and a
spectrum of skin lesions may present with DRESS.
Eosinophils and other inflammatory cells infiltrate
skin, lymph nodes, and organs, including the liver.
Fulminant hepatitis is associated with a mortality rate
of 10%, and transplanted livers may also be affected.
Eosinophil infiltration with and without granulomas
with hepatocyte necrosis and cholestasis are prominent in liver failure that occurs with DRESS.244246
::
DRUG REACTIONS
Chapter 36
eratinocytes and eosinophils in atopic dermatitis was

k
reported through activity of a novel TH2 cytokine,
IL-31.234 Prurigo nodularis235 and pachydermatous
eosinophilic dermatitis236 exhibit a pattern of dermal
extracellular eosinophil granule protein deposition
similar to that seen in atopic dermatitis and onchocercal dermatitis. In both atopic dermatitis and prurigo
nodularis, eosinophil granule products are deposited
around cutaneous nerves,235,237 and there is evidence
that eosinophils play a role in itch provocation.238242 A
particularly difficult clinical presentation is the patient
with intractable itching and peripheral blood eosinophilia. Such patients may satisfy criteria for the hypereosinophilic syndromes, but their itch is refractory to
most therapies. Understanding the eosinophils role in
the pathogenesis of this disorder may help with identifying effective therapies.
FIBROSIS
Eosinophils are found in association with fibrotic reactions, including those resulting from parasitic infections, pulmonary and hepatic drug sensitivity reactions,
and HES.254 Eosinophils elaborate mediators (see Chapter 31) that degrade collagen and stimulate dermal
fibroblast DNA synthesis and matrix production.255
Figure 36-9 Eosinophilic fasciitis. Puckered skin of the

thighs.
399
is a prominent inflammatory infiltrate in the perimysium and fascia, and striking evidence of eosinophil granule protein deposition in skin and around
muscle bundles.257
Section 5
::
TOXIC OIL SYNDROME. Toxic oil syndrome

(TOS), which resembles EMS, was linked to consumption of adulterated rapeseed oil distributed in the
industrial belt around Madrid.263 Patients experienced
acute respiratory symptoms followed by intense myalgias, thromboembolism, weight loss, and sicca syndrome, followed by a chronic phase characterized by
eosinophilic fasciitis-like lesions, peripheral neuropathy, muscle atrophy, and pulmonary hypertension. The
cutaneous manifestations of TOS were nonspecific
pruritic, erythematous skin lesions that persisted up to
4 weeks, followed over the next 2 months by subcutaneous edema, mainly of the extremities, accompanied
by myalgias, arthralgias, contractures, and peripheral
blood eosinophilia. Over many years, patients developed indurated plaques of the pretibial areas, and,
occasionally, the forearms and abdomen,263 with
marked fibrosis extending into subcutaneous fat.
Eosinophil infiltration and degranulation were especially prominent in the acute phase of TOS, and serum
eosinophil granule protein levels were elevated during
all phases.264 Potential pathogenic links between TOS
and EMS and also eosinophilic fasciitis have been
identified.265,266
VASCULITIS
In 1951, Churg and Strauss described the complex of
systemic vasculitis, asthma, and eosinophilia as allergic
granulomatosis.267 Cutaneous lesions develop in approximately two-thirds of cases and are variable consisting
of nodules, urticaria, livedo reticularis, purpura, digital gangrene, and blisters. Histologically, the lesions
are characterized by eosinophil infiltration, necrotizing vasculitis, and extravascular granulomas with
prominent extracellular eosinophil granule protein
deposition268270 (see Chapter 164). Granuloma faciale
is characterized clinically by brownred infiltrative
plaques of the face and represents a localized type of
necrotizing vasculitis that contains infiltration of
eosinophils as well as neutrophils, lymphocytes, and
histiocytes (see Chapter 34). Eosinophilic vasculitis
(EV) is associated with peripheral blood eosinophilia
and is characterized by chronic, recurrent, widespread
pruritic, erythematous, purpuric papules as well as
angioedema of face and hands; skin biopsies show necrotizing small vessel vasculitis with prominent infiltration of eosinophils.271,272 EV may be idiopathic or
associated with connective tissue disease,273 Raynaud
phenomenon, or HES.58
MALIGNANCY
400
Eosinophils may be observed in a variety of cutaneous

and extracutaneous neoplasms. Their presence in
tumors appears to be independent of immune surveil-
lance and likely is part of an early inflammatory reaction at the site of tumorigenesis.274 Various types of
peripheral T-cell lymphomas are eosinophil-rich,
including follicular mycosis fungoides and cutaneous
anaplastic large cell lymphoma275277; the prognostic
significance of tissue eosinophilia in such lesions is not
established. Underlying malignancy may prompt
lesions associated with eosinophil infiltration, such as
the exaggerated arthropod-bite reactions seen in
patients with chronic lymphocytic leukemia.278
Eosinophilic, polymorphic and pruritic eruption
associated with radiotherapy (EPPER) is an uncommon idiopathic disorder that appears in patients
undergoing radiation treatment for malignancy.
Women are affected more often than men. Onset of the
eruption is typically during radiation treatment, but
delays up to 7 months are reported.279,280 Cutaneous
findings are not localized to irradiated areas and may
include local and generalized pruritus, erythematous
papules, wheals, and vesicles and bullae. Eosinophils
are prominent in affected skin, but not characteristically in the tumors.
KEY REFERENCES
1. Leiferman KM: A current perspective on the role of
eosinophils in dermatologic diseases. J Am Acad Dermatol
24(6 Pt 2):1101-1112, 1991
4. Simon D, Wardlaw A, Rothenberg ME: Organ-specific
eosinophilic disorders of the skin, lung, and gastrointestinal tract. J Allergy Clin Immunol 2010
44. Roufosse F, Weller PF: Practical approach to the patient
with hypereosinophilia. J Allergy Clin Immunol 2010
45. Ogbogu PU et al: Hypereosinophilic syndrome: A multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol
124(6):1319-1325, e3, 2009
137. Moossavi M, Mehregan DR: Wells syndrome: A clinical
and histopathologic review of seven cases. Int J Dermatol
42(1):62-67, 2003
138. Espana A et al: Wells syndrome (eosinophilic cellulitis):
Correlation between clinical activity, eosinophil levels,
eosinophil cation protein and interleukin-5. Br J Dermatol
140(1):127-130, 1999
150. Helander SD et al: Kimuras disease and angiolymphoid
hyperplasia with eosinophilia: New observations from
immunohistochemical studies of lymphocyte markers,
endothelial antigens, and granulocyte proteins. J Cutan
Pathol 22(4):319-326, 1995
151. Olsen TG, Helwig EB: Angiolymphoid hyperplasia with
eosinophilia. A clinicopathologic study of 116 patients. J
Am Acad Dermatol 12(5 Pt 1):781-796, 1985
160. Kung IT, Gibson JB, Bannatyne PM: Kimuras disease:
A clinico-pathological study of 21 cases and its distinction from angiolymphoid hyperplasia with eosinophilia.
Pathology 16(1):39-44, 1984
166. Chong WS, Thomas A, Goh CL: Kimuras disease and
angiolymphoid hyperplasia with eosinophilia: Two disease entities in the same patient: case report and review
of the literature. Int J Dermatol 45(2):139-145, 2006
176. Nervi SJ, Schwartz RA, Dmochowski M: Eosinophilic
pustular folliculitis: A 40 year retrospect. J Am Acad Dermatol 55(2):285-289, 2006
208. Fukamachi S et al: Therapeutic effectiveness of various
treatments for eosinophilic pustular folliculitis. Acta
Derm Venereol 89(2):155-159, 2009
Inflammatory Diseases Based on

Abnormal Humoral Reactivity and Other
Inflammatory Diseases
Chapter 37 :: Humoral Immunity and Complement

:: Lela A. Lee
HUMORAL IMMUNITY AND
ANTIBODY STRUCTURE AT A GLANCE
Humoral immunity, mediated by antibodies
produced by B lymphocytes, is a form of
specific immunity directed primarily toward
extracellular antigens.
Antibody molecules consist of two identical
light chains covalently linked to two
identical heavy chains. The variable region
of the antibody molecule is responsible for
antibody binding, and the constant region
mediates most effector functions.
The five antibody classes serve distinct
functions. Immunoglobulin (Ig) M is
involved in primary antibody responses, IgD
is an antigen receptor on naive B cells, IgA
is critical for mucosal immunity, IgG is the
major Ig in the circulation and is important
in secondary antibody responses, and IgE
mediates immunity to parasites.
An individual is capable of generating
millions of distinct antibodies in millions of
distinct B-cell clones through the processes of
gene rearrangement and junctional diversity.
B LYMPHOCYTES
During evolution, jawed vertebrates developed the
capacity to respond with exquisite specificity to foreign organisms.1 Specific immunity is characterized
by an enormous diversity of possible responses and
by refinement in the immune response with successive exposures to the organism.2 The cells that can
discriminate with fine specificity through their vast
repertoire of receptors are lymphocytes. Specific immunity, also called adaptive immunity because it develops
as an adaptation to infection, can be segregated into
humoral immunity, mediated by antibodies produced
by B lymphocytes, and cellular immunity, mediated by
T lymphocytes. These two forms of specific immunity
developed to serve different functions. Humoral immunity is directed primarily toward extracellular antigens
such as circulating bacteria and toxins. Cellular immunity is directed primarily toward antigens that infect or
inhabit cells (see Chapter 10). To combat extracellular
pathogens, the defending agent needs to be abundant
and widely distributed in the body, particularly at its
interfaces with the environment. Antibodies fulfill
these characteristics by being capable of being secreted
in great quantity from the cells that produce them and
by being distributed in blood, mucosa, and interstitial fluid. In addition, antibodies can attach through
Fc receptors (FcRs) to the surface of certain other cells
of the immune system, such as mast cells, conferring
antigen specificity to cells that do not have their own
endogenously produced antigen-specific receptors. In
addition to their major function in humoral immunity
as antibody producers, B lymphocytes have a role in
antigen presentation, regulation of T-cell subsets and
dendritic cells, organization of lymphoid tissues, and
cytokine and chemokine production.3,4
ANTIBODY STRUCTURE
Antibodies, or immunoglobulins (Ig), are a family of
glycoproteins that share a common structure.2,5,6 The
antibody molecule has a symmetric Y-shape consisting
of two identical light chains, each about 24 kDa, that are
covalently linked to two identical heavy chains, each
about 55 or 70 kDa, that are covalently linked to one
another (Fig. 37-1). Within the light and heavy chains
are variable and constant regions. The major function
of the variable region is to recognize antigen, whereas
the constant region mediates effector functions. The
light and heavy chains contain a series of repeating, homologous units of about 110 amino acids that
assume a globular structure and are called Ig domains.
The Ig domain motif is found not only in antibody molecules but also in a variety of other molecules of the Ig
superfamily, including the T-cell receptor, the major
histocompatibility complex (MHC), CD4, CD8, intercellular adhesion molecule 1, among other molecules. The
light chain has two major domains, (1) a variable (VL)
and (2) a constant (CL) domain. The heavy chains have
four or five domains, a variable (VH) and three (in IgA,
IgD, and IgG) or four (in IgM and IgE) constant (CH14)
domains. In IgA, IgD, and IgG, there is a hinge region
Immunoglobulin G (IgG) molecule
VL
CL
CL
S
CH1
S
S
S
Section 6
Complement
and Fc receptor
binding sites
Antigen
binding
region
VH
VH
VL
S
S
CH1
Hinge region
CH2
S
S
S
S
CH2
CH3
S
S
S
S
CH3
::
Inflammatory Diseases Based on Abnormal Humoral Reactivity
402
ANTIBODY CLASSES
KEY
Ig domain
Light chain
Heavy chain
S
tively. The different heavy chain classes have significantly different functions, as discussed in Section
Antibody Classes. The IgA and IgG classes contain
closely related subclasses, consisting of IgA1 and IgA2,
and IgG1, IgG2, IgG3, and IgG4 (Table 37-1).
Enzymatic digestion of IgG molecules by papain
results in three cleavage products, two identical Fab
fragments consisting of a light chain bound to the V
CH1 region of the heavy chain and an Fc portion consisting of two CH2CH3 heavy chains bound to each
other. Fab was so named for its property of antigen
binding, and Fc was so named for its property of crystallizing. When IgG is digested by pepsin, the C-terminal region is digested into small fragments. The
remaining product consists of the Fab region along
with the hinge region. Fab fragments containing the
hinge region are termed Fab. When the two Fab fragments in an antibody molecule remain associated, the
fragment is called F(ab)2.
Disulfide bond
Carbohydrate
Papain cleavage site
Pepsin cleavage site
Figure 37-1 Schematic representation of an immunoglobulin G (IgG) molecule.

between CH1 and CH2 that confers additional flexibility
to the molecule. The variable domains are at the N-terminus. At the C-terminus are the constant domains
and, in the heavy chains of membrane-bound antibodies, the transmembrane and cytoplasmic domains.
Within the variable regions of the light and heavy
chains are three areas of intense variability called hypervariable regions. These three regions, which are in proximity to one another in the three-dimensional structure
of the antibody, are the areas most responsible for binding antigen. Because the hypervariable regions form a
shape complementary to that of the antigen, the hypervariable regions are also called the complementaritydetermining regions. The unique areas formed by the
hypervariable regions are present in too low an amount
in the individual to generate self-tolerance. Thus, the
immune system may not distinguish the unique portion of the antibody as self and may produce antibodies
to that region of the antibody. The area of the antibody
capable of generating an immune response is called an
idiotope, and antibody responses to idiotopes result in
a network of idiotypicanti-idiotypic interactions that
may help regulate the humoral immune response.7
There are two types of light chains, and , each
encoded on different chromosomes. Each antibody
molecule has either two or two chains, never one of
each. The functional differences, if any, between and
are not known. There are five types of heavy chains,
(1) , (2) , (3) , (4) , and (5) , corresponding to the
antibody classes IgA, IgD, IgE, IgG, and IgM, respec-
(See Table 37-1)
IMMUNOGLOBULIN M
IgM is evolutionarily the most ancient antibody class
and is the first Ig molecule to be expressed during B-cell
development.1 Its secretory form exists mainly as a pentamer consisting of five IgM molecules joined at their
C-termini by tail pieces and stabilized by a molecule
called a joining (J) chain. The engagement of membranebound IgM by antigen results in the activation of naive B
cells. Secreted IgM recognizes antigen, usually through
low-affinity interactions, and it can activate complement. IgM is the major effector of the primary antibody response. Although IgM interactions are typically
low affinity, IgM can be very effective in responding
to a polyvalent antigen (such as a polysaccharide with
repeating epitopes) because its pentameric structure
allows for multiple low-affinity interactions, resulting
in a high-avidity interaction. (Avidity refers to the overall strength of attachment, whereas affinity refers to the
strength of attachment at a single antigen-binding site.)
IMMUNOGLOBULIN D
The IgD molecule exists primarily in a membranebound form and is the second antibody class to be
expressed during B-cell development. Its function is
not completely understood, but in its membrane-bound
form it can serve as an antigen receptor for naive B cells.8
Secreted IgD has been found on the surface of basophils,
where it induces production of antimicrobial, opsonizing, inflammatory, and B-cellstimulating factors.9
IMMUNOGLOBULIN A
IgA is the most abundant Ig in the body, being present in large quantity at mucosal sites. It is responsible
TABLE 37-1
Immunoglobulin Classes and Their Functions
Secreted
Form
Approximate
Molecular Weight
of Secreted Form
(kDa)
Serum
Serum
Concentration Half-Life
(mg/mL)
(Days)
IgM
None
Pentamer,
hexamer
970
1.5
Primary antibody
response; antigen
receptor on naive B cells;
complement activation
IgD
None
Monomer
180
Trace
Antigen receptor on naive

B cells
IgA
IgA1
Monomer,
polymer
(usually
dimer)
Monomer,
polymer
(usually
dimer)
160 (monomer), 390

(secretory IgA)
Mucosal immunity;
neonatal immunity
160 (monomer), 390

(secretory IgA)
0.5
IgA2
Functions
::
Subtypes
IgG1
IgG2
IgG3
IgG4
Monomer
Monomer
Monomer
Monomer
150
150
170
150
9
3
1
0.5
23
23
7
23
Neonatal immunity;
opsonization; complement
activation (except IgG4);
phagocytosis; antibodydependent cell-mediated
cytotoxicity; feedback
inhibition of B cells
IgE
None
Monomer
190
0.05
Immediate
hypersensitivity; defense
against parasites
Ig = immunoglobulin.
IMMUNOGLOBULIN G
IgG is the most abundant Ig in the circulation. Its
secreted form is a monomer. IgG plays an important
role in secondary antibody responses, and its interactions with antigen tend to be high affinity, particularly
as the immune response matures. A number of cells
have FcRs for IgG, including monocytes, neutrophils,
eosinophils, natural killer (NK) cells, and B cells. IgG
opsonizes (coats) antigen, allowing phagocytosis of
the antigen, and activates complement. An exception
is IgG4, which does not activate complement. IgG is
important in neonatal immunity, as it is the only Ig class
Humoral Immunity and Complement
IgG
for mucosal immunity and is secreted in breast milk,

thus contributing to neonatal immunity. In its secreted
form, it exists as a monomer, dimer, or trimer, with
the multimers being formed by interactions between
tail pieces and stabilized by the J chain. For transport
across epithelial surfaces, IgA dimers attach to a type of
FcR called the polymeric Ig receptor.10 Once the transport
process is complete, the IgA dimers remain attached to
the extracellular portion of the receptor, called the secretory component, which protects the IgA from proteolysis.
Cells of the immune system that have receptors for IgA
include neutrophils, eosinophils, and monocytes.
Chapter 37
to cross the placenta, and it is secreted in breast milk.

The interaction of IgG with the MHC class I-related
receptor FcRn is involved in the delivery of IgG across
the placenta as well as in prolonging its level in the circulation.11 The serum half-life of IgG is 23 days, considerably longer than that of the other Ig classes.
IMMUNOGLOBULIN E
IgE is found in very small amounts in the circulation.
High-affinity receptors for the Fc portion of IgE are
present on mast cells, basophils, and eosinophils, and
low-affinity receptors are present on B cells and Langerhans cells. In mast cells and basophils, IgE engagement with antigen activates the cells. IgE mediates
immediate hypersensitivity, but its principal protective role may be to combat parasites.
MECHANISMS FOR THE

GENERATION OF ANTIBODY
DIVERSITY
The information encoded by an individuals DNA is
limited by the need for the DNA to fit into a package of
403
Section 6
::
the size of a cell. This space is far too small for sufficient
DNA to encode billions of different lymphocyte receptors if the genes were encoded separately. Lymphocytes
have adapted to this limitation by special mechanisms
that increase by orders of magnitude the number of
different possible antigen receptors.12 Each clone of B
cells produces identical antigen receptors (i.e., antibodies) with unique specificity. It is estimated that an individual has approximately 107 different B-cell clones,
resulting in 107 distinct antibodies. A major mechanism for generating this enormous diversity is gene
rearrangement, whereby segments of DNA within a
lymphocyte undergo somatic recombinations.13 Light
chain genes contain three regions, (1) V (variable), (2)
J (joining), and (3) C (constant), and heavy chain genes
contain four regions, (1) V, (2) D (diversity), (3) J, and
(4) C. Within each region are many gene segments from
which to select for the final antibody product, which
is comprised of one gene segment randomly selected
from each region. The initial event in antibody formation is the joining of one D and one J segment from a
heavy chain gene, with subsequent deletion of the
DNA between the two segments. Next, a V segment is
selected to join to the DJ segment, and any remaining
D segments are deleted. The VDJ complex has attached
3 to it any remaining J segments plus the C region. The
unused J segments are removed during RNA processing. A similar process occurs in light chain loci; because
there are no D segments in light chain loci, a VJ rather
than a VDJ complex is formed. (Particularly in the k
locus, VJ recombination may occur through a somewhat different mechanism involving inversion of the
DNA without deletion of intervening sequences, but
the functional result is the same.)
The ability to select one segment each from the many
segments available in the V, D, and J regions leads to
a vast increase in the repertoire of possible antibodies.
Additional diversity is generated by the juxtaposition of a rearranged light chain to a rearranged heavy
chain; by the addition, deletion, or transposition of
nucleotides at the junctions between V and D, D and J,
and V and J segments, a phenomenon called junctional
diversity; and by somatic hypermutation after antigen
stimulation (see below).
B-CELL MATURATION
404
Cells destined to become mature B cells undergo an

orderly progression of events during development,
resulting in the formation sequentially of heavy chains,
light chains, and whole antibody molecules, with
checkpoints to select against cells making unproductive gene rearrangements or autoreactive antibodies,
and survival signals to select for cells making potentially useful antibodies. The process of B-cell development occurs in distinct stages, characterized by specific
events and identifiable by specific cell surface markers
and Ig gene expression.
Bone marrow and fetal liver stem cells that give rise
to B cells are initially pluripotent.2,14 Stem cells developing in the lymphocytic pathway initially become
common lymphoid progenitors, which can give rise to B,
B-CELL MATURATION AT A GLANCE

The pro-B cell expresses enzymes needed for
gene rearrangement and junctional diversity,
but neither heavy nor light chains are
expressed.
The pre-B cell expresses heavy chains in
the cytoplasm. On the cell surface, the heavy
chains associate with surrogate light chains
to form pre-B cell receptors.
The immature B cell produces light
chains and can therefore express antibody
molecules on the cell surface. If antigen
exposure occurs at this stage, negative
selection may take place.
During the transitional stage, B cells
gradually lose sensitivity to negative
selection and acquire immune competence.
The mature B cell expresses both IgM and
IgD and is competent to respond to antigen.
T, or NK cells. B cells originating from fetal liver are

mainly B1 cells (see Section B-Cell Activation and
Antibody Function), whereas B cells originating in
the bone marrow are primarily follicular B cells. Cells
and extracellular molecules in the stromal microenvironment provide signals required for differentiation of
lymphocytes. Induction of the transcriptional regulators EBF, E2A, and Pax-5 leads to the expression of proteins critical to B-cell development. Posttranscriptional
regulation of mRNA by RNA-binding proteins and
microRNAs provides further control over the process
of B-cell differentiation.15
The earliest cell committed to the B-cell lineage
is called a pro-B cell. At the pro-B cell stage, the cell
expresses recombination activating gene (RAG) and
terminal deoxyribonucleotidyl transferase (TdT) proteins, which will be needed subsequently for somatic
recombination and nucleoside transfers involved in
junctional diversity, respectively. At the pro-B-cell
stage, limited somatic recombination has taken place,
and Ig is not yet expressed.
The next stage of B-cell maturation is represented
by the pre-B cell and is marked by the synthesis of a
cytoplasmic heavy chain. Because light chains are
not yet expressed at this stage, surface Ig is not present. Some of the heavy chains associate with invariant molecules called surrogate light chains and with the
signal transducing proteins Ig and Ig to form complexes called pre-B cell receptors. Cells that have synthesized heavy chains that are capable of forming part of
a pre-B cell receptor are selected for at this stage, as
pre-B cell receptors provide important signals for survival, proliferation, and maturation.
The formation of light chains marks the next stage
in B-cell maturation, the immature B-cell stage. When
B-CELL ACTIVATION AND ANTIBODY

FUNCTION AT A GLANCE
When the B-cell receptor (surface antibody)
binds antigen, a second signal provided by
C3d engagement with complement receptor
2 significantly augments B-cell activation.
B cells recognize a variety of macromolecules, including proteins, lipids, carbohydrates, and nucleic acids.
The portion of the molecule recognized by the antibody
is called an epitope or determinant. B cells recognize both
linear epitopes (epitopes formed by several adjacent
amino acids) and, quite commonly, conformational epitopes (epitopes present as a result of folding of the macromolecule).21 In contrast to B cells, T-cell responses are
almost entirely restricted to linear epitopes of peptides.
Macromolecules, particularly large proteins, may contain several different epitopes, and a humoral response
B-CELL ACTIVATION AND

ANTIBODY FUNCTION
::
ANTIGENS BOUND BY B CELLS
to a macromolecule typically is comprised of multiple

different antibodies. Although each different antibody is
specific for a given epitopic configuration, similarities in
epitopes may exist such that an antibody to a given epitope on a given macromolecule also may be able to bind
a different epitope on a different macromolecule. This
phenomenon is called cross-reactivity, and may be important in the genesis of autoimmune antibody responses.
Macromolecules that have multiple identical epitopes are classified as being polyvalent or multivalent.
Antibodies to these macromolecules or aggregates of
macromolecules may form complexes called immune
complexes with the antigen. At a particular concentration of antibody and antigen, called the zone of
equivalence, a large network of linked antigens and
antibodies forms. At lower or higher concentrations of
antibody or antigen, the complexes are much smaller.
Immune complexes, formed in the circulation or in tissue, may be responsible for disease through the initiation of an inflammatory response.
Chapter 37
light chains join with the heavy chains, an IgM molecule results and can be expressed on the cell surface
in association with Ig and Ig . Although the presence of a B-cell receptor complex confers the ability to
recognize specific antigens, at this stage such recognition does not result in proliferation or differentiation.
Rather, the cells may undergo negative selection when
antigen is encountered. Immature B cells recognizing
self-antigen may be negatively selected through deletion,16 anergy, or receptor editing, a process of secondary gene rearrangement by which a new, nonself
specificity is acquired.17
The exit of immature B cells from the bone marrow
to the spleen marks the beginning of the next stage, the
transitional B-cell stage.18 Transitional cells gradually
acquire surface IgD, CD21, and CD23 expression and
become more immune competent. Alternative splicing of RNA allows the simultaneous expression of IgM
and IgD. At the beginning of the stage, cross-linking of
the B-cell receptor leads to negative selection. With further maturation, transitional cells become responsive
to T-cell help and lose sensitivity to negative selection.
The mature B cell expresses IgM and IgD and is competent to respond to antigen. The cell is considered
naive because it has not been activated by antigen. The
majority of mature B cells circulate through peripheral
lymphoid tissues (spleen, lymph nodes, mucosal lymphoid tissue) and are called follicular B cells, or recirculating B cells. B cells are recruited to the follicle by the
chemokine CXCL13, secreted by follicular dendritic
cells, and survive in the follicle with the assistance of
a cytokine called BAFF (B-cell activating factor), also
known as BLyS (B lymphocyte stimulator). A small
percentage of mature B cells home to the marginal
zone of the spleen and remain resident there.
The encounter of antigen by mature naive B cells
leads to B-cell activation, proliferation, and differentiation (see Section B Cell Activation and Antibody
Function). A subset of B cells become memory B cells,
which can persist for long periods apparently without
stimulation by antigen, and which respond rapidly if
the antigen is encountered subsequently.19 Another
subset of B cells differentiates into cells that make progressively less membrane-bound Ig and more secreted
Ig. The terminally differentiated B cells committed to
the production of secreted Ig are plasma cells and have
abundant rough endoplasmic reticulum, consistent
with the function of the cells as antibody factories.20
B-cell responses to protein antigens typically

involve T-cell help, with resultant antibody
class switching and affinity maturation.
Activated B cells may become short-lived
plasma cells, memory B cells, or longlived plasma cells. Long-lived plasma cells
migrate to the bone marrow, where they may
persist indefinitely and are a major source of
antigen-specific antibodies in the circulation.
Effector functions of antibodies include
neutralization of antigen, complement
activation, cell activation, phagocytosis,
and antibody-dependent, cell-mediated
cytotoxicity. Most of these are mediated
through the binding of Ig to Fc receptors
containing an immunoreceptor tyrosinebased activation motif.
Negative signaling to B cells is provided by
binding of IgG to a B-cell Fc receptor that
contains an immunoreceptor tyrosine-based
inhibition motif. The availability of excess
IgG to bind this receptor is an indication that
antigen is being successfully eliminated and
the immune response is no longer required.
405
Section 6
::
406
On cross-linking of the mature B-cell receptor by antigen, clustering of receptors initiates signaling transduced by Ig and Ig. The complex signaling cascade
involving the phosphorylation of tyrosine kinases,
including Lyn, Fyn, Btk, and Syk, eventuates in the
expression of genes involved in B-cell activation.22
B-cell activation is facilitated by second signals, one of
which is provided by the complement protein C3d.23
Complement fragment C3d is formed as a result of
complement activation through any of the complement
activation pathways (see Section Complement). The
B-cell surface contains a coreceptor complex consisting of complement receptor 2 (CR2), CD19, and CD81
(also called TAPA-1, or target for antiproliferative antigen-1). Simultaneous binding of antigen by antibody
on the B-cell surface and of C3d by CR2 leads to markedly increased B-cell activation. B-cell activation may
also occur through Toll-like receptors that recognize
specific microbial products.24
The subsequent response to an antigen often
involves a complex interaction between B cells and T
cells, leading to a fine-tuning of the immune response.25
Recognition of antigen by both B cells and T cells leads
to increased expression of cell surface proteins and
cytokines that render these cells increasingly capable
of migrating toward and productively interacting with
each other. T cells recognizing peptide-class II MHC
complexes on dendritic cells receive a primary signal
from the complex and a secondary signal from costimulatory interactions involving the binding of B71 and
B72 on dendritic cells to CD28 on T cells.26 These activated T cells express CXCR5, the ligand for CXCL13,
which results in T-cell migration toward the follicle
and therefore increasingly toward B cells. In response
to a protein antigen, B cells take up the antigen, process
it, and present processed antigen on the cell surface in
complex with class II MHC. Activated B cells express
less CXCR5, which allows them to migrate from the follicle toward the T-cell zone. At the boundary between
follicles and T-cell zones, activated T cells interact with
B cells and provide signals to the B cells through the
binding of CD40 on B cells to CD40 ligand (CD154)
on T cells and through the action of cytokines, notably interleukin 2 (IL-2), IL-4, IL-21, BAFF, and APRIL
(a proliferation-inducing ligand).2 These signals will be
necessary for subsequent class (heavy chain isotype)
switching, affinity maturation, and memory B-cell
generation. The overall effects on B cells are stimulation of proliferation and differentiation.
At this phase, some of the activated B cells become
short-lived plasma cells, which provide a prompt initial response to an antigen, while others migrate back
from the periphery of the follicle to proliferate rapidly
and form germinal centers. It is primarily in the germinal centers that class switching, affinity maturation,
and generation of memory B cells occur. Class switching from IgM to IgA, IgE, or IgG occurs as a result of
T cellB cell interactions.27,28 The determination of the
antibody class selected is based on the site where the
antigen is encountered and the cytokine milieu. For
example, B-cell responses to antigens encountered
on mucosal surfaces characteristically result in class
switching to IgA, and transforming growth factor- is
an important contributing cytokine. IL-4 is an important signal for class switching to IgE.
T-cell interaction with B cells also results in affinity maturation, whereby the affinity of antibodies
for the antigen progressively increases. During affinity maturation, somatic hypermutations in antibody
genes result in antibodies with both greater and lesser
affinity for the antigen.29,30 Those antibodies with
greater affinity confer a survival advantage on the B
cells that produce them. Progressively, the population
of B cells evolves in favor of those producing higher
affinity antibodies for the antigen. Both class switching and affinity maturation require the expression of
an enzyme called activation-induced cytosine deaminase
(AID).31
The culmination of germinal center activity is the
formation of memory B cells and long-lived plasma
cells.32 A number of transcriptional regulators are
involved in late B-cell development, including BLIMP1
(B-lymphocyte maturation protein 1), IRF4 (interferonregulatory factor 4), and XBP1 (X-box-binding protein
1). Plasma cells may arise from and be replenished by
memory B cells or may arise from an intermediate cell,
the plasmablast. Long-lived plasma cells migrate to
and have a survival niche in the bone marrow, where
they can persist indefinitely. These bone marrow longlived plasma cells are the major source of antigenspecific antibody in the circulation.
As noted in Section Antigens Bound by B Cells,
T-cell responses are limited almost entirely to peptides.
Thus, B-cell responses to nonprotein antigens may not
result in T-cell help through the mechanisms described
earlier.33 In selected cases, T-cell independent nonprotein antigens can induce class switching, but in general, T-cell independent responses are characterized
by IgM antibodies of lower affinity. One type of T-cellindependent B-cell response produces so-called natural
antibodiesIgM antibodies that are largely anticarbohydrate antibodies produced without apparent antigen
exposure.34 These natural antibodies are characterized
by a limited repertoire and are produced primarily by
B1 peritoneal cells either spontaneously or in response
to bacteria that colonize the gut. Marginal zone B cells,
located near the marginal sinus in the spleen, may also
produce natural antibodies.
Antigen occupation of antibody-binding sites on B
cells leads to functional results, called effector functions.
With the exception of direct neutralization of antigen
by antibody binding, effector functions are typically
mediated through the binding of Ig to FcRs.35,36 FcRs
can be categorized as those that trigger cell activation
and those that do not. Those that can trigger activation contain one or more motifs called immunoreceptor tyrosine-based activation motifs. Of those that do not
trigger activation, some can inhibit cell activation and
contain a motif called immunoreceptor tyrosine-based
inhibition motif. FcRs that neither activate nor inhibit cell
activation are involved in the transport of Ig through
epithelia and the prolongation of the half-life of IgG.
The effector functions of antibodies serve to eliminate the antigen that initiated the immune response
and also to downregulate the immune response
when activation is not required. Effector functions of
a ntibodies include neutralization of antigen, complement activation, cell activation (of monocytes, neutrophils, eosinophils, and B cells), phagocytosis (by
monocytes and neutrophils), and antibody-dependent
cell-mediated cytotoxicity (mediated by NK cells and
eosinophils). In addition, engagement of IgG by antigen provides a negative signal to B cells, mediated
through the binding of the antigen-antibody complex
to an immunoreceptor tyrosine-based inhibition motifcontaining Fc receptor, FcIIB, on the B cell.37
The complement system was discovered through its

ability to contribute to, or complement, bacterial cell
lysis by antibodies.46,47 At physiologic temperatures,
serum containing antibacterial antibodies lysed bacteria effectively, whereas serum heated to 56C (133F)
lost its ability to lyse bacteria. Because antibodies are
quite stable at 56C (133F), it was postulated that the
The early steps in complement activation are

triggered enzyme cascades in which cleavage
of an inactive protein into fragments results in
cleavage of subsequent proteins in the cascade.
The alternative and lectin pathways are
primarily pathways of innate immunity;
the classical pathway is a pathway
characteristically initiated by humoral
immunity.
The complement pathways converge at the
cleavage of C3 and subsequent cleavage of
C5. The final steps of activation consist of the
addition of C68 to C5b, and polymerization
of C9 to form the membrane attack complex.
loss of lytic ability was due to the degradation of heatlabile nonantibody molecules.
Although the complement system was first identified
through its role in humoral immunity, a primitive complement system emerged more than 1.3 billion years
ago as a component of innate immunity (see Chapter
10).48 The complement system is constituted in part by
a set of plasma proteins that are normally inactive or
minimally active. The initial steps of activation involve
the cleavage of an inactive protein into a smaller and
a larger fragment. The larger fragment, then, is itself
able to cleave other proteins in the cascade. Because
an activated molecule in one step is capable of generating many activated molecules in the following step,
the sequential cleavage and activation of complement
proteins result in amplification of the cascade.
COMPLEMENT
The three pathways of complement

activation are the alternative, classical, and
lectin pathways.
::
Disorders of B cells or antibodies cause or contribute

to many diseases of dermatologic relevance. Immunodeficiency diseases may result from abnormalities of
B-cell development or activation, or from abnormalities in effector function pathways.38 B-cell lymphomas
may result from failure to regulate proliferation, differentiation, or programed cell death.39 Ectopic lymphoid
aggregates can arise as a result of aberrant chemokinemediated lymphocyte homing.40 Antibodies may initiate an inflammatory response that results in injury, as
in IgE-mediated allergic reactions or immune-complex
diseases.41,42 In some cases, the antigen may not be obviously harmful, but the response to the antigen is. In other
cases, the antigen may be pathogenic, but the character
or magnitude of the immune response is inappropriate
or inadequately controlled. The regulatory systems that
protect an organism from attack by its own immune
system occasionally go awry.43,44 Failure to eliminate
autoreactive cells may be a major underlying abnormality in many patients with autoimmunity. In some
cases, autoimmunity may be initiated as a result of an
immune response to a pathogen.45 The pathogen may
act as a nonspecific activator of the immune system, or
may activate the immune response specifically (e.g., by
containing an epitope or epitopes that are cross-reactive
with an autoepitope). These responses may be particularly difficult to control because the major stimulus for
the immune response, the antigen, is a normal component of self and cannot be eliminated. As mentioned
earlier, B cells have important roles beyond antibody
production. Abnormalities or imbalance of immune regulatory functions by B cells may lead to autoimmunity.
Thus, through many mechanisms, the normal protective
B-cell response, which developed as an elegant means to
discriminate very finely among various potential pathogens, can be subverted to result in harm to the organism.
The complement system functions to kill

microbes via lysis or phagocytosis, to clear
immune complexes and apoptotic debris from
the circulation, to promote inflammation, and
to stimulate humoral immunity.
Chapter 37
B CELLS AND ANTIBODIES

IN DISEASE
COMPLEMENT SYSTEM AND

ACTIVATION PATHWAYS AT A GLANCE
PATHWAYS OF COMPLEMENT
ACTIVATION
The early stages of the activation of complement ultimately result in cleavage of the complement protein C3.
This is followed by the cleavage of C5 and initiation of
the final steps of complement activation. There are three
distinct pathways that lead to the cleavage of C3, the classical, the alternative, and the lectin pathways. Although
the classical pathway was the first to be described, the
alternative pathway is evolutionarily older.49
407
ALTERNATIVE PATHWAY
Section 6
(Fig. 37-2)
The first step in the activation of the alternative pathway is the binding of C3b to a cell surface such as a
bacterial cell surface. Intact C3 is an inactive molecule,
but there is a low-level spontaneous cleavage of C3,
called tickover, which results in the continuous availability of the C3b fragment. C3b can bind stably to a
cell surface through an interaction between a thioester
group of C3b and a hydroxyl group of the cell surface.
In intact C3, the thioester domain is covered by hydrophobic residues that prevent hydrolysis of the thioester bond. The anaphylatoxin (ANA) domain of C3
stabilizes this inactive conformation. When the ANA
domain is cleaved to release C3a, the thioester group is
exposed, and conformational change results in its abil-
::
Alternative pathway of compliment activation

Tickover
C3
C3b
C3b
Microbial cell surface
C3a
Factor B
Factor D
Properidin
C3 convertase
C3bBb
Ba
C3
C3b
C5 convertase
C3bBbC3b
C3a
C3b
Amplification
of pathway
C5
408
C5b
C5a
Figure 37-2 The alternative pathway of complement activation. Shown are the steps from the initial attachment
of C3b to a microbial cell surface through the cleavage of
C5 into C5a and C5b. The final steps of complement activation are shown in Fig. 37-4. See Section Alternative
Pathway for details.
ity to bond to the cell surface.50,51 If this chemical bonding does not occur, the thioester group is hydrolyzed
and C3b is inactivated.
Once stable attachment of C3b to the cell surface
takes place, a plasma protein called Factor B binds to
C3b. Factor B is in turn cleaved by factor D, generating Bb and Ba. The complex of C3b and Bb, stabilized
by the plasma protein properidin, is the alternative
pathway C3 convertase (i.e., it cleaves C3 into C3a and
C3b). The result of the activity of the C3 convertase is
an amplification of the pathway by two or three orders
of magnitude. The addition of further C3b to the complex results in C3bBbC3b, which constitutes the alternative pathway to C5 convertase. The late steps of
complement activation, after the cleavage of C5, are
common to the three pathways and are described in
Final Steps of Complement Activation.
Thus, the low level of C3b in the plasma acts as a
sentinel for microbes. Once C3b is bound to the cell
surface, subsequent molecular interactions result in a
substantial amplification of the alternative pathway
and cleavage of C5. The requirement for binding of
C3b to a structural element serves to limit the effect
of complement activation to the area where complement activation is needed. The alternative pathway of
complement activation does not require finely specific
recognition of antigen and so is considered a component of innate immunity. It follows that if specific recognition is not required, C3b can bind to human cells as
well as microbes. However, activation on human cells
is generally prevented by the intervention of regulatory
proteins present on the surface of human cells, protecting these cells from inappropriate and harmful attack.52
CLASSICAL PATHWAY
(Fig. 37-3)
The initial step in the activation of the classical pathway is characteristically the binding of the portion
of the C1 complex called C1q to IgG or IgM antibodies.46 The C1q molecule consists of six identical arms
attached to a central trunk. The globular ends of the
arms attach to the complement-binding regions of the
heavy chains of certain Ig classes. In order for C1q to be
activated, it must bind simultaneously to at least two
Ig heavy chains. This means, in effect, that the Ig must
have bound antigen. In the case of IgG, binding of multiple epitopes by antibodies results in close proximity
of the antibodies and thus the proper configuration for
C1q activation. (As mentioned in Section Immunoglobulin G, IgG4 is an exception, in that it does not
bind C1q or activate complement.) Because IgM exists
as a pentamer, theoretically IgM without bound antigen could activate complement. However, when IgM
is not bound by antigen, the C1q binding site is not
accessible. When antigen is bound, a conformational
change results in exposure of the C1q binding site.
The complement component C1 is a complex of C1q,
C1r, and C1s. Binding of two or more of the globular
heads of C1q results in activation of C1r. Activated
C1r is a protease that cleaves and activates C1s, and
activated C1s, in turn, cleaves C4 into C4a and C4b.
Classical pathway of compliment activation
C1q
C1r2s2
C1 complex
Microbial cell surface

with antibodies
C3 convertase
C2a
C4bC2b
C4a
C4b
::
C4bC2
Chapter 37
C4
(The numbering of the complement proteins differs

from their positions in the activation sequence, as
components were discovered before the elucidation
of their positions in the pathway.) C4b, like C3b, contains a thioester group that can form stable bonds with
hydroxyl groups on a particular structure. Bound C4b
is then bound by C2, which is cleaved into C2a and
C2b. The C4bC2b complex is the classical pathway
C3 convertase. (Note: Typically, suffix a denotes the
smaller and b the larger complement fragment. Historically, the exception was C2, where C2a represented
the larger and C2b the smaller fragment. Some recent
textbooks now identify the smaller fragment as C2a
and the larger as C2b, to maintain consistency with the
nomenclature of the other complement proteins. However, many recent publications continue to adhere to
the historic nomenclature.)
The cleavage of C3 results in C3a and C3b. The C3b
fragment may then go on to activate complement
by the alternative pathway, or act in concert with
C4bC2b to form C4bC2bC3b, the classical pathway C5
convertase.
The major characteristics of the classical pathway
are much the same as those of the alternative pathway.
Activation of the pathway requires attachment of a
complement protein to a structure such as a cell surface or immune complex, so that the effects of complement activation are spatially limited. Initial activation
steps result in the formation of a C3 convertase that
cleaves C3. Cleavage of C3 leads to the formation of
a C5 convertase that cleaves C5 into C5a and C5b. A
major difference is the initiation of the classical pathway by specific recognition of antigen by antibodies,
in contrast to the less specific binding that occurs to
initiate the alternative pathway.
LECTIN PATHWAY
C3
C3b
C3a
C5 convertase
C4bC2bC3b
C3b
Amplification
of pathway
C5
C5b
C5a
Figure 37-3 The classical pathway of complement activation. Shown are the steps from the initial binding of C1q to
antibodyantigen complex through the cleavage of C5 into
C5a and C5b. The final steps of complement activation are
shown in Fig. 37-4. See Section Classical Pathway for details.
The lectin pathway is very similar to the classical pathway, with the exception of the initiating steps. The
first step is the binding of a plasma lectin, mannosebinding protein (MBP), to polysaccharides on microbial cell surfaces.53 MBP, a member of the collectin (collagenous lectin) family, is structurally similar to C1q
and can associate with C1r and C1s. MBP attachment to
a microbe can begin the cascade through the activation
of C1r and C1s. MBP also interacts with MBP-associated serine proteases (MASPs), which are analogous to
C1r and C1s. Binding of MBP to microbial cell surfaces
results in cleavage of MBP-associated serine protease
and thence cleavage of C4.54 In either event, the effect
is the formation of C4b and its stable binding to a cell
surface. As is the case for the alternative pathway, the
lectin pathway is a component of innate immunity.
FINAL STEPS OF COMPLEMENT

ACTIVATION
(Fig. 37-4)
The alternative, classical, and lectin pathways converge at the cleavage of C5. The C5b fragment remains
409
Formation of the membrane attack complex
C5b
C5 convertase
C5b6
C5b67
Section 6
::
410
C5b678
C5b678 + unpolymerized C9
C5b678 + polymerized C9
Figure 37-4 Formation of the membrane attack complex.

The alternative, classical, and lectin pathways converge at
the formation of C5b and its sequential attachment to C6,
C7, C8, and C9. The polymerization of C9 results in tubular
structures on the cell membrane.
surface bound. The next steps do not involve enzymatic cleavage, but rather the sequential binding of C6,
C7, and C8 to C5b. The C5b-8 complex stably bound
to a cell membrane becomes an active membrane
attack complex (MAC) through the addition of C9. C9
polymerizes around the complex and forms pores in
cell membranes. These pores may result in cell death
through osmotic rupture, particularly in nonnucleated
erythrocytes.
Nucleated cells are more resistant to lysis, but may
still exhibit effects attributable to MAC binding.55 It is
quite possible that the nonlytic changes induced by
MAC are of more functional and pathologic significance overall than is MAC-induced cell lysis.56 These
nonlytic effects may differ depending on cell type and
milieu, and similar effects may lead to different outcomes. For example, MAC insertion into phagocyte
cell membranes can lead to the production of inflammatory mediators such as reactive oxygen species and
prostaglandins, resulting in phagocyte activation.57
Glomerular epithelial cells may also exhibit inflammatory mediator production, but, in that setting, the
inflammatory mediators may lead to tissue injury.58
MAC has also been reported to cause proliferation of
certain cells, and MAC has been reported to have both
apoptotic and antiapoptotic properties.55
ADDITIONAL INITIATORS OF
COMPLEMENT ACTIVATION
In addition to the characteristic initiators of the three
pathways, certain additional structures can trigger
complement activation.59 These include, among others,
the following: in the alternative pathway, IgA immune
complexes and endotoxin; in the classical pathway,
C-reactive protein, apoptotic bodies, and serum amyloid P; and in the lectin pathway, serum ficolins (lectins
which bind N-acetylglucosamine).53,60
FUNCTIONS OF COMPLEMENT
PROTEINS
As mentioned earlier, the earliest function of the complement system to be discovered was the lysis of bacteria. Killing of microbes through direct lysis is mediated
by the MAC, C5b-9. Microbes may also be destroyed
through coating, or opsonization, by complement and
phagocytosis of the opsonized particles by phagocytic
cells. The processes of opsonization and phagocytosis
are also mechanisms for another important function of
complementthe clearance of immune complexes and
apoptotic debris from the circulation.
An ancillary function of complement activation is the
induction of inflammation. Inflammation, characterized
by vascular changes and ingress and activation of leukocytes and inflammatory proteins, serves to augment
the localized immune response in tissue. Three mediators of inflammation initiated by complement activation
are the complement fragments C3a, C4a, and C5a. These
are called anaphylatoxins because of their ability to induce
degranulation of mast cells.61 The most potent of these
ANAs is C5a. Receptors for C5a are expressed on endothelial cells, mast cells, eosinophils, basophils, monocytes,
neutrophils, smooth muscle cells, and epithelial cells.
Binding of C5a to endothelial cells results in increased
vascular permeability and expression of P-selectin, both
of which promote leukocyte accumulation in tissue. Binding to neutrophils results in increased neutrophil motility,
adhesion to endothelial cells, and production of reactive
oxygen species. The overall result is the accumulation of
inflammatory cells at local sites in tissue where they can
phagocytose and efficiently kill microbes.
The activation of complement also results in stimulation of the humoral immune system through the generation of C3d. B cells whose cell surface antibodies
recognize complement-bound antigen are upregulated
by the concurrent binding of C3d to CR2 on the B-cell
surface. Opsonization by complement also facilitates
antigen presentation to B cells by follicular dendritic cells.
COMPLEMENT RECEPTORS
COMPLEMENT RECEPTORS AND
REGULATORY PROTEINS AT A GLANCE
There are several proteins that interact with complement and serve to mediate or regulate its functions. The
C5a receptor, which is a member of the seven-transmembrane a-helical G-protein-coupled receptor family,
was mentioned in the previous section. Some of the best
described of the complement receptors are CR1CR4.
The type 1 complement receptor, CR1 (CD35), is a
member of a family of proteins called regulators of complement activation (RCA), which share a common structure consisting of multiple short consensus repeats,
also known as complement control protein repeats.52 CR1
binds C3b or C4b and is expressed on peripheral blood
cells, including monocytes, B and T lymphocytes,
neutrophils, eosinophils, and erythrocytes; on follicular
dendritic cells; and on keratinocytes.62 On phagocytic
cells, binding of CR1 to C3b or C4b results in phagocytosis of particles opsonized by complement fragments,
as well as activation of microbicidal mechanisms in
the phagocytic cells. On erythrocytes, binding of CR1
to C3b- or C4b-coated immune complexes results in
transport of the complexes to the spleen and liver,
where they are cleared from the circulation by phagocytes. Thus, CR1 serves as an important mediator of
complement function. It can also serve as a downregulator of complement activation, as it is involved in the
dissociation of C3 convertase complexes.
The type 2 complement receptor, CR2 (CD21), is also
a member of the RCA family.59 CR2 binds C3 fragments
iC3b (i stands for inactive), C3dg, and C3d, as well
as EpsteinBarr virus, interferon-, and the immuno-
REGULATION OF COMPLEMENT
ACTIVATION
Molecules involved in the regulation of complement
activation serve to downregulate the immune response
once an immune response is no longer needed and to
limit the immune response to the sites required, specifically protecting self from complement attack.
The C1 inhibitor (C1 INH) is a protease inhibitor that
inhibits certain plasma serine proteases, including C1,
kallikrein, and factor XII.46 C1 exists as a complex of
C1q and a tetramer of two C1r and two C1s fragments.
When C1q binds antibody, C1 INH can act to limit
complement activation by binding to the C1rC1s tetramer, dissociating it from C1q and preventing downstream activation of the pathway.
Another major point of interaction of regulatory
proteins is with bound C3b or C4b.52 As mentioned
earlier, the thioester group of unbound C3b or C4b is
rapidly hydrolyzed, rendering these molecules inactive. For surface-bound C3b or C4b, inactivation occurs
through the displacement of components of the alternative or classical pathway C3 convertase from C3b
or C4b or through proteolysis of C3b or C4b. In the
alternative pathway, inactivation of the C3 convertase
complex, C3bBb, can take place through the displacement of Bb from C3b by the plasma protein factor H or
the cell surface proteins decay accelerating factor (DAF,
CD55), membrane cofactor protein (MCP, CD46), and
CR1. These three cell surface proteins, all members of
the RCA family, are expressed on human cells but not
Some of the regulatory proteins

downregulate complement activation by
displacing components of the early steps
of the cascade. These include C1 inhibitor,
factor H, C4 binding inhibitor, decay
accelerating factor, membrane cofactor
protein, and CR1.
::
Regulation of complement activation is

provided by certain serum and cell surface
proteins. Many of the regulatory cell surface
proteins are expressed on human cells but
not microbes, thus protecting human cells
from complement damage.
Chapter 37
Some of the important effects of

complement are mediated through
binding of complement proteins to
complement receptors. CR1 functions in
phagocytosis, immune complex clearance,
and downregulation. CR2 is important in
stimulation of humoral immunity. CR3 and
-4 promote phagocytosis.
regulatory protein CD23. CR2 is expressed on subsets

of B and T lymphocytes, basophils, mast cells, follicular dendritic cells, and some epithelial cells, including
keratinocytes. On B cells, CR2 serves as a coreceptor for
B-cell activation. When CR2 is bound by C3d, the level
of B-cell activation is increased by orders of magnitude.63
On dendritic cells, CR2 engagement results in a trapping
of immune complexes in germinal centers. CR2 also
appears to play a role in antigen presentation to T cells.
The type 3 complement receptor, CR3 (CD11b/CD18,
Mac-1), is an integrin cell surface molecule expressed
on monocytes, neutrophils, NK cells, and mast cells.64
It functions to promote phagocytosis of microbes
through binding to iC3b and through direct binding to
microbes. It interacts with intercellular adhesion molecule 1 expressed endogenously on endothelial cells to
stabilize the adhesion of leukocytes to endothelium,
facilitating the recruitment of leukocytes from the circulation into tissue.
The type 4 complement receptor, CR4 (CD11c/CD18),
is also an integrin cell surface molecule. It is expressed
on monocytes, neutrophils, NK cells, and dendritic
cells, and probably functions similarly to CR3.
Among the recently described complement receptors are SIGN-R1,65 which binds C1q and is expressed
on splenic marginal zone macrophages, and CRIg
(complement receptor of the immunoglobulin family),66 which binds C3b and iC3b and is expressed on a
subset of tissue-resident macrophages.
411
Section 6
::
412
microbes, thereby allowing complement activation to

proceed on microbes while protecting human cells from
injury. Factor H preferentially binds cell surfaces with
high levels of sialic acid, and the relative abundance
of sialic acid on human cells but not microbes further
focuses the downregulation of complement activation
on human cells. In the classical and lectin pathways,
the C3 convertase is C4bC2b. DAF, MCP, and CR1 can
displace C2b from C4b, as can the plasma protein C4binding protein (C4BP). Thus, the cell surface proteins
DAF, MCP, and CR1 can dissociate the C3 convertases of
both the alternative and the classical/lectin pathways,
whereas the plasma proteins factor H and C4BP are specific for alternative or classical/lectin, respectively. Proteolysis of C3b or C4b is mediated by factor I, a plasma
protein that requires cofactors for its activity. MCP, CR1,
factor H, and C4BP can all serve as cofactors for factor I.
Regulation of complement at the late steps is mediated in part by CD59, a cell surface protein expressed on
human cells but not microbes. It binds the C5b-8 complex and inhibits addition of C9, blocking formation of
the MAC. Plasma S protein binds the C5b-7 complex
and blocks its insertion into the cell membrane and
also inhibits C9 polymerization.67 Intact MACs may be
removed from cells through shedding on membrane
vesicles or by internalization and degradation.55
Carboxypeptidase N can remove the terminal arginine of C3a, C4a, and C5a and has been referred to as
ANA inactivator.68 Carboxypeptidase R has also been
shown to remove the terminal arginine of C3a and C5a.69
COMPLEMENT AND DISEASE

GENETIC ABNORMALITIES OF THE
COMPLEMENT SYSTEM
Deficiencies of complement cascade proteins, complement receptors, or complement regulatory proteins
can lead to a variety of diseases.70 Genetic deficiencies of complement have been associated primarily
with increased risk for infection or autoimmunity. As
examples, deficiencies of many complement components, particularly the early complement components
C1C4, have been associated with early-onset systemic lupus erythematosus (SLE), C3 deficiency has
been associated with life-threatening pyogenic infections, and C5C9 deficiencies have been associated
with Neisserial infections (reviewed in Chapter 143).
Genetic deficiency of mannose-binding lectin is relatively common, with significantly low levels occurring in about 10% of Caucasians, and is associated
with increased risk for infection and autoimmunity,
including SLE.71,72
Altered expression of CR3 (CD11b/CD18) and CR4
(CD11c/CD18) occurs in leukocyte adhesion deficiency-1, a congenital disorder resulting from mutations
in the gene encoding CD18. Mutation in CD18 also affects
expression of CD11a/CD18 (leukocyte function-associated antigen-1). Patients with leukocyte adhesion deficiency-1 exhibit significant abnormalities of leukocyte
adhesion and have recurrent infections (see Chapter 143).
COMPLEMENT AND DISEASE

AT A GLANCE
Genetic deficiencies of complement components
have been associated primarily with susceptibility
to infection or autoimmunity. Genetic deficiencies
of regulatory complement proteins may result
in inappropriately prolonged complement
activation, such as occurs with C1 inhibitor
deficiency.
Complement is associated with systemic
lupus erythematosus through several possible
mechanisms. These include increased risk
of autoimmunity conferred by certain
complement deficiencies, tissue damage
resulting from autoantibody-induced
complement activation, ineffective clearance of
autoimmunity-promoting apoptotic debris, and
failure to eliminate self-reactive B cells.
Complement activation has been implicated in
the pathogenesis of atherosclerosis, reperfusion
injury after myocardial ischemia, diabetic
microvascular disease, and cerebral infarct in
ischemic stroke.
Certain infectious agents have evolved
mechanisms for evasion of destruction by
complement, and some use complement
receptors or regulatory proteins to gain entry
into the cell.
Deficiency of the complement regulatory protein

C1 INH causes angioneurotic edema as a result both
of poorly regulated classical pathway activation and
of excess bradykinin due to the actions of kallikrein
and factor XII. Angioedema may also occur if one has
markedly reduced levels of the ANA inactivator, carboxypeptidase N73 (see Chapter 38).
Deficiency of a protein required for the proper
expression of DAF and CD59 on the cell surface is
associated with paroxysmal nocturnal hemoglobinuria, a disease characterized by complement-mediated
erythrocyte lysis.74 Hemolytic-uremic syndrome has
been associated with mutations in MCP, factor H, and
factor I.75 Factor H deficiency has also been associated
with membranoproliferative glomerulonephritis.
The risk for developing age-related macular degeneration is affected significantly by the presence of certain
polymorphisms in genes of the complement system, particularly complement factor H but also factor B and C2.76
COMPLEMENT, SYSTEMIC
LUPUS ERYTHEMATOSUS, AND
AUTOANTIBODIES
Complement has been closely associated with SLE
(see also Chapter 155), albeit in seemingly paradoxical
EVASION OR SUBVERSION OF
COMPLEMENT BY MICROBES
The observation that individuals with deficiencies of
components of the late stages of complement activation
Complement activation has been implicated in the

pathogenesis of atherosclerosis, reperfusion injury
after myocardial ischemia, and cerebral infarct in ischemic stroke.82,83 In the microvascular proliferative disease associated with diabetes, glycation, and thereby
inactivation of CD59, may result in cellular proliferation due to nonlytic proliferative effects of MAC.84
Complement activation has also been implicated in
hyperacute rejection of xenotransplants due to the
presence of natural antibodies to components of the
endothelial cells of the transplanted organ, with resultant complement activation, endothelial cell injury,
and intravascular coagulation.
KEY REFERENCES
::
COMPLEMENT AND
VASCULAR DISEASE
are at increased risk for only a limited set of infections

illustrates that infectious agents have evolved means
of evading destruction by complement.85 Gram-positive bacteria have thick cell walls that are difficult to
penetrate by MAC.46 Group A streptococcus M protein
binds factor H, which downregulates complement activation, and many pathogens have evolved mechanisms
to attract factor H through the expression of sialic acids
on their surfaces. Staphylococcus aureus expresses several proteins that inhibit C3 activation. A protein of vaccinia virus (VCP-1, vaccinia virus complement control
protein-1) acts as a cofactor for factor I, leading to proteolysis of C3b and C4b. In human immunodeficiency
virus (HIV) infection, the inclusion of downregulatory
molecules of the complement system into the viral or
host cell membrane allows HIV to evade complementmediated destruction.86 DAF and CD59 can be subsumed into the HIV virus membrane upon budding
from infected human cells, and factor H can bind to
HIV surface glycoproteins on infected human cells.
The complement system has been subverted by certain infectious agents for entry into the cell. Epstein
Barr virus penetrates B cells via binding to CR2 on the
B-cell surface.46 Measles virus binds to cells via MCP.
Mycobacteria make C4-like molecules that bind C2b and
then cleave C3. The deposition of C3b on the mycobacterial cell membrane leads to its uptake into macrophages, where it exists as an intracellular parasite.
Knowledge of these evasive and subversive strategies
of pathogens may be useful in designing vaccines and
targeted therapies.85
Chapter 37
ways.77,78 Genetic deficiencies of complement components are associated with SLE, but some of the tissue
injury seen in SLE appears to be mediated in part by
complement activation. Thus, complement seems to be
simultaneously protective and deleterious. These observations underscore the protean roles of complement in
the immune system. Complement activation has the
potential for causing tissue injury, but complement
components may be important in clearance of immune
complexes and apoptotic debris. Apoptotic bodies that
are not cleared effectively may be able to trigger autoimmunity through presentation of normally sequestered
autoantigens to the immune system. It has also been
suggested that complement participates in eliminating
self-reactive immature B cells, a further mechanism for
a protective effect of complement in SLE.78
Altered expression of both CR1 and CR2 has been
observed in patients with SLE.79 In murine models of
lupus, knockout mice lacking expression of CR1 and
CR2 (located on the same gene in mice and produced
through alternative splicing) have accelerated autoimmunity if the mice otherwise have the optimal genetic
background. These findings indicate that the interaction
of CR2 and C3d, important in B-cell response to antigen,
is another factor that determines susceptibility to SLE.
Autoantibodies to complement components can
result in or exacerbate disease.80 Autoantibodies to C1q
are relatively common in SLE and have been associated with more severe renal disease, possibly through
an adverse affect on the clearance of immune complexes or apoptotic bodies.81 C3 nephritic factor is an
autoantibody to the C3 convertase, C3bBb, which acts
to stabilize the complex. Its clinical significance is its
association with membranoproliferative glomerulonephritis type II and partial lipodystrophy.

1. Flajnik MF, Kasahara M: Origin and evolution of the
adaptive immune system: Genetic events and selective
pressures. Nat Rev Genet 11(1):47-59, 2010
2. Abbas AK, Lichtman AH, Pillai S: Cellular and Molecular
Immunology, 6th edition. Philadelphia, Elsevier Saunders,
2010
3. LeBien TW, Tedder TF: B lymphocytes: How they develop
and function. Blood 112(5):1570-1580, 2008
13. Jung D et al: Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev
Immunol 24:541-570, 2006
20. Fairfax KA et al: Plasma cell development: From B-cell
subsets to long-term survival niches. Semin Immunol
20(1):49-58, 2008
46. Walport MJ: Complement. First of two parts. N Engl J Med
344(14):1058-1066, 2001
48. Nonaka M, Kimura A: Genomic view of the evolution of
the complement system. Immunogenetics 58(9):701-713,
2006
50. Janssen BJ et al: Structures of complement component C3
provide insights into the function and evolution of immunity. Nature 437(7058):505-511, 2005
52. Kim DD, Song WC: Membrane complement regulatory
proteins. Clin Immunol 118(23):127-136, 2006
55. Cole DS, Morgan BP: Beyond lysis: How complement influences cell fate. Clin Sci (Lond) 104(5):455-466, 2003
413
Chapter 38 :: Urticaria and Angioedema

:: Allen P. Kaplan
URTICARIA AND ANGIOEDEMA
AT A GLANCE
Occurs acutely at some time in 20% of the
population; incidence of chronic urticaria/
angioedema is approximately 0.5%.
Section 6
::
414
Acute urticaria/angioedema is caused

by drugs, foods, occasionally infection in
association with immunoglobulin E-dependent
mechanisms (allergy), or metabolic factors.
Chronic urticaria/angioedema is an
autoimmune disorder in 45% of patients.
In the absence of urticaria, angioedema
can be due to overproduction or impaired
breakdown of bradykinin.
Treatment of acute urticaria/angioedema
relies on antihistamines and short courses of
corticosteroids, and identification and elimination
of endogenous and exogenous causes.
Treatment of C1 inhibitor deficiency includes
androgenic agents, antifibrinolytic agents, and
C1 inhibitor (C1 INH) concentrates, a kallikrein
inhibitor, and bradykinin receptor antagonist.
Treatment of physical urticaria/angioedema
includes high-dose antihistamine prophylaxis,
except for delayed pressure urticaria.
Treatment of chronic idiopathic or
autoimmune urticaria/angioedema includes
antihistamines (nonsedating preparations
primarily), low-dose daily or alternate day
corticosteroids, or cyclosporine.
Urticaria is defined as a skin lesion consisting of a

wheal-and-flare reaction in which localized intracutaneous edema (wheal) is surrounded by an area of redness (erythema) that is typically pruritic. Individual
hives can last as briefly as 30 minutes to as long as
36 hours. They can be as small as a millimeter or 68
inches in diameter (giant urticaria). They blanch with
pressure as the dilated blood vessels are compressed,
which also accounts for the central pallor of the wheal.
The dilated blood vessels and increased permeability
that characterize urticaria are present in the superficial
dermis and involves the venular plexus in that location. Angioedema can be caused by the same pathogenic mechanisms as urticaria but the pathology is in
the deep dermis and subcutaneous tissue and swelling

is the major manifestation. The overlying skin may be
erythematous or normal. There is less pruritus (fewer
type C nerve endings at the deeper cutaneous levels)
but there may be pain or burning.
EPIDEMIOLOGY
Urticaria and angioedema are common. Age, race, sex,
occupation, geographic location, and season of the year
may be implicated in urticaria and angioedema only
insofar as they may contribute to exposure to an eliciting agent. Of a group of college students, 15%20%
reported having experienced urticaria, while 1%3%
of the patients referred to hospital dermatology clinics in the United Kingdom noted urticaria and angioedema. In the National Ambulatory Medical Care
Survey data from 1990 to 1997 in the United States,
women accounted for 69% of patient visits. There was
a bimodal age distribution in patients aged birth to 9
years and 3040 years.1
Urticaria/angioedema is considered to be acute if it
lasts less than 6 weeks. Most acute episodes are due to
adverse reactions to medications or foods and in children, to viral illnesses. Episodes of urticaria/angioedema persisting beyond 6 weeks are considered
chronic and are divided into two major subgroups: (1)
chronic autoimmune urticaria (45%) and (2) chronic
idiopathic urticaria (55%) with a combined incidence in the general population of 0.5%.2 Physically
induced urticaria/angioedema is not included in the
definition. Various types of physical urticaria/angioedema may last for years, but the individual lesions
last fewer than 2 hours (except delayed pressure urticaria) and are intermittent. Whereas 85% of children
experience urticaria in the absence of angioedema,
40% of adult patients with urticaria also experience
angioedema.
Approximately 50% of patients with chronic urticaria (with or without angioedema) are free of lesions
within 1 year, 65% within 3 years, and 85% within 5
years; fewer than 5% have lesions that last for more
than 10 years. Angioedema alters the natural history,
and only 25% of patients experience resolution of
lesions within 1 year. There are no data regarding the
remission rate in patients with only angioedema. The
hereditary group is considered to be life long once
the diagnosis becomes clinically manifest.
PATHOGENESIS
MAST CELL AND HISTAMINE RELEASE
The mast cell is the major effector cell in most forms
of urticaria and angioedema, although other cell types
undoubtedly contribute. Cutaneous mast cells adhere
sure urticaria is a variant of a late-phase reaction while

mast cell degranulation in most other physical urticarias has no associated late phase. These include typical
acquired cold urticaria, cholinergic urticaria, dermatographism, and type I solar urticaria.
AUTOIMMUNITY AND CHRONIC

URTICARIA
::
Urticaria and Angioedema
The first suggestion that patients with chronic

urticaria and angioedema might have an autoimmune diathesis was the observation that there is an
increased incidence of antithyroid antibodies in such
patients relative to the incidence in the population at
large.9 These include antimicrosomal (perioxidase)
and antithyroglobulin antibodies, as seen in patients
with Hashimotos thyroiditis.10 Patients may have
clinical hypothyroidism, but a small number might be
hyperthyroid if inflammation is at an early stage when
thyroid hormone is released into the circulation. This
atypical presentation should be distinguished from
the occasional patient with Graves disease. Nevertheless, most patients are euthyroid. The incidence of
antithyroid antibodies in chronic urticaria, as reported
in the literature, varies between 15% and 24%,11,12 but
the most recent data are closer to the latter figure12
and demonstrate segregation of antithyroid antibodies with chronic autoimmune urticaria rather than
chronic idiopathic urticaria. However, the association is not absolute. The incidence in the autoimmune
subgroup was 27%, in the chronic idiopathic urticaria
subgroup 11%, while in the population at large it is
7%8%. Gruber et al (1988)13 considered the possibility
that patients might have circulating and anti-IgE antibodies that are functional and did indeed find these
in about 5%10% of patients. Gratten et al14,15 sought
antibodies reactive with skin mast cells by performing an autologous skin test and found a 30% incidence
of positive reactions in patients with chronic urticaria.
There were only rare positive reactions in healthy
control subjects or patients with other forms of urticaria. Subsequently, this level of positivity was shown
by Hide et al16 to be due to an IgG antibody reactive
with the subunit of the IgE receptor; in addition a
5%10% incidence of functional anti-IgE antibodies
was confirmed (eFig. 38-1.1 in online edition).17
Chapter 38
to fibronectin and laminin through the very late activation (VLA) 1 integrins VLA-3, VLA-4, and VLA-5 and
to vitronectin through the v3 integrin. Cutaneous mast
cells, but not those from other sites, release histamine
in response to compound 48/80, C5a, morphine, and
codeine. The neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), and somatostatin, (but
not neurotensin, neurokinins A and B, bradykinin, or
calcitonin gene-related peptide), activate mast cells for
histamine secretion. Dermal microdialysis studies of the
application of SP on skin indicate that it induces histamine release only at 106 M, which suggests that after
physiologic nociceptor activation, SP does not contribute significantly to histamine release.3 Yet it is a major
contributor to the flare reaction induced by histamine
stimulation of afferent type C fibers (mediating pruritus) with release of SP from adjacent nerve endings by
antidromic conduction. Histamine is found associated
with the wheal.4 Recently, the spinal cord afferent fibers
mediating pruritis have, for the first time, been distinguished from pain fibers in the lateral spinothalamic
tracts.5
Not all potential biologic products are produced
when cutaneous mast cells are stimulated. For example, SP releases histamine from cutaneous mast cells
above 106 M but does not generate prostaglandin D2
(PGD2). Vascular permeability in skin is produced predominantly by H1 histamine receptors (85%); H2 histamine receptors account for the remaining 15%.
The current hypothesis regarding cellular infiltration that follows mast cell degranulation suggests that
the release of mast cell products (histamine, leucotrienes, cytokines, chemokines) leads to alterations in
vasopermeability, upregulation of adhesion molecules
on endothelial cells, and rolling and attachment of
blood leukocytes, followed by chemotaxis and transendothelial cell migration.
Various forms of physical urticaria/angioedema
have provided experimental models for the study of
urticaria/angioedema by allowing the observation of
the elicited clinical response, examination of lesional
and normal skin biopsy specimens, assay of chemical
mediators released into the blood or tissues, and characterization of peripheral leukocyte responses.6,7 The
intracutaneous injection of specific antigen in sensitized individuals has provided an experimental model
for analysis of the role of immunoglobulin (Ig) E and
its interaction with the mast cell. In many subjects,
the challenged cutaneous sites demonstrate a biphasic response, with a transient, pruritic, erythematous
wheal-and-flare reaction followed by a tender, deep,
erythematous, poorly demarcated area of swelling
that persists for up to 24 hours. This is the late-phase
response with recruitment of variable numbers of
neutrophils, prominent eosinophils, monocytes, small
numbers of basophils, and CD4+ T-lymphocytes of the
TH2 subclass.8 Chemokines (chemotactic cytokines)
strongly associated with Th2 lymphocyte predominance include those reactive with chemokine receptors
CCR3, CCR4, and CCR8 on T lymphocytes. Characteristic cytokines produced by Th2 lymphocytes include
interleukins (ILs) 4, 5, 9, 13, 25, 31 and 33. The cellular
infiltrate seen in biopsy specimens of delayed pres-
CELLULAR INFILTRATE
Mast cell degranulation certainly initiates the inflammatory process in autoimmune chronic urticaria and
is assumed to also do so in idiopathic chronic urticaria. Evidence for an increased number of mast cells
in chronic urticaria has been presented,36,37 but there
are also publications indicating no significant differences from normal;38 these studies did not discriminate
the autoimmune from the idiopathic groups. However,
no alternative mechanisms for mast cell degranulation
in the idiopathic groups have been suggested to date.
Yet the histology of the two groups differs only in minor
ways. Common to all biopsy specimens is a perivascular
415
Section 6
::
studied. The presence of increased plasma IL-4 levels25

in patients with chronic urticaria provides indirect evidence of lymphocyte activation, basophil activation,
or both, and isolated CD4+ lymphocytes of patients
were shown to secrete greater amounts of both IL-4
and IFN- compared with that seen in healthy control
subjects on stimulation with phorbol myristate acetate.
A direct comparison between cutaneous latephase reactions and the histology of chronic urticaria
revealed that infiltrating cells had characteristics of
both TH1 and TH2 cells, with production of IFN- by
the former cells and IL-4 and IL-5 by the latter.46 Alternatively, this might represent activated TH0 cells (i.e.,
activated CD4+ lymphocytes that are not differentiated
to TH1 or TH2 cells). When the histology of autoimmune
and idiopathic chronic urticarias was compared,41 the
autoimmune subgroup had greater prominence of
granulocytes within the infiltrate, whereas other infiltrating cells were quite similar, with a small increment
in cytokine levels in the autoimmune group and greater
tryptase positivity (? less degranulation) in the autoantibody-negative group. The patients with autoimmune
chronic urticaria generally had more severe symptoms
than those with idiopathic chronic urticaria.47
BASOPHIL RELEASIBILITY
(Figs. 38-1 and 38-2)
The basophils of patients with chronic urticaria
have been shown to be hyporesponsive to anti-IgE,
an observation made by Kern and Lichtenstein48 long
before there were any clues to the pathogenesis of
this disorder. These findings were confirmed49 and
Basophil histamine release

100
80
Percentage histamine release
infiltrate that surrounds small venules within the

superficial and deep venular plexus, with a prominence of CD4+ T lymphocytes and monocytes and
virtually no B cells.36,39 Granulocytes are quite variable
but are plentiful if the lesion undergoes biopsy early
in its development. Neutrophils and eosinophils are
both present,40,41 although the degree of eosinophils
accumulation varies greatly.39 Even when eosinophils
are not evident, major basic protein can be identified within lesions (in at least two-thirds of patients),
which most likely represents evidence of prior eosinophil degranulation.42 The presence of basophils has
also been recently demonstrated by using an antibody
(BB1) that is specific for this cell type.41 Thus, the infiltrate resembles that of an allergic late-phase reaction,
as suggested previously,43 although the percentage of
each cell types differs, with neutrophils and monocytes
being relatively more prominent in urticaria. Endothelial cell activation is suggested by the presence of intercellular adhesion molecule 1 and E-selectin in biopsy
specimens of urticarial lesions.44 Sources of chemokines
include the mast cell and the activated endothelial cell;
the latter cells are stimulated not only by cytokines
or monokines, such as IL-4, IL-1, and tumor necrosis
factor- (TNF-), but also by the vasoactive factors,
for example, histamine and leukotrienes released from
activated mast cells.45 Complement activation and the
release of C5a results not only in augmented mast cell
(and basophil) histamine release, but C5a is also chemotactic for neutrophils, eosinophils, and monocytes.
The presence of C5a is one of the factors that would
distinguish this lesion from a typical allergen-induced
cutaneous late-phase reaction. The particular chemokines released in chronic urticaria have not been
60
40
20
0
No urticaria
416
CU-idiopathic
CU-autoimmune
Figure 38-1 Basophil histamine release comparing normal sera (N = 35) with sera from patients with chronic urticaria
(N = 104). Those designated as having chronic autoimmune urticaria are shown on the right.
Activation of cutaneous mast cells by IgG antireceptor

C3
C4b2a
C4 + C2
C1
C3b
Activated C1
Antigen-antibody (IgG)
complex
C4b2a3b
C5
C5b
C5a
C5a receptor
Figure 38-2 Schematic diagram of the activation of cutaneous mast cells by IgG antireceptor antibody, followed by
activation of complement, release of C5a, and augmentation of mast cell release.
appeared to be associated with basopenia50 and to segregate with the autoimmune subgroup. One obvious
interpretation is that there is in vivo desensitization of
basophils in the presence of circulating anti-IgE receptor. Vonakis et al have demonstrated that patients
basophil hyporesponsiveness to anti-IgE is due to
augmented levels of SHIP phosphatase51 that limits
phosphorylation reactions critical for histamine secretion. Although manifest in about half the patients with
chronic urticaria (and not segregated with either the
autoimmune or idiopathic subgroups), the abnormality appears to reverse when patients remit. Thus, it
may be a marker of disease activity. We have found
a paradoxical result when the isolated basophils of
patients with chronic urticaria were activated and compared with the basophils of healthy control subjects.
Although the basophils of the patients with urticaria
were clearly less responsive to anti-IgE, they demonstrated augmented histamine release when incubated
with serum and it did not matter whether the sera
were taken from normal subjects, other patients with
chronic urticaria, or was their own.52
ROLE OF THE EXTRINSIC

COAGULATION CASCADE
Studies of the plasma of patient with chronic urticaria
demonstrate the presence of d-dimer and prothrombin
1 and 2 fragments indicating activation of prothrombin to thrombin as well as digestion of fibrinogen by
thrombin.53 The reaction is not specific for chronic
BRADYKININ: ROLE IN ANGIOEDEMA

Kinins are low-molecular-weight peptides that participate in inflammatory processes by virtue of their ability
to activate endothelial cells and, as a consequence, lead
to vasodilatation, increased vascular permeability, production of nitric oxide, and mobilization of arachidonic
acid. Kinins also stimulate sensory nerve endings to
cause a burning dysesthesia. Thus, the classical parameters of inflammation (i.e., redness, heat, swelling, and
pain) can all result from kinin formation. Bradykinin is
the best characterized of this group of vasoactive substances.
There are two general pathways by which bradykinin is generated. The simpler of the two has only
two components: (1) an enzyme tissue kallikrein57
and (2) a plasma substrate, low-molecular-weight
kininogen.58,59 Tissue kallikrein is secreted by many
cells throughout the body; however, certain tissues
produce particularly large quantities. These include
glandular tissues (salivary and sweat glands and pancreatic exocrine gland) and the lung, kidney, intestine,
and brain.
The second pathway for bradykinin formation is far
more complex and is part of the initiating mechanism
by which the intrinsic coagulation pathway is activated
(eFig. 38-1.2 in online edition).60 Factor XII is the initiating protein that binds to certain negatively charged macromolecular surfaces and autoactivates (autodigests) to
form factor XIIa.61,62 This is synonymous with Hageman
factor as designated in the figure. There are two plasma
substrates of factor XIIa, namely (1) prekallikrein63 and
(2) factor XI,64,65 and each of these circulates as a complex
with high-molecular-weight kininogen (HK).66,67 These
complexes also attach to initiating surfaces, and the
major attachment sites are on two of the domains of HK,
which thereby places both prekallikrein and factor XI in
optimal conformation for cleavage to kallikrein (plasma
kallikrein) and factor XIa, respectively. It is important
to note that plasma kallikrein and tissue kallikrein are
IgE receptor
::
Mast cell
Cell activation
mediator release
Histamine
Leukotrienes
Cytokines
Chemokines
Chapter 38
Anti-FcRI
IgG
urticaria as similar observations have been noted in

multiple nonsteroidal hypersensitivity syndrome.54
Nevertheless, the data are of considerable interest and
activation of the coagulation cascade is dependent on
tissue factor rather than factor XII, i.e., the extrinsic
coagulation cascade. Although activated endothelial
cells are a well-known source of the tissue factor, histologic studies suggest that eosinophils are a prominent source.55 The relationship of these observations
to histamine release by basophils or mast cells is not
clear. Whereas thrombin activation of mast cells has
been reported, the amounts required are large and the
observations thus far are confined to rodent mast cells.
One publication relating to eosinophil to histamine
release found IgG antibody to FceRII in the serum of
patients with chronic urticaria which activates eosinophils to release cationic proteins.56 They propose basophil activation by these eosinophil cationic proteins
but do not demonstrate it; however, they offer an additional mechanism for basophil and possibly mast cell
histamine release.
417
Section 6
::
separate gene products and have little amino acid

sequence homology, although they have related functions (i.e., cleavage of kininogens). Tissue kallikrein
prefers low-molecular-weight kininogen but is capable
of cleaving HK, whereas plasma kallikrein cleaves HK
exclusively. The two kininogens have an identical amino
acid sequence starting at the N-terminus and continuing to 12 amino acids beyond the bradykinin moiety59
but differ in C-terminal domains because of alternative
splicing at the transcription level.68,69 Both factor XII and
HK bind to endothelial cells (which may function as the
natural surface in the presence of physiologic zinc
ion), thus activation may occur at the cell surface.70,71
A scheme for both production and degradation of
kinins is shown in eFig. 38-1.2 in online edition. The
enzymes that destroy bradykinin consist of kininases
I and II. Kininase I is also known as plasma carboxypeptidase N,72 which removes the C-terminal arg from
bradykinin or kallidin to yield des-arg73 bradykinin or
des-arg74 kallidin, respectively.75 It is the same enzyme
that cleaves the C-terminal arg from the complement
anaphylatoxins C3a and C5a. Kininase II is identical
to angiotensin-converting enzyme (ACE).76 Kininase
II is a dipeptidase that cleaves the C-terminal phearg from bradykinin to yield a heptapeptide, which is
cleaved once again to remove ser-pro and to leave the
pentapeptide arg-pro-pro-gly-phe.75 If the C-terminal
arg of bradykinin is first removed with kininase I, then
ACE functions as a tripeptidase to remove ser-pro-phe
and to leave the above pentapeptide.77 Bradykinin and
kallidin stimulate constitutively produced B2 receptors,78 whereas des-arg73-BK or des-arg74 lys-BK both
stimulate B1 receptors,79 which are induced as a result
of inflammation. Stimuli for B1 receptor transcription
include IL-1 and TNF-.80,81
CLINICAL FINDINGS
Circumscribed, raised, erythematous, usually pruritic,
evanescent areas of edema that involve the superficial
portion of the dermis are known as urticaria (Fig. 38-3);
when the edematous process extends into the deep
dermis and/or subcutaneous and submucosal layers,
it is known as angioedema. Urticaria and angioedema
may occur in any location together or individually.
Angioedema commonly affects the face or a portion of
an extremity, may be painful but not pruritic, and may
last several days. Involvement of the lips, cheeks, and
periorbital areas is common, but angioedema also may
affect the tongue, pharynx, or larynx. The individual
lesions of urticaria arise suddenly, rarely persist longer
than 2436 hours, and may continue to recur for indefinite periods. They are highly pruritic.
IMMUNOLOGIC: IMMUNOGLOBULIN
E- AND IMMUNOGLOBULIN E
RECEPTOR-DEPENDENT URTICARIA/
ANGIOEDEMA
418
ATOPIC DIATHESIS. Episodes of acute urticaria/

angioedema that occur in individuals with a personal
Figure 38-3 Urticaria and angioedema. This patient has

urticaria occurring on the face, neck, and upper trunk with
angioedema about the eyes.
or family history of asthma, rhinitis, or eczema are
presumed to be IgE dependent. However, in clinical
practice, urticaria/angioedema infrequently accompanies an exacerbation of asthma, rhinitis, or eczema.
The prevalence of chronic urticaria/angioedema is not
increased in atopic individuals.
SPECIFIC ANTIGEN SENSITIVITY. Common

examples of specific antigens that provoke urticaria/
angioedema include foods such as shellfish, nuts, and
chocolate; drugs and therapeutic agents notably penicillin; aeroallergens; and Hymenoptera venom (see
Fig. 38-3). Urticaria in patients with helminthic infestations has been attributed to IgE-dependent processes;
however, proof of this relationship is often lacking.
Specific allergens and nonspecific stimuli may activate
local reactions termed recall urticaria at sites previously
injected with allergen immunotherapy.
PHYSICAL URTICARIA/
ANGIOEDEMA5,6
DERMOGRAPHISM. Dermographism is the most
common form of physical urticaria and is the one
most likely to be confused with chronic urticaria.
A lesion appears as a linear wheal with a flare at a
site in which the skin is briskly stroked with a firm
object (Fig. 38-4). A transient wheal appears rapidly
and usually fades within 30 minutes; however, the
patients normal skin is typically pruritic so that an
itchscratch sequence may appear. The prevalence
of dermographism in the general population was
reported as 1.5% and 4.2%, respectively, in two studies, and its prevalence in patients with chronic urticaria is 22%. It is not associated with atopy. The peak
prevalence occurs in the second and third decades.
In one study, the duration of dermographism was
greater than 5 years in 22% of individuals and greater
than 10 years in 10%.
pressure urticaria and no spontaneously occurring

hives. An IgE-mediated mechanism has not been
demonstrated; however, histamine and IL-6 have
been detected in lesional experimental suction-blister
aspirates and in fluid from skin chambers, respectively.8789
PRESSURE URTICARIA. Delayed pressure urticaria appears as erythematous, deep, local swellings, often painful, that arise from 3 to 6 hours after
sustained pressure has been applied to the skin.85,86
Spontaneous episodes are elicited on areas of contact
after sitting on a hard chair, under shoulder straps
and belts, on the feet after running, and on the hands
after manual labor. The peak prevalence occurs in the
third decade. Delayed pressure urticaria may occasionally be associated with fever, chills, arthralgias,
and myalgias, as well as with an elevated erythrocyte
sedimentation rate and leukocytosis. In one study,
it accompanied chronic urticaria in 37% of patients.
This is far more commonly seen than patients with
Figure 38-5 Positive ice cube test in a patient with cold

urticaria.
Elevations in blood histamine levels have been documented in some patients after experimental scratching, and increased levels of histamine,82 tryptase, SP,
and VIP, but not calcitonin gene-related peptide, have
been detected in experimental suction-blister aspirates. The dermographic response has been passively
transferred to the skin of normal subjects with serum
or IgE.83
In delayed dermographism, lesions develop 36
hours after stimulation, either with or without an
immediate reaction, and last 2448 hours. The eruption is composed of linear red indurated wheals.
This condition may be associated with delayed pressure urticaria and these two may, in fact, represent
the same entity. Cold-dependent dermographism is
a condition characterized by marked augmentation
of the dermatographic response when the skin is
chilled.84
::
Figure 38-4 Topical dermatographic response to scratching the skin.
COLD URTICARIA. There are both acquired and

inherited forms of cold urticaria/angioedema; however, the familial form is rare. Idiopathic or primary
acquired cold urticaria may be associated with headache, hypotension, syncope, wheezing, shortness of
breath, palpitations, nausea, vomiting, and diarrhea.
Attacks occur within minutes after exposures that
include changes in ambient temperature and direct
contact with cold objects. The elicitation of a wheal
after the application of ice has been called a diagnostic
cold contact test (Fig. 38-5). This can be performed with
thermoelectric elements with graded temperatures so
that the temperature threshold for producing a wheal
can be determined and a dose-response (sensitivity) in
terms of stimulus duration can be readily obtained.92 If
the entire body is cooled (as in swimming), hypotension and syncope, which are potentially lethal events
(by drowning), may occur. In rare instances, acquired
cold urticaria has been associated with circulating
cryoglobulins, cryofibrinogens, cold agglutinins, and
cold hemolysins, especially in children with infectious
mononucleosis.9395
Passive transfer of cold urticaria by intracutaneous
injection of serum or IgE to the skin of normal recipients has been documented.96,97 Histamine, chemotactic
Chapter 38
VIBRATORY ANGIOEDEMA. Vibratory angioedema may occur as an acquired idiopathic disorder, in association with cholinergic urticaria, or after
several years of occupational exposure to vibration.90
It has been described in families with an autosomal
dominant pattern of inheritance.91 The heritable form
often is accompanied by facial flushing. An increase
in the level of plasma histamine was detected during
an experimental attack in patients with the hereditary form and in patients with acquired disease.91,92 A
typical symptom is hives across the back when toweling off after a shower (in the absence of dermatographism).
419
Section 6
::
420
factors for eosinophils and neutrophils, PGD2, cysteinyl leukotrienes, platelet-activating factor, and TNF-
have been released into the circulation after experimental challenge.98104 Histamine, SP, and VIP, but not
calcitonin gene-related peptide, have been detected
in experimental suction-blister aspirates. Histamine
has been released in vitro from chilled skin biopsy
specimens that have been rewarmed.105 Neutrophils
harvested from the blood of an experimentally coldchallenged arm manifested an impaired chemotactic
response suggesting in vivo desensitization. Whereas
complement has no role in primary acquired cold urticaria, cold challenge of patients with cold urticaria
who have circulating immune complexes (such as
cryoglobulins) can provoke a cutaneous necrotizing
venulitis with complement activation.106109
Rare forms of acquired cold urticaria have been
described mainly in case reports include systemic cold
urticaria,84 localized cold urticaria,110 cold-induced
cholinergic urticaria, cold-dependent dermographism,84 and localized cold reflex urticaria.111,112 Three
forms of dominantly inherited cold urticaria have
been described. Familial cold urticaria which has been
termed familial cold autoinflammatory syndrome and is
considered a type of periodic fever.113 It is a disorder
showing an autosomal dominant pattern of inheritance with a genetic linkage to chromosomes 1q44.
The responsible gene has been identified as CIASI,
which codes for a protein involved in regulation of
inflammation and apoptosis.114 The eruption occurs as
erythematous macules and infrequent wheals and is
associated with burning or pruritus. Fever, headaches,
conjunctivitis, arthralgias, and a neutrophilic leukocytosis are features of attacks. The delay between cold
exposure and onset of symptoms is 2.5 hours, and the
average duration of an episode is 12 hours. Renal disease with amyloidosis occurs infrequently. Skin biopsy
specimens show mast cell degranulation and an infiltrate of neutrophils. Results of the cold contact test
and passive transfer with serum have been negative.
Serum levels of IL-6 and granulocyte colony stimulating factor were elevated in one patient. Other studies suggest a pathogenic role for IL-1. Delayed cold
urticaria occurs as erythematous, edematous, deep
swellings that appear 918 hours after cold challenge.
Lesional biopsy specimens show edema with minimal numbers of mononuclear cells; mast cells are not
degranulated; and neither complement proteins nor
immunoglobulins are detected. Cold immersion does
not release histamine, and the condition cannot be
passively transferred. Recently, a new form of familial cold urticaria with dominant inheritance has been
reported with pruritus, erythema, and urticaria with
cold exposure that can progress to syncope. The ice
cube test is negative and it lacks the fever, and flu-like
symptoms associated with familial cold autoinflammatory syndrome.115
CHOLINERGIC URTICARIA. Cholinergic urticaria develops after an increase in core body temperature, such as during a warm bath, prolonged
exercise, or episodes of fever.116 The highest prevalence
Figure 38-6 Lesions of cholinergic urticaria observed in a

patient after 15 minutes of exercise in a warm room.
is observed in individuals aged 2328 years. The eruption appears as distinctive, pruritic, small, 1- to 2-mm
wheals that are surrounded by large areas of erythema
(Fig. 38-6). Occasionally, the lesions may become confluent, or angioedema may develop. Systemic features include dizziness, headache, syncope, flushing,
wheezing, shortness of breath, nausea, vomiting, and
diarrhea. An increased prevalence of atopy has been
reported. The intracutaneous injection of cholinergic
agents, such as methacholine chloride, produces a
wheal with satellite lesions in approximately one-third
of patients.117,118 Alterations in pulmonary function
have been documented during experimental exercise
challenge119 or after the inhalation of acetylcholine, but
most are asymptomatic.
A major subpopulation of patients with cholinergic
urticaria have a positive skin test result and in vitro
histamine release in response to autologous sweat.120 It
is not clear whether this is IgE mediated and any antigen present in sweat is unidentified. This is the same
subpopulation with a positive methacholine skin test
with satellite lesions and a nonfollicular distribution
of the wheals. The remaining patients had negative
results on autologous sweat skin tests or in vitro histamine release. Results of the methacholine skin test are
negative for satellite lesions and the hives tend to be
follicular in distribution.
Familial cases have been reported only in men in
four families.121 This observation suggests an autosomal dominant pattern of inheritance. One of these
individuals had coexisting dermographism and aquagenic urticaria.
After exercise challenge, histamine and factors chemotactic for eosinophils and neutrophils have been released
into the circulation.99,119 Tryptase has been detected in
lesional suction-blister aspirates. The urticarial response
has been passively transferred on one occasion; however,
most other attempts to do so have been unsuccessful.
Cold urticaria and cholinergic urticaria are not
uncommonly seen together122,123 and cold-induced
cholinergic urticaria represents an unusual variant
in which typical cholinergic appearing lesions

occur with exercise, but only if the person is chilled,
for example, with exercise outside on a winters day.
The ice cube test and methacholine skin test are both
negative.124
AQUAGENIC URTICARIA AND AQUAGENIC PRURITIS. Contact of the skin with water
EXERCISE-INDUCED ANAPHYLAXIS. Exercise-induced anaphylaxis is a clinical symptom complex consisting of pruritus, urticaria, angioedema
respiratory distress, and syncope that is distinct
from cholinergic urticaria.134137 In most patients, the
wheals are not punctate and resemble the hives seen
in acute or chronic urticaria. The symptom complex
is not readily reproduced by exercise challenges as is
cholinergic urticaria. There is a high prevalence of an
atopic diathesis. Some cases are food dependent, i.e.,
exercise will lead to an anaphylaxis-like episode only
ADRENERGIC URTICARIA. Adrenergic urticaria

occurs as wheals surrounded by a white halo that
develop during emotional stress. The lesions can be
elicited by the intracutaneous injection of norepinephrine.
::
SOLAR URTICARIA. Solar urticaria occurs as pruritus, erythema, wheals, and occasionally angioedema
that develop within minutes after exposure to sun or
artificial light sources. Headache, syncope, dizziness,
wheezing, and nausea are systemic features. Most
commonly, solar urticaria appears during the third
decade.126 In one study, 48% of patients had a history of
atopy. Although solar urticaria may be associated with
systemic lupus erythematosus and polymorphous
light eruption, it is usually idiopathic. The development of skin lesions under experimental conditions
in response to specific wavelengths has allowed classification into six subtypes; however, individuals may
respond to more than one portion of the light spectrum. In type I, elicited by wavelengths of 285320 nm,
and in type IV, elicited by wavelengths of 400500 nm,
the responses have been passively transferred with
serum, suggesting a role for IgE antibody. In type I, the
wavelengths are blocked by window glass.127,128 Type
VI, which is identical to erythropoietic protoporphyria,
is due to ferrochelatase (hemesynthetase) deficiency
(see Chapter 132).74 There is evidence that an antigen
on skin may become evident once irradiated with the
appropriate wave length of light followed by complement activation and release of C5a.129131
Histamine and chemotactic factors for eosinophils
and neutrophils have been identified in blood after
exposure of the individuals to ultraviolet A, ultraviolet B, and visible light.132,133 In some individuals,
uncharacterized serum factors with molecular weights
ranging from 25 to 1,000 kDa, which elicit cutaneous
wheal-and-erythema reactions after intracutaneous
injection, have been implicated in the development of
lesions.
Chapter 38
LOCAL HEAT URTICARIA. Local heat urticaria

is a rare form of urticaria in which wheals develop
within minutes after exposure to locally applied heat.
An increased incidence of atopy has been reported.
Passive transfer has been negative. Histamine, neutrophil chemotactic activity, and PGD2 have been detected
in the circulation after experimental challenge.125 A
familial delayed form of local heat urticaria in which
the urticaria occurred in 12 hours after challenge and
lasted up to 10 hours has been described.
if food was ingested within 5 hours of the exercise.

The food dependency is subdivided into two groups:
in the first the nature of the food eaten is not relevant, whereas in the second a specific food to which
there is IgE-mediated hypersensitivity must be eaten
for hives to appear.138141 Yet in these cases, eating the
food without exercise does not result in urticaria.
The food-dependent group is easier to treat because
avoidance of food (or a specific food) for 56 hours
before exercise prevents episodes. Cases not related to
food require therapy for acute episodes and attempts
to prevent episodes with high-dose antihistaminics
or avoidance of exercise. Results of a questionnaire
study of individuals who had had exercise-induced
anaphylaxis for more than a decade142 disclosed that
the frequency of attacks had decreased in 47% and
had stabilized in 46%. Forty-one percent had been
free of attacks for 1 year. Rare familial forms have
been described. In exercise-induced anaphylaxis,
baseline pulmonary function tests are normal. Biopsy
specimens show mast cell degranulation, and histamine and tryptase are released into the circulation
when symptoms appear.
of any temperature may result in pruritus alone or,

more rarely, urticaria. The eruption consists of small
wheals that are reminiscent of cholinergic urticaria.
Aquagenic urticaria has been reported in more than
one member in five families.143 Aquagenic pruritus
without urticaria is usually idiopathic but also occurs
in elderly persons with dry skin and in patients with
polycythemia vera, Hodgkins disease, the myelodysplastic syndrome, and the hypereosinophilic
syndrome. Patients with aquagenic pruritus should
be evaluated for the emergence of a hematologic disorder. After experimental challenge, blood histamine
levels were elevated in subjects with aquagenic pruritus and with aquagenic urticaria. Mast cell degranulation was present in lesional tissues. Passive transfer
was negative.
CONTACT URTICARIA
Urticaria may occur after direct contact with a variety
of substances. It may be IgE mediated or nonimmunologic. The transient eruption appears within minutes,
and when it is IgE mediated, it may be associated with
systemic manifestations. Passive transfer has been documented in some instances. Proteins from latex products are a prominent cause of IgE-mediated contact
urticaria.144 Latex proteins also may become airborne
allergens, as demonstrated by allergen-loaded airborne
glove powder used in inhalation challenge tests. These
patients may manifest cross-reactivity to fruits, such
421
as bananas, avocado, and kiwi.145 Associated manifestations include rhinitis, conjunctivitis, dyspnea, and
shock. The risk group is dominated by biomedical
workers and individuals with frequent contact with
latex, such as children with spina bifida. Agents such
as stinging nettles, arthropod hairs, and chemicals may
release histamine directly from mast cells.
PAPULAR URTICARIA
Section 6
::
422
Papular urticari occurs as episodic, symmetrically distributed, pruritic, 3- to 10-mm urticarial papules that
result from a hypersensitivity reaction to the bites of
insects such as mosquitoes, fleas, and bedbugs. This
condition appears mainly in children. The lesions
tend to appear in groups on exposed areas such as the
extensor aspects of the extremities.146
URTICARIA/ANGIOEDEMA MEDIATED
BY BRADYKININ, THE COMPLEMENT
SYSTEM OR OTHER EFFECTOR
MECHANISMS
KININS AND C1 INHIBITOR DEFICIENCY.
C1 inhibitor (C1 INH) is the sole plasma inhibitor of

factor XIIa and factor XIIf,147,148 and it is one of the
major inhibitors of kallikrein149 as well as factor XIa.150
Thus, in the absence of C1 INH, stimuli that activate
the kinin-forming pathway will do so in a markedly
augmented fashion; the amount of active enzyme and
the duration of action of the enzymes are prolonged.
C1 INH deficiency can be familial, in which there is
a mutant C1 INH gene, or it can be acquired. Both
the hereditary and acquired disorders have two subtypes. For the hereditary disorder, type I hereditary
angioedema (HAE) (85%) is an autosomal dominant
disorder with a mutant gene (often with duplication,
deletions, or frame shifts) leading to markedly suppressed C1 INH protein levels as a result of abnormal
secretion or intracellular degradation.151 Type 2 HAE
(15%) is also a dominantly inherited disorder, typically
with a point (missense) mutation leading to synthesis of a dysfunctional protein.152 The C1 INH protein
level may be normal or even elevated, and a functional assay is needed to assess activity. The acquired
disorder has been portrayed as having two forms, but
they clearly overlap and have in common B cell activation that is often clonal. One group is associated with
B-cell lymphoma153155 or connective tissue disease,156
in which there is consumption of C1 INH. Examples
are systemic lupus erythematosus and cryoglobulinemia, in which complement activation is prominent,
and B-cell lymphomas, in which immune complexes
are formed by anti-idiotypic antibodies to monoclonal immunoglobulin expressed by the transformed B
lymphocytes.157 A second group has a prominence of
a circulating IgG antibody to INH itself,158160 but this
may be seen with lymphoma or systemic lupus erythematosus as well. Acquired types have depressed C1q
levels, whereas hereditary types do not, and depressed
C4 levels characterize all forms of C1 INH deficiency.
The acquired autoimmune subgroup has a circulating

95-kDa cleavage product of C1 INH because the antibody depresses C1 INH function yet allows cleavage
by enzymes with which it usually interacts.159162
It is now clear that depletion of C4 and C2 during episodes of swelling163,164 is a marker of complement activation but does not lead to release of a vasoactive peptide
responsible for the swelling. Bradykinin is, in fact, the
mediator of the swelling165167and the evidence in support of this conclusion is summarized below. Patients
with HAE are hyperresponsive to cutaneous injection
of kallikrein.168 They have elevated bradykinin levels,
and low prekallikrein and HK levels during attacks of
swelling.169171 The augmentation in complement activation seen at those times may be due to activation of
C1r and C1s by factor XIIf.172 The presence of kallikreinlike activity in induced blisters of patients with HAE
also supports this notion,173 as does the progressive
generation of bradykinin on incubation of HAE plasma
in plastic (noncontact-activated) tubes165,166 as well as
the presence of activated factor XII and cleaved HK levels seen during attacks.174 One unique family has been
described in which there is a point mutation in the C1
INH (A1a 443 Val) leading to an inability to inhibit
complement but normal inhibition of factor XIIa and
kallikrein.175,176 No family member of this type 2 mutation has had angioedema,175 although complement activation is present. In recent studies plasma bradykinin
levels have been shown to be elevated during attacks of
swelling in both hereditary and acquired C1 inhibitor
deficiency,169 and local bradykinin generation has been
documented at the sites of swelling.177 It is not known
whether bradykinin generation is predominantly seen
in the fluid phase, occurs along cell (endothelial) surfaces, or both. A rodent model of HAE demonstrated
that angioedema can be prevented by knockout of
the B-2 receptor.178 Figure 38-7 depicts a patient with
facial swelling due to HAE. Figure 38-8 is a diagram
depicting the steps in the bradykinin-forming cascade
that are inhibitable by C1 INH.
An estrogen-dependent form of hereditary angioedema has been recognized that is now designated type
3 HAE. One of the first reports involved a single family with seven affected individuals in three generations,
which suggests a hereditary (autosomal dominant) pattern.73 Clinical features include angioedema without
urticaria, laryngeal edema, and abdominal pain with
vomiting. Attacks occur during pregnancy and with
the administration of exogenous estrogen. Numerous
subsequent reports support these observations.179 In
one subgroup, there is a mutation in factor XII such that
the activated form (factor XIIa) is more potent than normal.180 These patients all have normal C4 and normal
C1 INH protein and function. Bradykinin is the likely
mediator; for those with a factor XII mutation, the active
enzyme may be less readily inhibited. Although uncommon, a male with the disorder has been described181 and
a bradykinin receptor antagonist (Icatibanit) has provided effective therapy for acute episodes.
ANGIOTENSIN-CONVERTING ENZYME INHIBI

TORS. Angioedema has been associated with the
administration of ACE inhibitors.182 The frequency of
Chapter 38
::
Figure 38-7 Hereditary angioedema. Extensive involvement (A) is to be contrasted with the patients normal facies (B).
angioedema occurring after ACE inhibitor therapy is

0.1%0.7%. There is a predilection to ACE inhibitor
reactions in the African-American population that
may relate to polymorphisms in the genes encoding
other enzymes that catabolize bradykinin such as
aminopeptidase P or neutral endopeptidase. Low levels of these would predispose to bradykinin accumulation. Angioedema develops during the first week of
therapy in up to 72% of affected individuals and usually involves the head and neck, including the mouth,
tongue, pharynx, and larynx. Urticaria occurs only
rarely. Cough and angioedema of the gastrointestinal
tract are associated features. It has been suggested
that therapy with ACE inhibitors is contraindicated
in patients with a prior history of idiopathic angioedema, HAE, and acquired C1 INH deficiency.183 It
Pathways for formation of bradykinin
Trace HFa or
trace activity in native HF
HF
HFa
Prekallikrein
surface
HMW-kininogen
HMW-kininogen
Kallikrein
HMW-kininogen
Bradykinin
Inhibited by C1 INH
HF
surface
HFa
HFf
Autodigestion
kallikrein
C1
C1
C4 and C2
digestion
Figure 38-8 Pathways for formation of bradykinin, indicating all steps inhibitable by C1 inhibitor as well as complement
activation by means of factor XIIf.
423
Section 6
::
appears that this swelling is also a consequence of

elevated levels of bradykinin;169 however, the accumulation of bradykinin is due to a defect in degradation rather than an excessive production. ACE, being
identical to kininase II, is the major enzyme responsible for bradykinin degradation (See eFig. 38-1.2 in
online edition) and although it is present in plasma,
the vascular endothelium of the lung appears to be
its major site of action.184 The action of ACE always
leads to the formation of degradation products with
no activity, whereas kininase I alone yields the desarg products, which are capable of stimulating B1
receptors.
The excessive accumulation of bradykinin implies
that production is ongoing, with activation of the
plasma cascade or release of tissue kallikrein faulty
inactivation of bradykinin then leads to swelling.
Continuous turnover of the plasma cascade is implied
by data demonstrating activation along the surface of
cells and cellular expression or secretion of a prekallikrein activator other than factor XIIa.185,186
URTICARIAL VENULITIS
Chronic urticaria and angioedema may be manifestations of cutaneous necrotizing venulitis, which is
known as urticarial venulitis (See Chapter 163).187,188
Associated features include fever, malaise, arthralgia,
abdominal pain, and less commonly conjunctivitis,
uveitis, diffuse glomerulonephritis, obstructive and
restrictive pulmonary disease, and benign intracranial hypertension. The term hypocomplementemic
urticarial vasculitis syndrome is used in patients with
more severe clinical manifestations of urticarial venulitis with hypocomplementemia and a low-molecularweight C1q-precipitin that has been identified as an
IgG autoantibody directed against the collagen-like
region of C1q.
SERUM SICKNESS
Serum sickness, which was defined originally as an
adverse reaction that resulted from the administration
of heterologous serum to humans, but may similarly
occur after the administration of drugs. Serum sickness occurs 721 days after the administration of the
offending agent and is manifested by fever, urticaria,
lymphadenopathy, myalgia, arthralgia, and arthritis.
Symptoms are usually self-limited and last 45 days.
More than 70% of patients with serum sickness experience urticaria that may be pruritic or painful. The initial manifestation of urticaria may appear at the site of
injection.189197
REACTIONS TO THE ADMINISTRATION

OF BLOOD PRODUCTS
424
Urticaria/angioedema may develop after the administration of blood products. It usually is the result of
immune complex formation and complement activa-
tion that leads to direct vascular and smooth muscle

alterations and indirectly, via anaphylatoxins, to mast
cell mediator release. Aggregated IgG may also be
responsible for human reactions to immunoglobulins
as evidenced by the fact that the administration of IgG
from which aggregates have been removed is not associated with urticaria or anaphylaxis.
An uncommon mechanism for the development of
urticaria after the administration of blood products is
the transfusion of IgE of donor origin directed toward
an antigen to which the recipient is subsequently
exposed. Another mechanism may be the transfusion
of a soluble antigen present in the donor preparation
into a previously sensitized recipient.
INFECTIONS
Episodes of acute urticaria can be associated with
upper respiratory tract viral infections, most commonly in children.198 The acute urticaria resolves
within 3 weeks. Hepatitis B virus infection has been
associated with episodes of urticaria lasting up to 1
week that are accompanied by fever and arthralgias as
part of the prodrome. The mechanism is analogous to
that seen in serum sickness-like reactions with virus
antibody immune complexes. The mechanism for
urticaria occasionally associated with infectious monomucleosis may be analogous.
URTICARIA/ANGIOEDEMA AFTER
DIRECT MAST CELL DEGRANULATION
Various therapeutic and diagnostic agents have been
associated with urticaria/angioedema. Up to 8% of
patients receiving radiographic contrast media experience such reactions, which occur most commonly
after intravenous administration. Decreased serum
alternative pathway complement protein levels and
increased serum histamine levels have been detected
in patients receiving radiocontrast media. Opiate
analgesics, polymyxin B, curare, and d-tubocurarine induce release of histamine from mast cells and
basophils.
URTICARIA/ANGIOEDEMA RELATING
TO ABNORMALITIES OF ARACHIDONIC
ACID METABOLISM
Intolerance to aspirin manifested as urticaria/angioedema occurs in otherwise normal individuals or in
patients with allergic rhinitis and/or bronchial asthma.
Urticaria/angioedema in response to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) occurred
in approximately 10%20% of individuals referred to
a hospital dermatology clinic in the United Kingdom.
Patients intolerant of aspirin also may react to indomethacin and to other NSAIDs.
Reactions to aspirin are shared with other NSAIDs
because they reflect inhibition of prostaglandin endoperoxide synthase 1 (PGHS-1, cyclooxygenase I)199 as
MISCELLANEOUS
MuckleWells syndrome consists of urticaria, amyloidosis, and nerve deafness and is due to the same gene
defect as is seen in familial cold urticaria.114 Schnitzler
syndrome is a chronic urticaria with histology resembling an urticarial vasculitis associated with fever,
joint pain, an IgM monoclonal protein, and osteosclerosis. An antibody to IL-1 has been shown to be
present.212

The evaluation of patients with urticaria/angioedema (Fig. 38-9) begins with a comprehensive history, with particular emphasis on the recognized
causes, and a physical examination. Some varieties
of urticaria may be identified by their characteristic
appearance, such as the small wheals with a large
erythematous flare of cholinergic urticaria, the linear wheals in dermographism, and the localization
of lesions to exposed areas in light- or cold-induced
urticaria. If suggested by the history, the physical
examination in all patients with urticaria should
include tests for physical urticaria, such as a brisk
stroke to elicit dermographism, the use of a weight to
elicit delayed pressure urticaria, and application of a
cold or warm stimulus for cold-induced urticaria and
localized heat urticaria, respectively. Exercise, such
as running in place, may elicit cholinergic urticaria
and, in some instances, exercise-induced anaphylaxis. Phototests to elicit solar urticaria usually are
performed in referral centers, as are challenges for
exercise-induced anaphylaxis.
When urticaria has been present for days or weeks
at a time (but less than 6 weeks) or occurs recurrently
for similar intervals, the main considerations are allergic reactions (IgE mediated) to food or drugs. A careful history regarding possibilities is essential. Skin
testing can corroborate IgE-mediated hypersensitivity
to foods or can provide suspects when the history is
unrevealing. Double-blind placebo-controlled food
challenge can demonstrate clinical relevance in cases
in which the role of a food is uncertain. Non-IgEmediated causes of urticaria include adverse reactions
to NSAIDs and opiates. Any of these can be associated with concomitant angioedema or, less commonly,
present as angioedema in the absence of urticaria.
Children may have acute urticaria in association with
viral illnesses; it is unclear whether infection with bacteria such as Streptococcus can induce urticaria as well,
but neither form occurs in adults with the exception of
urticaria in association with infectious mononucleosis
(EpsteinBarr virus) or as a prodrome to hepatitis B
Because the clinical entities of chronic idiopathic

urticaria (with or without angioedema) and idiopathic angioedema are frequently encountered, have
a capricious course, and are recognized easily, they
are frequently associated with concomitant events.
Such attributions must be interpreted with caution.
Although infections, food allergies, adverse reactions
to food additives, metabolic and hormonal abnormalities, malignant conditions, and emotional factors
have been claimed as causes, proof of their etiologic
relationship often is lacking. Among the recent considerations is chronic urticaria as a consequence of
infection with Helicobacter pylori. Articles both supporting203205 and denying206209 a relationship are numerous
and a definite answer is not available. However, the
H. pylori infection rate in the population at large is far
greater than the incidence of chronic urticaria and in
the opinion of this author, the association is spurious.
The controversy has been put in perspective by M.
Greaves.210 Idiopathic angioedema is diagnosed when
angioedema is recurrent, when urticaria is absent, and
when no exogenous agent or underlying abnormality
is identifiable. An extensive review of angioedema has
been recently published.184
Cyclic episodic angioedema has been associated
with fever, weight gain, absence of internal organ
damage, a benign course, and peripheral blood eosinophilia.211 Biopsy specimens of tissues show eosinophils,
eosinophil granule proteins, and CD4 lymphocytes
exhibiting HLA-OR. Blood levels of IL-1, soluble IL-2
receptor, and IL-5 are elevated.
Idiopathic angioedema is characterized by recurrent
episodes of angioedema in the absence of any urticaria,
which may include the face (lips, tongue, periorbital
region, pharynx), extremities, and genitalia, but is not
associated with laryngeal edema or massive tongue/
pharyngeal swelling that yield airway obstruction. It
may not be a continuum with chronic urticaria with or
without concomitant angioedema, as is often considered, because the incidence in men and women is about
::
CHRONIC IDIOPATHIC URTICARIA

AND IDIOPATHIC ANGIOEDEMA
the same and the presence of antithyroid antibodies or

anti-IgE receptor antibodies is far less. Extreme cases,
particularly if associated with laryngeal edema, could
represent type 3 HAE in a patient with a new mutation (i.e., no family history) or a variant of idiopathic
anaphylaxis.
Chapter 38
well as inhibition of the inducible PGHS-2 (cyclooxygenase 2). Sodium salicylate and choline salicylate
generally are well tolerated because of their weak
activity against PGHS-1. PGHS-2 inhibitors are generally well tolerated in those with NSAID-induced
urticaria.200,201 Reactions to NSAIDs increase the levels of cysteinyl leukotrienes,202 which may relate to
the appearance of urticaria, although their role in
NSAID-induced asthma is better characterized. Prick
skin tests are of no diagnostic value, passive transfer
reactions are negative, and neither IgG nor IgE antibodies have been associated with clinical disease. The
clinical manifestations elicited by aspirin challenge
of aspirin-intolerant patients are blocked when such
patients are protected with a cysteinyl leucotriene
receptor blocker or biosynthetic inhibitor; this finding confirms a pathobiologic role for the cysteinyl
leukotrienes.
425
Approach to patient with urticaria/angioedema

History:
Recurrent transient hives or swelling
30 min. to 2 hrs.
Section 6
History physical
stimulus
Physical
challenge
::
426
Physical urticaria
Clinical Appearance:
wheals, angioedema
Wheals + angioedema
Angioedema only
Duration of individual hive
Drugs, ACE inhibitor,

other family history
4 hrs. to 36 hrs.
Course < 6 weeks
Course > 6 weeks
Consider drugs,
foods, food skin
testing, infection
(particularly in
children), other
identifiable
stimulus
Thyroid function
tests, anti microsomal antibody,
anti thyroglobulin
antibody, autologous skin test,
in vitro anti IgE
receptor
Acute urticaria/
angioedema
24-48 hrs with either bruising,

severe arthralgia, fever, _ C4
Chronic
autoimmune
urticaria
C4 level
C1 inhibitor by
protein and function
Skin biopsy
Idiopathic
angioedema
Normal
C1Q
Chronic
idiopathic
urticaria
Urticarial
vasculitis
Hereditary angioedema
C1 INH protein and
function abnormal
Type I
C1 INH protein normal
or elevated, function
abnormal Type II
Acquired C1 INH
deficiency , depressed
C1Q level
Search for lymphoma,

connective tissue
disease, Type I
Anti C1 INH,
Type II
Overlap
situation
Figure 38-9 Approach to the patient with urticaria/angioedema. ACE = angiotensin-converting enzyme; IgE, immunoglobulin E; INH = inhibitor; = decreased.
infection. In each of these circumstances, individual

lesions last anywhere from 4 hours to 24 hours and
fade without associated purpura. If hives last less
than 2 hours, the cause is usually physical urticaria,
the most common being dermatographism, cholinergic urticaria, and cold urticaria. The main exception is
delayed pressure urticaria, in which lesions typically
last 1236 hours and first appear 36 hours after the
initiating stimuli. Once urticaria continues for longer
than 6 weeks (particularly if present for many months
or years) chronic urticaria is present. The term chronic
spontaneous urticaria has been employed recently to
eliminate confusion with physical urticarias. Chronic
urticaria is now divided into chronic idiopathic urticaria for which a cause has not yet been found and
chronic autoimmune urticaria. Angioedema accompanies chronic urticaria in 40% of cases and is more
problematic in the autoimmune subgroup. Swelling
in association with chronic urticaria can affect hands,
feet, eyes, cheeks, lips, tongue, and pharynx, but not

the larynx. When angioedema is present in the absence
of an identifiable antigen or exogenous stimulus,
the main entities to consider are C1 INH deficiency
(hereditary or acquired) and idiopathic angioedema.
Approximately 0.5% of patients have an urticarial
vasculitis with palpable purpura or other stigmata
of a possible vasculitis, such as fever, elevated sedimentation rate, petechiae or purpura, elevated white
blood cell count, or lesions of unusual duration (3672
hours). The differential diagnosis of acute, chronic,
and physical urticaria/angioedema is summarized in
Box 38-1.
LABORATORY FINDINGS
In most patients with chronic urticaria/angioedema,
no underlying disorders or causes can be discerned.
Box 38-1 Differential Diagnosis of Urticaria/Angioedema

ACUTE (<6 WEEK)
CHRONIC (>6 WEEK)
indicated, unavailable, or unrevealing despite a highly

suspected history.
A finding of the release of histamine from peripheral
basophilic leukocytes has supported the diagnosis of
anaphylactic sensitivity to a variety of antigens, which
include pollens and insect venom.
Diagnostic studies should be based on findings elicited

by the history and physical examination. Evaluation of
chronic urticaria/angioedema should include thyroid
function tests, assays for antimicrosomal and antithyroglobulin antibodies, and the autologous skin test can
be done, even in an office setting.213 Routine screening
laboratory tests are of little value. The histamine release
assay for anti-IgE receptor or anti-IgE antibodies are
now available in specialized laboratories. Serum hypocomplementemia is not present in chronic idiopathic
urticaria or chronic autoimmune urticaria and mean
levels of serum IgE in these patients are not different
from the general population in which the incidence of
atopy is 20%.
Cryoproteins should be sought in patients with
acquired cold urticaria. An antinuclear antibody test
should be obtained in patients with solar urticaria.
Assessment of serum complement proteins may be
helpful in identifying patients with urticarial venulitis or serum sickness (C4-, C3-, C1q-binding assay
for circulatory immune complexes), as well as those
with hereditary and acquired forms of C1 INH deficiency (C4, C1 INH by protein and function, C1q
level).
Skin biopsy of chronic urticarial lesions should be
undertaken to identify urticarial venulitis or to assess
rashes where the urticarial nature is not clear.
There is little role for routine prick skin testing or
the radioallergosorbent test in the diagnosis of specific
IgE-mediated antigen sensitivity in chronic urticaria/
angioedema. Inhalant materials are uncommon causes
of urticaria/angioedema, and food skin tests may be
difficult to interpret. The tests for drugs are limited to
penicillin but cannot be performed in patients with
dermographism. The radioallergosorbent test should
be reserved for those in whom skin testing is contra-
Autoimmune, often with antithyroid antibodies

Idiopathic
Urticarial vasculitis
Idiopathicskin only
Associated with other connective tissue disease
Familial febrile syndromes with
urticaria-like rash
Schnitzlers syndrome
::
Individual lesions last <2 hours

Cold urticaria
Cholinergic urticaria
Dermatographism
Local heat urticaria
Aquagenic urticaria
Cold-induced cholinergic
urticaria
Cold-dependent dermatographism
Lesions last >2 hours
Delayed pressure urticaria
Vibratory angioedema
Familial cold-induced
syndromes, usually with
fever
Chapter 38
Drug reaction
Immunoglobulin E (IgE)
mediated
Metabolicidiosyncratic
Cellular immunity
Food reactions
IgE mediated
Non-IgE mediated (e.g., scombroid poisoning)
Intravenous administration
Blood products
Contrast agents
Intravenous globulin
Infection
Viral in children
Infectious mononucleosis or
hepatitis B prodrome
? Bacterial in children
PHYSICAL
HISTOPATHOLOGY
Edema involving the superficial portion of the dermis is characteristic of urticaria, whereas angioedema
involves the deeper dermis and subcutaneous tissue.
Both disorders are associated with dilatation of the
venules.
In chronic urticaria, the dermal infiltrating inflammatory cells may be sparse or dense and include more
CD4 than CD8 T lymphocytes, neutrophils, eosinophils, and basophils46,214 without B lymphocytes or
natural killer (NK) cells. NKT cells have not been
assessed. Increased expression of TNF- and IL-3 on
endothelial cells and perivascular cells was detected
in the upper dermis of patients with acute urticaria,
chronic idiopathic urticaria, and delayed-pressure
urticaria and in one patient with cold urticaria.215
TNF- also was detected on epidermal keratinocytes in lesional and nonlesional biopsy specimens.
In chronic idiopathic urticaria, CD11b and CD18 cells
were detected about the blood vessels in the superficial and deep dermis. Direct immunofluorescence
tests for immunoglobulins and complement proteins
were negative.
Major basic protein and eosinophil cationic protein, which are derived from the eosinophils granule,
are present around blood vessels and are dispersed
in the dermis in lesions of acute urticaria, chronic
427
Section 6
::
428
idiopathic urticaria, delayed-pressure urticaria,

cholinergic urticaria, and solar urticaria. In chronic
idiopathic urticaria, free eosinophil granules in the
dermis were increased in wheals of greater than 24
hours duration as compared with wheals lasting
fewer than 24 hours. The secreted form of eosinophil
cationic protein and eosinophil-derived neurotoxin
were detected on cells in greater amounts in biopsy
specimens from patients with chronic urticaria without autoantibodies than in those with autoantibodies. P-selectin, E-selectin, intercellular adhesion
molecules 1, and vascular cellular adhesion molecule
1 have been demonstrated on the vascular endothelium of patients with chronic idiopathic urticaria and
dermographism. Major histocompatability complex
class II antigen also is upregulated on the endothelial cells of patients with chronic urticaria, and the
peripheral blood lymphocytes have increased CD40
ligand expression and higher Bcl-2 expression; these
observations suggest an augmentation of autoimmune phenomena.216
In papular urticaria, the epidermis is thick with
intercellular edema and lymphocytes. In the dermis,
there is edema with an infiltrate containing T lymphocytes, macrophages, eosinophils, and neutrophils
without B lymphocytes or the deposition of immunoglobulins, fibrin and C3.
TREATMENT
Therapy of acute urticaria uses antihistamines as
described in Fig. 38-10; however, the rash can be severe
and generalized, and angioedema may be present as well.
Thus, if relief provided by nonsedating antihistamines
appears insufficient, one can try hydroxyzine or diphenhydramine at 2550 mg qid.217 Alternatively nonsedating
antihistamines can be tried employing up to 46 tablets/
day as has been reported for treatment of cold urticaria.92
A course of corticosteroid can be used, for example,
4060 mg/day for 3 days and taper by 510 mg/day.
Epinephrine can relieve severe symptoms of urticaria or
angioedema (generalized urticaria, severe pruritus, accelerating angioedema) and is indicated if laryngeal edema
is present. Edema of the posterior tongue and/or pharyngeal edema can be confused with it.
The ideal treatment for urticaria/angioedema is
identification and removal of its cause. Many patients
with acute urticaria and angioedema probably are not
treated by physicians because the cause is identified
by the individual or the course is limited. Treatment
of chronic urticaria focuses on measures that provide
symptomatic relief. The physician should provide not
only medications but also support and reassurance.
In a questionnaire study, patients with chronic idiopathic urticaria considered the worst aspects to be
pruritus and the unpredictable nature of the attacks.
The presence of facial angioedema can be particularly disconcerting and tongue and/or pharyngeal
edema is often considered life threatening. This is
not the case and is confused with the potential for
laryngeal edema seen with anaphylaxis, or anaphy-
lactic-like reactions, C1 INH deficiency, or reactivity to ACE inhibitors. Affected individuals reported
sleep disturbances, diminished energy, social isolation, and altered emotional reactions as well as difficulties in relation to work, home activities, social life,
and sex life.218,219 Another study showed a correlation
between the severity of chronic idiopathic urticaria
and depression. In a questionnaire study, individuals with delayed pressure urticaria and cholinergic
urticaria had the most quality-of-life impairment.220
Those with cholinergic urticaria suffered in relation
to their sporting activities and sexual relationships.
Although urticaria/angioedema may be a source
of frustration to both physicians and patients, most
individuals can achieve acceptable symptomatic
control of their disease without identification of the
cause. In some individuals, it is important to avoid
aspirin and other NSAIDs. Antipruritic lotions, cool
compresses, and ice packs may provide temporary
relief. H1-type antihistaminic drugs are the mainstays
in the management of urticaria/angioedema. The
older H1-type antihistaminics are known as classic,
traditional, or first generation H1-type antihistamines.
Newer, low-sedating, or second- and third-generation H1-type antihistamines with reduced sedative
and anticholinergic side effects have become the
initial therapeutic agents of choice. The drug should
be taken on a regular basis and not as needed. If the
initial drug chosen is ineffective, an agent from a
different pharmacological class should be used and
nonsedating antihistaminics can be combined or the
dose of any one of them increased. When this is ineffective, doses of hydroxyzine or diphenhydramine
in the 2550 mg qid may be tried. The same is true
for the treatment of dermatographism when it is particularly severe. It should be noted that if the molar
release of histamine in the skin exceeds that of the
delivered antihistamine (as can be seen with dermatographism), the histamine will keep the receptors
to which it is bound in the active conformation, and
therapeutic efficacy with the antihistamine will be
achieved only when its molar concentration is much
greater than that of histamine. Diphenhydramine is
an alternative to hydroxyzine or cetirizine for dermatographism but not for cholinergic urticaria.221,222
Cold urticaria can be treated with most antihistaminics but cyproheptadine at 48 mg tid or qid seems
to be particularly effective.223226 Excellent results
have been recently reported with desloratadine at
four times/day.92 Local heat urticaria is treated with
antihistaminics; no regimen is particularly favored.
Although anecdotal reports suggest that delayed
pressure urticaria will respond to NSAIDs, dapsone, cetirizine, or sulfasalazine, most require corticosteroids (used as in chronic urticaria) to control
symptoms and cyclosporine can be a particularly
effective alternative. Familial cold autoinflammatory
syndrome (urticaria) responds to parenteral IL-1
receptor antagonist (anakinra) as does some cases of
Schnitzler syndrome.
Treatment choices for chronic urticaria (idiopathic
or autoimmune) have been reviewed227 and are
Chapter 38
::
Figure 38-10 Treatment of chronic idiopathic or autoimmune urticaria/angioedema. Note that the following agents are
expected to be effective rarely, if ever: hydroxychloroquine, colchicine, dapsone, sulfasalazine, mycophenolate mofetil.
Hydroxychloroquine is, however, the drug of choice for the hypocomplementemic urticarial vasculitis syndrome. Urticarial
vasculitis may respond to dapsone or colchicine. Omalizumab (IgG anti IgE monoclonal antibody), not yet approved for
treatment of chronic spontaneously occurring urticaria and angioedema is as effective as cyclosporine with far less toxicity and when available, will be a major therapeutic advance.
summarized in Fig. 38-10. It is important to use first-generation antihistamines at a maximal dose if nonsedating
antihistamines have not been helpful before resorting to
corticosteroids or cyclosporine. H2-receptor antagonists
may yield some additional histamine receptor blockade, although their contribution is usually modest.
The efficacy of leucotriene antagonists is controversial,
with equal numbers of pro and con articles. If steroids
are used, this author recommends not exceeding 25 mg
q.o.d. or 10 mg daily. With either approach, attempts to
slowly taper the dose should be made every 23 weeks.
One mg prednisone tablets can be very helpful when
the daily dose is less than 10 mg. Double-blind placebocontrolled studies of cyclosporine indicate that it is a
good alternative to corticosteroid,228,229 and can be safer
when used appropriately. Measurement of blood pres-
sure, blood urea nitrogen level, and creatinine level, and

a urinalysis should be done every 68 weeks. The starting adult dose is 100 mg bid; it can be slowly advanced
to 100 mg tid, but not higher. The response rate is 75%
in the autoimmune groups and 50% in the idiopathic
group. No comparable studies (or clinical effects) have
been obtained with dapsone, hydroxychloroquine, colchicine, sulfasalazine, or methotrexate and only small
numbers cases have been treated successfully with
intravenous globulin or plasmapheresis.230,231 Successful treatment of chronic autoimmune urticaria has been
reported with Omalizumab232 with results comparable
to that seen with cyclosporine. The rate of response can
be very striking, for example, remission with a single
dose. Additional articles have appeared,233,234 although
uncontrolled.
429
Section 6
::
430
Urticarial vasculitis is treated with antihistamines

and if severe, with low-dose corticosteroid. Here dapsone or hydroxychloroquine may be steroid sparing.
When urticarial vasculitis is part of a systemic disease,
the treatment will focus on what is needed for the
underlying disorders. The drug of choice for the hypocomplementemic urticarial vasculitis syndrome (with
circulating immune complexes due to IgG anti-C1q)195
is hydroxychloroquine.235
Angioedema caused by ACE inhibitors can be an
acute emergency with laryngeal edema or tongue
or pharyngeal edema that is so extensive the patient
cannot manage secretions and intubation is necessary. Supportive therapy, epinephrine, and time are
needed; there is no response to antihistamines or
corticosteroids. Other antihypertensive agents can be
substituted, including those that block angiotensin II
receptors.
Acute attacks of HAE are unresponsive to antihistaminics or corticosteroid. Epinephrine may be given but
a positive response is actually uncommon. Intubation
or tracheostomy may be needed when severe laryngeal
edema is encountered. Recently, a preparation of C1
INH (Berinert) has been approved in the United States
for intravenous infusion to treat acute attacks of HAE.
It is effective and has been available and employed in
Europe and Brazil for over two decades. Icatibant,236 a
bradykinin B-2 receptor antagonist, has been approved
for acute treatment in Europe but not in the United
States. It is given by subcutaneous injection. Kalbitor,
a plasma kallikrein inhibitor (ecallantide), has been
approved for the treatment of acute attacks of HAE in
the United States. It too is administered by subcutaneous injection.237 In the past, fresh frozen plasma was
an option. It has been used with excellent success for
years, but occasional dramatic worsening of symptoms has been reported because all the plasma factors needed for bradykinin generation are also being
infused.
A second C1 INH nanofiltered preparation (Cinryze)
has been approved in the United States for prophylactic
treatment of AHE types I and II. It is administered by
intravenous injection up to twice weekly. Prophylaxis
with androgens such as Danazol (200 mg tablets) or
Stanazolol (2 mg tablets)238,239 or antifibrinolytics such
as E-aminocaprioc acid or tranexamic acid240 have been
employed (used) successfully for many years.241,242 The
androgens are more commonly usedone watches
for hirsutisum, irregular menses, and abnormal liver
chemistries, as potential side effects. In the long term,
hepatic adenomas may appear. Increased dosages may
be used when a patient undergoes elective surgical
procedures (e.g., 3 tablets/day for 23 days before the
procedure, the day of the procedure, and 1 day after).
Fresh frozen plasma is a safe alternative given a few

hours prior to the procedure and clearly C1 INH concentrate can be used. Acquired C1 INH deficiency can
be treated with low-dose androgens in addition to
therapy for the underlying condition. C1 INH concentrate may be helpful but the presence of anti-C1 INH
will limit responsiveness to reasonable doses. Plasmapheresis and/or cytotoxic agents may be used.
ACKNOWLEDGMENT
I wish to thank Dr Nicholas Soter who reviewed this
manuscript, made many helpful suggestions, and contributed two of the photos.
KEY REFERENCES
6. Gorevic P, Kaplan A: The physical urticarias. Int J Dermatol 19:417, 1980
13. Gruber B et al: Prevalence and functional role of anti-IgE
autoantibodies in urticarial syndromes. J Invest Dermatol
90:213, 1988
15. Grattan C et al: A serological mediator in chronic idiopathic urticariaA clinical, immunological and histological evaluation. Br J Dermatol 114:583, 1986
35. Kikuchi Y, Kaplan A: A role for C5a in augmenting IgGdependent histamine release from basophils in chronic
urticaria. J Allergy Clin Immunol 109:114, 2002
41. Sabroe R et al: Cutaneous inflammatory cell infiltrate in
chronic idiopathic urticaria: Comparison of patients with
and without anti-FcepsilonRI or anti-IgE autoantibodies.
J Allergy Clin Immunol 103:484, 1999
60. Kaplan AP, Joseph K, Silverberg M: Pathways for bradykinin formation and inflammatory disease. J Allergy Clin
Immunol 109:195, 2002
166. Fields T, Ghebrehiwet B, Kaplan AP: Kinin formation in
hereditary angioedema plasma: Evidence against kinin
derivation from C2 and in support of spontaneous formation of bradykinin. J Allergy Clin Immunol 72:54, 1983
183. Kaplan A, Greaves M: Angioedema. J Am Acad Dermatol
53:373, 2005
210. Greaves M: Chronic idiopathic urticaria and Helicobacter pyloriNot directly causative but could there be a
link. Allergy Clin Immunol Int 13:23, 2001
213. Sabroe R et al: The autologous serum skin test: A screening test for autoantibodies in chronic idiopathic urticaria.
222. Zuberbier T et al: Double-blind crossover study of highdose cetirizine in cholinergic urticaria. Dermatology
193:324, 1996
227. Kaplan A: Clinical practice. Chronic urticaria and angioedema. N Engl J Med 346:175, 2002
232. Kaplan A et al: Treatment of chronic autoimmune urticaria with omalizumab. J Allergy Clin Immunol 122:569,
2008
Chapter 39 :: Erythema Multiforme

:: Jean-Claude Roujeau
ERYTHEMA MULTIFORME
AT A GLANCE
Rare cutaneous and/or mucocutaneous
eruption characterized by target lesions.
Benign course but frequent recurrences.
Erythema Multiforme
Erythema multiforme (EM) is an acute self-limited,

usually mild, and often relapsing mucocutaneous
syndrome. The disease is usually related to an acute
infection, most often a recurrent herpes simplex virus
(HSV) infection. EM is defined only by its clinical
characteristics: target-shaped plaques with or without central blisters, predominant on the face and
extremities.
The absence of specific pathology, unique cause, and
biologic markers has contributed to a confusing nosology. Recent medical literature still contains an overwhelming number of figurate erythema reported as EM,
and the International Classification of Diseases (ICD9)
still classifies StevensJohnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) under the heading of EM.
The definition of EM in this chapter is based on the
classification proposed by Bastuji-Garin et al.1 The
principle of this classification is to consider SJS and
TEN as severity variants of the same process, i.e., epidermal necrolysis (EN), and to separate them from
EM (see Chapter 40). The validity of this classification
has been challenged by some reports, especially for
cases in children and cases related to Mycoplasma pneumoniae. It has been confirmed by several others studies however, especially the prospective international
Severe Cutaneous Adverse Reactions study.2 That
study demonstrated that, compared with SJS and TEN,
EM cases had different demographic features, clinical
presentation, severity, and causes.
The original name proposed by von Hebra was erythema exudativum multiforme. The term erythema multiforme has now been universally accepted (Box 39-1).
EM is usually called minor when mucous membranes are spared or minimally affected, for example,
lips, and majus (or major) when at least two mucosal
sites are involved.
EM is considered relatively common, but its true incidence is unknown because largely cases severe enough
to require hospitalization have been reported. Such
cases are in the range of 1 to 6 per million per year.
Even though the minor form of EM is frequent than the
major form, many other eruptions (including annular
urticaria and serum sickness-like eruption) are erroneously called EM.3
EM occurs in patients of all ages, but mostly in adolescents and young adults. There is a slight male preponderance (malefemale sex ratio of approximately
3:2). EM is recurrent in at least 30% of patients.
No established underlying disease increases the
risk of EM. Infection with human immunodeficiency
virus and collagen vascular disorders do not increase
the risk of EM, in contrast to their increasing the risk
of epidermal necrolysis. Cases may occur in clusters,
which suggests a role for infectious agents. There is no
indication that the incidence may vary with ethnicity
or geographic location.
Predisposing genes have been reported, with 66% of
EM patients having HLA-DQB1*0301 allele, compared
with 31% of controls.4 The association is even stronger
in patients with herpes-associated EM. Nevertheless,
the association is relatively weak, and familial cases
remain rare.
::
Frequent recurrences can be prevented by

long-term use of anti-HSV medications.
Thalidomide is usually effective in
recalcitrant recurrent cases.
EPIDEMIOLOGY
Chapter 39
Most cases related to herpes simplex

virus (HSV) infection. Medications are not
frequent causes.
ETIOLOGY
Most cases of EM are related to infections. Herpes
virus is definitely the most common cause, principally
in recurrent cases. Proof of causality of herpes is firmly
established from clinical experience, epidemiology,2
detection of HSV DNA in the lesions of EM,5,6 and prevention of EM by suppression of HSV recurrences.7
Clinically, a link with herpes can be established in about
one-half of cases. In addition 10% to 40% of cases without clinical suspicion of herpes have also been shown
to be herpes related, because HSV DNA was detected
BOX 39-1 Erythema Multiforme

Subtypes
Erythema multiforme minor: Skin lesions without
involvement of mucous membranes
Erythema multiforme major: Skin lesions with
involvement of mucous membranes
Herpes-associated erythema multiforme
Mucosal erythema multiforme (Fuchs syndrome,
ectodermosis pluriorificialis): Mucous membrane
lesions without cutaneous involvement
431
Section 6
::
in the EM lesions by polymerase chain reaction (PCR)

testing.6 EM eruptions begin on average 7 days after
a recurrence of herpes. The delay can be substantially
shorter. Not all symptomatic herpes recurrences are
followed by EM, and asymptomatic ones can induce
EM. Therefore, this causality link can be overlooked
by both patients and physicians. HSV-1 is usually the
cause, but HSV-2 can also induce EM. The proportion
probably reflects the prevalence of infection by HSV
subtypes in the population.
M. pneumoniae is the second major cause of EM and
may even be the first one in pediatric cases.810 In cases
related to M. pneumoniae, the clinical presentation is often
less typical and more severe than in cases associated
with HSV. The relationship to M. pneumoniae is often difficult to establish. Clinical and radiologic signs of atypical pneumonia can be mild, and M. pneumoniae is usually
not directly detected. PCR testing of throat swabs is the
most sensitive technique. Serologic results are considered diagnostic in the presence of immunoglobulin (Ig)
M antibodies or a more than twofold increase in IgG
antibodies to M. pneumoniae in samples obtained after 2
or 3 weeks. M. pneumoniae-related EM can recur.11
Many other infections have been reported to be
causes of EM in individual cases or small series, but the
evidence for causality of these other agents is only circumstantial. Published reports have implicated infection with orf virus, varicella zoster virus, parvovirus
B19, and hepatitis B and C viruses, as well as infectious
mononucleosis and a variety of other bacterial or viral
infections. Immunization has been also implicated as a
cause in children.
Drugs are a rare cause of EM with mucous membrane lesions. Most literature reports of drug-associated EM actually deal with imitators, for example,
annular urticaria12 or maculopapular eruption with
some lesions resembling targets. EM-like dermatitis
may result from contact sensitization. These eruptions
should be viewed as imitators of EM, despite some
clinical and histopathologic similarities.
Idiopathic cases are those in which neither HSV
infection nor any other cause can be identified. Such
cases are fairly common under routine circumstances.
However, HSV has been found in situ by PCR in up to
40% of idiopathic recurrent cases.9 Some such cases
respond to prophylactic antiviral treatment and are
thus likely to have been triggered by asymptomatic
HSV infection; others are resistant.
PATHOGENESIS
432
The underlying mechanisms have been extensively

investigated for herpes-associated EM.13 It is unknown
whether similar mechanisms apply to EM due to other
causes.
Complete infective HSV has never been isolated
from lesions of herpes-associated EM. The presence
of HSV DNA in EM lesions has been reported in
numerous studies using the PCR assay. These studies
have demonstrated that keratinocytes do not contain
complete viral DNA, but only fragments that always
include the viral polymerase (Pol) gene. HSV Pol DNA
is located in basal keratinocytes and in lower spinous

cell layers, and viral Pol protein is synthesized. HSVspecific T cells, including cytotoxic cells, are recruited,
and the virus-specific response is followed by a nonspecific inflammatory amplification by autoreactive
T cells. The cytokines produced in these cells induce
the delayed hypersensitivity-like appearance in histopathologic evaluation of biopsy sections of EM lesions.
HSV is present in the blood for a few days during an
overt recurrence of herpes. If keratinocytes are infected
from circulation virus, one would expect disseminated
herpes, rather than EM. In fact, HSV DNA is transported to the epidermis by immune cells that engulf
the virus and fragment the DNA. These cells are monocytes, macrophages, and especially CD34+ Langerhans
cell precursors harboring the skin-homing receptor cutaneous lymphocyte-associated (CLA) marker.
Upregulation of adhesion molecules greatly increases
binding of HSV-containing mononuclear cells to endothelial cells and contribute to the dermal inflammatory
response. When reaching the epidermis the cells transmit the viral Pol gene to keratinocytes. Viral genes may
persist for a few months, but the synthesis and expression of the Pol protein will last for only a few days. This
may explain the transient character of clinical lesions
that are likely induced by a specific immune response
to Pol protein and amplified by autoreactive cells. To
the best of current knowledge, the mechanisms and
regulation of this immune response are different from
drug reactivity leading to SJS or TEN.14,15
Incomplete fragmentation of viral DNA, increased
number of circulating CD34+ cells, and/or increased
immune response to Pol protein may explain why only
a small proportion of individuals with recurrent herpes infections develop EM.
CLINICAL FINDINGS
The first step is to suspect EM, based on clinical features. A skin biopsy and laboratory investigations are
useful mainly if the diagnosis is not definite clinically.
The second step is to determine whether hospitalization is needed when EM major (EMM) occurs with oral
lesions severe enough to impair feeding, when a diagnosis of SJS is suspected, or when severe constitutional
symptoms are present. The third step is to establish the
cause of EM by identifying a history of recurrent herpes, performing chest radiography, or documenting M.
pneumoniae infection (Fig. 39-1).
HISTORY
Prodromal symptoms are absent in most cases. If present, they are usually mild, suggesting an upper respiratory infection (e.g., cough, rhinitis, low-grade fever). In
EMM, fever higher than 38.5C (101.3F) is present in
one-third of cases.2 A history of prior attack(s) is found
in at least one-third of patients and thus helps with the
diagnosis. The events of the preceding 3 weeks should
be reviewed for clinical evidence of any precipitating
agent, with a special focus on recurrent herpes.
Approach to the patient with erythema multiforme (EM)
Pro:
Typical papules with target features
Acral distribution
Mucous membrane erosions
Previous episodes
Is it EM?
YES
Is hospitalization needed?
Biopsy
Direct IF
Serum antibodies
NO
NO
Urticaria
ADR with some EM-like features
Autoimmune blisters
SJS
::
What is the cause?
Cough,
URT infection
Other patient
infection, e.g., orf
HAEM
MP-related EM
Post-infection EM
Positive
No clue
Herpes serology
Negative
Frequent recurrences
Acyclovir
prophylaxis
Erythema Multiforme
History of
recurrent herpes
Possible
HAEM
Chapter 39
YES
MAYBE
Con:
Transient lesions
Widespread erythema
Macules and blisters, flat targets
Subacute evolution
Idiopathic EM
Frequent recurrences
Azathioprine
thalidomide
Figure 39-1 Approach to the patient with erythema multiforme (EM). ADR = adverse drug reaction; HAEM = herpesassociated erythema multiforme; IF = immunofluorescence; MP = Mycoplasma pneumoniae; SJS = StevensJohnson syndrome; URT = upper respiratory tract.
CUTANEOUS LESIONS
The skin eruption arises abruptly. In most patients,
all lesions appear within 3 days, but in some, several
crops follow each other during a single episode of EM.
Often there are a limited number of lesions, but up to
hundreds may form. Most occur in a symmetric, acral
distribution on the extensor surfaces of the extremities
(hands and feet, elbows, and knees), face, and neck,
and less frequently on the thighs, buttocks, and trunk.
Lesions often first appear acrally and then spread in
a centripetal manner. Mechanical factors (Koebner
phenomenon) and actinic factors (predilection of sunexposed sites) appear to influence the distribution of
lesions. Although patients occasionally report burning and itching, the eruption is usually asymptomatic.
The diversity in clinical pattern implied by the
name multiforme is mainly due to the findings in each
single lesion; most lesions are usually rather similar

in a given patient at a given time. The typical lesion
is a highly regular, circular, wheal-like erythematous
papule or plaque that persists for 1 week or longer
(Fig. 39-2). It measures from a few millimeters to
approximately 3 cm and may expand slightly over
24 to 48 hours. Although the periphery remains erythematous and edematous, the center becomes violaceous and dark; inflammatory activity may regress
or relapse in the center, which gives rise to concentric
rings of color (see Fig. 39-2). Often, the center turns
purpuric and/or necrotic or transforms into a tense
vesicle or bulla. The result is the classic target or iris
lesion.
According to the proposed classification, typical target lesions consist of at least three concentric
components: (1) a dusky central disk, or blister; (2)
more peripherally, an infiltrated pale ring; and (3) an
433
Section 6
::
434
Figure 39-2 Mixture of typical targets and papules in a case

of EM minor
erythematous halo. Not all lesions of EM are typical; some display two rings only (raised atypical
targets). However, all are papular, in contrast with
macules, which are the typical lesions in epidermal
necrolysis (SJSTEN). In some patients with EM, most
lesions are livid vesicles overlying a just slightly darker
central portion, encircled by an erythematous margin
(Figs. 39-339-5, Fig. 39-8). Larger lesions may have a
central bulla and a marginal ring of vesicles (herpes
iris of Bateman) (Figs. 39-6 and 39-7).
Unusual presentations include cases in which recurrent EM in the same patient produces typical target
lesions in one instance but plaques in a subsequent
event. Mucous membranes can be severely involved
in some episodes and spared in others (see section
Mucous Membrane Lesions).
Figure 39-3 Typical target lesions on the palm.
Figure 39-4 Late lesions of EM with nonspecific blisters

and erosions but target shapes still visible.
In most cases, EM affects well under 10% of the body
surface area. In 88 hospital cases of EMM prospectively
included in the Severe Cutaneous Adverse Reactions
study, the median involvement was 1% of the body surface area.2 Very rare instances of extensive skin lesions
with giant targets and prominent involvement of several mucous sites may be difficult to distinguish from SJS.
The duration of an individual lesion is shorter than
2 weeks, but residual discoloration may remain for
months. There is no scarring.
MUCOUS MEMBRANE LESIONS

Mucosal lesions are present in up to 70% of patients,
most often limited to the oral cavity.
Figure 39-5 Typical targets around the knee.
Chapter 39
::
Figure 39-8 Unusual location of EM.
Erythema Multiforme
Figure 39-6 Gianttargets in a case of recurrent EMM associated to recurrent Mycoplasma pneumoniae infection.
Predilection sites for mucosal lesions are the lips (eFig.

39-7.1 in online edition), on both cutaneous and mucosal sides, nonattached gingivae, and the ventral side of
the tongue. The hard palate is usually spared, as are the
attached gingivae. On the cutaneous part of the lips, identifiable target lesions may be discernible (see Fig. 39-9).
On the mucosa proper there are erosions with fibrinous
deposits, and occasionally intact vesicles and bullae can
be seen (Fig. 39-10). The process may rarely extend to the
throat, larynx, and even the trachea and bronchi.
Eye involvement begins with pain and bilateral conjunctivitis in which vesicles and erosions can occur
(Fig. 39-11).
The nasal, urethral, and anal mucosae also may be
inflamed and eroded.
Figure 39-7 Multiple concentric vesicular rings (herpes

iris of Bateman). This pattern may be more frequent in
Mycoplasma pneumoniae-related cases of erythema multiforme major.
Figure 39-9 Erythema multiforme major. Involvement of

the lips with a target pattern.
435
tions. EM usually follows recurrent herpes but may

also occur after primary HSV infection. The average
interval is 7 days (range, 2 to 17 days); the duration
of the lag period appears to be specific for individual
patients. In a small number of patients, HSV recrudescence and EM may occur simultaneously. Not all episodes of EM are preceded by clinically evident HSV
infection, and not all HSV episodes are followed by
EM. Episodes of recurrent HSV infection may precede
the development of HSV-related EM by many years.

Section 6
Figure 39-10 Erythema multiforme major (EMM). Mouth

lesions of EMM usually manifest as erosions.
::
Ectodermosis pluriorificialis (synonym Fuchs syndrome) is a rare occurrence characterized by severe

involvement of two or three mucosal sites in the
absence of skin lesions. Its often relapsing nature suggests that it is HSV related. Moreover, typical target
lesions may arise on the skin with new attacks.
RELATIONSHIP TO
RECURRENT HERPES
In more than 70% of patients with recurrent EM, an
episode of recurrent HSV infection precedes the rash;
the association with herpes labialis predominates
over that with genital herpes or herpes in other loca-
Fever and other constitutional symptoms are usually

absent in EM minor, and the physical examination is
normal. Fever higher than 38.5C (101.3F) is present
in 32% of cases of EMM. Mouth erosions may be very
painful and may impair alimentation. The patient may
be unable to close the mouth and may constantly drool
bloodstained saliva. Cervical lymphadenopathy is usually present in these patients. The pain of genital erosions
may lead to reflex urinary retention. Cough, polypnea,
and hypoxia may occur in M. pneumoniae-related cases.
LABORATORY FINDINGS
HISTOPATHOLOGIC ANALYSIS
Early lesions of EM exhibit lymphocyte accumulation
at the dermalepidermal interface, with exocytosis
into the epidermis, lymphocytes attached to scattered
necrotic keratinocytes (satellite cell necrosis), spongiosis, vacuolar degeneration of the basal cell layer, and
focal junctional and subepidermal cleft formation (eFig.
39-11.1 in online edition). The papillary dermis may
be edematous but principally contains a dense mononuclear cell infiltrate, which is more abundant in older
lesions. The vessels are ectatic with swollen endothelial cells; there may be extravasated erythrocytes and
eosinophils. Immunofluorescence findings are negative
or nonspecific. In advanced lesions subepidermal blister formation may occur, but necrosis rarely involves
the entire epidermis (see eFig. 39-11.2 in online edition).
In late lesions, melanophages may be prominent.
The histopathologic appearance of EM lesions is different from that of SJSTEN lesions, in which dermal
inflammation is moderate to absent and epidermal
necrosis much more pronounced (see Chapter 40). Still,
the histopathologic appearances are somewhat overlapping and do not allow the distinction of EM from
SJSTEN in all instances. The main reason for performing a biopsy in EM is to rule out other diagnoses, for
example, autoimmune blistering diseases, Sweet syndrome, and vasculitis.

436
Figure 39-11 Erythema multiforme major. Eye lesions.

Conjunctivitis with erosions.
There are no specific laboratory tests for EM. In more

severe cases, an elevated erythrocyte sedimentation rate, moderate leukocytosis, increased levels of
COURSE AND COMPLICATIONS
Erythema Multiforme
(Table 39-1)
In a retrospective analysis of 66 pediatric cases discharged from hospital with a diagnosis of EM 24 (36%)
were clearly not EM.8 Diseases that had been frequently
erroneously called EM were urticaria (eFig. 39-11.3 in
online edition) and maculopapular drug eruption (Fig.
39-12).8,15
The designation of Rowell syndrome16,17 is used for a
variety of cutaneous lupus erythematosus with often erosive circinate lesions resembling those of EM. Subacute
evolution, a positive result on direct fluorescence testing,
and the presence of antinuclear antibodies exclude EM.
::
Sweet syndrome can mimic EM minor; biopsy easily

distinguishes the two.
Paraneoplastic pemphigus and more rarely other
autoimmune blistering diseases occasionally present
with target-like lesions that can be confused with those
of EM (Figs. 39-13 and eFig. 39-14 in online edition).
Original cases were reported as EMM with antidesmoplakin antibodies.18 Clinical features resemble
EMM in their acute and recurrent course, but the presence of acantholysis, deposits of IgG around basal cells,
and serum antibodies against desmoplakin distinguish
such cases from EM.
Better considered a separate disease, SJS should be
recognized promptly for three reasons: (1) the possibility of life-threatening complications, (2) the risk of
progression to TEN, and (3) the need for urgent withdrawal of suspected causative drug(s) (see Chapter
40). Pain, constitutional symptoms, severe erosions of
mucosae, rapid progression, and dusky or violaceous
skin lesions are alerting features.
In rare cases of EM affecting only mucous membranes, the diagnosis is especially difficult and often
made when further bouts include a few skin lesions.
In such cases, pemphigus, cicatricial pemphigoid,
allergic or toxic contact stomatitis, toxic erosive stomatitis, aphthous lesions, and lichen planus should
be considered.
Chapter 39
acute-phase proteins, and mildly elevated liver aminotransferase levels may occur. In the presence of
respiratory symptoms a chest radiograph is needed,
and documentation of M. pneumoniae infection by PCR
assay of a throat swab and serologic testing (a pair at a
2- or 3-week interval) should be sought. Investigations
to document causality are important in cases with frequent recurrences when prevention with long-term
antiviral treatment is considered and when there is no
clinical evidence of association with herpes. HSV can
rarely still be isolated from the initial lesion of labial
herpes. Amplification of HSV Pol gene from biopsy
samples of EM lesions is not done routinely. A negative result on serologic testing for HSV may be helpful to exclude the possibility of herpes-associated EM.
The positive predictive value of the presence of HLADQB1*0301 is too low to have any clinical value.
EM runs a mild course in most cases, and each individual attack subsides within 1 to 4 weeks. Recovery is
TABLE 39-1
Differential Diagnosis of Erythema Multiforme (EM)

Mucous
Membrane
Lesions
Clinical Pattern
Pathologic
Findings
Urticaria
No
Circinate, transient
Edema
Maculopapular
drug eruption
Rare (lips)
Widespread polymorphous
target-like lesions, macules,
papules, plaques
Most often nonspecific
Lupus (Rowell
syndrome)
Possible (mouth)
Face and thorax

Large target-like lesions,
annular plaques
Positive result on DIF
(lupus band)
Antinuclear
antibodies
present
Subacute
Paraneoplastic
pemphigus
Constant; always
early and severe
EM-like lesion plus

lichenoid papules
Positive Nikolsky sign
Acantholysis
Antibodies
present
Chronic
Cicatricial
pemphigoid
Constant
Circinate erythematous
patches
Subepidermal blister,
Antibodies
present
Chronic
Antidesmoplakin
EM major
Constant
EM-like lesions
Basal acantholysis
Antibodies
present
Acute
relapsing
StevensJohnson
syndrome
Constant
Widespread small blisters

Atypical targets
Constitutional symptoms
Epidermal necrosis
DIF = direct immunofluorescence testing.
Laboratory
Testing
Course
More acute
than EM
Acute
437
Section 6
Figure 39-13 Figurate blisters, in a case of linear IgA blistering disease.
::
Figure 39-12 Figurate erythema in a cases of drug eruption to amoxicillin. Commonly and erroneously reported
as drug-induced EM.
complete, and there are usually no sequelae, except for
transient discoloration in some cases.
In rare instances the ocular erosions of EMM may
cause severe residual scarring of the eye. M. pneumoniae-related EMM may be associated with severe
erosive bronchitis that may rarely lead to sequelae.
Recurrences are common and may characterize the
majority of cases. In reports of large series of patients
with recurrent EM, the mean number of attacks was 6
per year (range, 2 to 36), and the mean total duration
of disease was 6 to 9 years. In 33%, the condition persisted for more than 10 years.19,20 Up to 50 recurrences
have been described in a single patient. The severity of
episodes in patients with recurrent EM is highly variable and unpredictable. The frequency of episodes and
cumulative duration of disease are not correlated with
the severity of attacks. The frequency and severity of
recurrent EM tend to decrease spontaneously over time
(after 2 years or longer), parallel with the improvement
of recurring HSV infection when it is the cause. In a
substantial proportion of recurrent cases a cause cannot be determined.20 A small fraction of patients experience a prolonged series of overlapping attacks of EM;
this has been labeled continuous EM or persistent EM.19
TREATMENT
438
The aims of treatment are to reduce the duration of

fever, eruption, and hospitalization. Based on retrospective series or small controlled trials, the use of
systemic corticosteroids seems to shorten the duration of fever and eruption, but may increase the
length of hospitalization because of complications.
However, the methodology of most studies was poor,
with small series often mixing the various forms
of idiopathic and virus-associated EM and druginduced SJS. The use of systemic corticosteroids cannot be recommended.21
Several series indicate that administering anti-HSV
drugs for the treatment of established episodes of
postherpetic EM is useless. When symptomatic, M.
pneumoniae infection should be treated with antibiotics (macrolides in children, macrolides or quinolone
in adults). There is no evidence indicating whether it
improves the evolution of the associated EM. Therefore, when asymptomatic infection is suggested by
serologic testing, treatment is not mandatory.
Liquid antacids, topical glucocorticoids, and local
anesthetics relieve symptoms of painful mouth erosions.
PREVENTION
Continuous therapy with oral anti-HSV drugs (see
Chapter 231) is effective to prevent recurrences of herpes-associated EM with or without clinical evidence
that herpes is the precipitating factor.7 Topical acyclovir therapy used in a prophylactic manner does not
prevent recurrent herpetic EM.
In a series of 65 patients with recurrent EM, 11
were treated with azathioprine when all other treatments had failed. Azathioprine was beneficial in all
11 patients.19 Mycophenolate mofetil can be also useful.20
Retrospective uncontrolled analyses of thalidomide therapy have indicated that it is moderately
effective for the treatment of EM.22 However, thalidomide is probably the most effective treatment
of recurrent/persistent cases when resistant to antiHSV drugs.
In one randomized controlled trial, levamisole
appeared useful. Because agranulocytosis is a severe and
not exceptional adverse effect, levamisole use is permitted in only a few countries. The benefitrisk ratio is probably too low to support its use in the treatment of EM.
KEY REFERENCES
1. Bastuji-Garin S et al: A clinical classification of cases of
toxic epidermal necrolysis, Stevens-Johnson syndrome
and erythema multiforme. Arch Dermatol 129:92, 1993
2. Auquier-Dunant A et al: Correlations between clinical
patterns and causes of erythema multiforme majus, Stevens-Johnson Syndrome and toxic epidermal necrolysis.
Arch Dermatol 138:1019, 2002
5. Weston WL: Herpes-associated erythema multiforme. J
Invest Dermatol 124:xv, 2005
7. Tatnall FM, Schofield JK, Leigh IM: A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol 132:267, 1995
13. Aurelian L, Ono F, Burnett J: Herpes simplex virus (HSV)associated erythema multiforme (HAEM): A viral disease
with an autoimmune component. Dermatol Online J 9:1,
2003
20. Wetter DA, Davis MD: Recurrent erythema multiforme:
Clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007.
J Am Acad Dermatol 62:45, 2010
21. Riley M, Jenner R: Towards evidence based emergency
medicine: Best BETs from the Manchester Royal Infirmary. Bet 2. Steroids in children with erythema multiforme.
Emerg Med J 25:594, 2008
Widespread apoptosis of keratinocytes

provoked by the activation of a cellmediated cytotoxic reaction and amplified
by cytokines, mainly granulysin.
Confluent purpuric and erythematous
macules evolving to flaccid blisters and
epidermal detachment predominating on the
trunk and upper limbs and associated with
mucous membrane involvement.
Pathologic analysis shows full-thickness
necrosis of epidermis associated with mild
mononuclear cell infiltrate.
A dozen high-risk drugs account for
one half of cases.
Up to 20% of cases remain idiopathic.
Early identification and withdrawal of
suspect drugs are essential for good patient
outcome.
Treatment is mainly symptomatic.
Sequelae are nearly constant, needing
systematic follow-up examinations.
Epidermal Necrolysis
Rare and life-threatening reaction, mainly

drug induced.
Toxic epidermal necrolysis (TEN) and Stevens

Johnson syndrome (SJS) are acute life-threatening
mucocutaneous reactions characterized by extensive
necrosis and detachment of the epidermis. Stevens
and Johnson first reported two cases of disseminated
cutaneous eruptions associated with an erosive stomatitis and severe ocular involvement.1 In 1956, Lyell
described patients with epidermal loss secondary to
necrosis and introduced the term toxic epidermal necrolysis.2 Both SJS and TEN are characterized by skin and
mucous membrane involvement. Because of the similarities in clinical and histopathologic findings, risk
factors, drug causality, and mechanisms, these two
conditions are now considered severity variants of an
identical process that differs only in the final extent of
body surface involved.35 Therefore, it is better to use
the designation epidermal necrolysis for both, as proposed by Ruiz-Maldonado (acute disseminated epidermal necrosis)6 and Lyell (exanthematic necrolysis).7
::
EPIDERMAL NECROLYSIS
AT A GLANCE
Chapter 40
Chapter 40 :: E
pidermal Necrolysis
(StevensJohnson Syndrome
and Toxic Epidermal Necrolysis)

:: L. Valeyrie-Allanore & Jean-Claude Roujeau
EPIDEMIOLOGY
Epidermal necrolysis (EN) is rare. The overall incidence of SJS and TEN was estimated at 1 to 6 cases
per million person-years and 0.4 to 1.2 cases per million person-years, respectively.8,9 EN can occur at any
age, with the risk increasing with age after the fourth
decade, and more frequently affects women, showing
a sex ratio of 0.6. Patients infected with human immunodeficiency virus and to a lesser degree patients with
collagen vascular disease and cancer are at increased
risk.1012 The overall mortality associated with EN is
20% to 25%, varying from 5% to 12% for SJS to more
than 30% for TEN. Increasing age, significant comorbidity, and greater extent of skin involvement correlate
with poor prognosis. In the United States, evaluation
439
TABLE 40-1
SCORTEN: A Prognostic Scoring System for

Patients with Epidermal Necrolysis
SCORTEN
Prognostic Factors

Points
Age >40 years

Heart rate >120 beats/minute
Cancer or hematologic malignancy
Body surface area involved >10%
Serum urea level >10 mM
Serum bicarbonate level >20 mM
Serum glucose level >14 mM
1
1
1
1
1
1
1
Section 6
::
SCORTEN
Mortality Rate
(%)
01
2
3
4
5
3.2
12.1
35.8
58.3
90
Data from Bastuji-Garin S et al: SCORTEN: A severity-of-illness score

for toxic epidermal necrolysis. J Invest Dermatol 115:149, 2000.
of death certificates suggested a seven time higher risk

of dying from EN among blacks than whites.13
A prognosis score (SCORTEN) has been constructed
for EN,14 and its usefulness has been confirmed by several teams.1518 (See Table 40-1.)
ETIOLOGY
The pathophysiology of EN is still unclear; however,
drugs are the most important etiologic factors. More
than 100 different drugs have been implicated,1921 but
fewer than a dozen high-risk medications account
for about one half of cases in Europe (Table 40-2), as
evidenced by two multinational casecontrol studies.12,2225 These high-risk drugs are antibacterial sulfon-
amides, aromatic anticonvulsants, allopurinol, oxicam

nonsteroidal anti-inflammatory drugs, lamotrigine,
and nevirapine.2627 The risk seems confined to the first
8 weeks of treatment. Slow dose escalation decreases
the rate of rash with lamotrigine and nevirapine,28,29 but
there is no evidence that it decreases the risk of EN.26
Oxcarbazepine, a 10-keto derivative of carbamazepine,
which was considered to carry a lower risk, seems to
significantly cross-react with carbamazepine.30 Many
nonsteroidal anti-inflammatory drugs (primarily oxicam derivatives and diclofenac) were suspected to be
associated with EN.12,31,32 A significant but much lower
risk has also been reported for non-sulfonamide antibiotics such as aminopenicillins, quinolones, cephalosporins, and tetracyclines.22Corticosteroids were
significantly associated with a high relative risk, but
confounding was not excluded.22
The role of infectious agents in the development
of EN is much less prominent than for erythema
multiforme. However, cases of EN associated with
Mycoplasma pneumoniae infection, viral disease, and
immunization have been reported, particularly in
children.33,34 These rare observations underscore the
fact that medications are not the only cause of EN, but
there is still little evidence that infections can explain
more than a very small percentage of cases.
Cases of EN have been reported after bone marrow transplantation. Some are an extreme form of
acute graft-versus-host disease (see Chapter 28); others could be drug induced. The relationship between
EN and graft-versus-host disease is difficult to assess
because clinical and histological skin features are
nearly indistinguishable.35 Lupus erythematosus
(systemic LE or subacute cutaneous LE) is associated
with an increased risk of EN.12,22 In such cases, drug
causality is often doubtful and necrolysis might be
an extreme phenotype of cutaneous lupus.36 Finally,
radiotherapy in addition to treatment with antiepileptic drugs, such as phenytoin, phenobarbital, or
carbamazepine, can trigger EN with lesions localized
predominantly at sites of radiation treatment.37,38 In
TABLE 40-2
Medications and the Risk of Epidermal Necrolysis
440
High Risk
Lower Risk
Doubtful Risk
No Evidence of Risk
Allopurinol
Sulfamethoxazole
Sulfadiazine
Sulfapyridine
Sulfadoxine
Sulfasalazine
Carbamazepine
Lamotrigine
Phenobarbital
Phenytoin
Phenylbutazone
Nevirapine
Oxicam NSAIDs
Thiacetazone
Acetic acid NSAIDs (e.g.,

diclofenac)
Aminopenicillins
Cephalosporins
Quinolones
Cyclins
Macrolides
Paracetamol (acetaminophen)
Pyrazolone analgesics
Corticosteroids
Other NSAIDs (except aspirin)
Sertraline
Aspirin
Sulfonylurea
Thiazide diuretics
Furosemide
Aldactone
Calcium channel blockers
Blockers
Angiotensin-converting enzyme inhibitors
Angiotensin II receptor antagonists
Statins
Hormones
Vitamins
NSAIDs = nonsteroidal anti-inflammatory drugs.
clinical practice, the causality of a medication can be

clearly established in approximately 60% of cases and
suspected in 20%. Other causes (infection, GVH, LE)
are rarely apparent, about 20% of cases as idiopathic.39
PATHOGENESIS
::
CLINICAL FINDINGS
Chapter 40
Even if the precise sequence of molecular and cellular events is incompletely understood, several studies
provided important clues to the pathogenesis of EN.
The immunologic pattern of early lesions suggests a
cell-mediated cytotoxic reaction against keratinocytes
leading to massive apoptosis.3941 Immunopathologic
studies have demonstrated the presence within early
lesions of cytotoxic cells including natural killer T
cells (NKT) and drug-specific CD8+ T lymphocytes;
monocytes/macrophages and granulocytes are also
recruited.4244 However, it is generally accepted that
specific and nonspecific cytotoxic cells are too few
within the lesions to explain the death of cells on the
full thickness and large areas of the epidermis and
mucous membranes. Amplification by cytokines has
been suspected for years, especially for factors activating death receptors on cell membranes, especially antitumor necrosis factor (TNF) and soluble
Fas ligand (Fas-L).42,45 In the past decade it had been
widely accepted that Fas-L was inducing the apoptosis of keratinocytes in EN,45,46 despite partial evidence
and discordant findings.4749 An important recent
study has challenged this dogma by demonstrating
the key role in EN of granulysin.50 Granulysin was
present in the blister fluid of EN at concentrations
much higher than those of perforin, granzyme B, or
Fas-L. At such concentrations, only granulysin, and to
a much lesser degree perforin, were able to kill human
keratinocytes in vitro; Fas-L was not. Furthermore
injection of granulysin in the dermis of normal mice
resulted in clinical and histological lesions of EN.50
When combined, the above results strongly suggest
that the effector mechanisms of EN have been deciphered. Cytotoxic T-cells develop and are usually specifically directed against the native form of the drug
rather than against a reactive metabolite, contrarily
to what has been postulated for 20 years. These cells
kill keratinocytes directly and indirectly through the
recruitment of other cells that release soluble death
mediators, the principal being granulysin.50,51
These advances on understanding the final steps of
the reaction point to inhibition of release and/or blockade of granulysin as major aims of therapeutic interventions.
Little is known on what are the initial and intermediate steps. We still do not understand why very
few individuals develop a violent immune response
to medications and why effector cells are especially
directed to the skin and other epithelia. Actually, most
drugs associated with a high risk for EN can also
induce a variety of milder and more frequent reactions.
Drug-specific CD8 cytotoxic T-lymphocytes were also
often found in skin reactions with more benign phenotype.52 Hence, it is tempting to speculate on an abnormal regulation of immune response. Regulatory CD4+
CD25+ T cells have been demonstrated to be potentially important in the prevention of severe epidermal
damage induced by reactive cytotoxic T lymphocytes
in a mouse model of EN.53 Similar regulatory cells may
play a role in drug eruptions in humans.54 Altered
regulation of the immune response to medications in
patients with EN could result from comorbidities that
are frequent, for example, cancer, HIV infection, collagen vascular disease; from comedications, for example, corticosteroids; or from genetic background.
Genetic susceptibility plays an important role in the
development of EN to a few high-risk medications.
A strong association was observed in Han Chinese
from Taiwan between the human leukocyte antigen
HLA-B*1502 and EN induced by carbamazepine, and
between HLA-B*5801 and EN induced by allopurinol.55,56 B*1502 association with carbamazepine-related
cases was confirmed in several Asian countries,57,58
with the remarkable exceptions of Japan and Korea.59,60
The association between carbamazepine-induced EN
and HLA-B*1502 was not present in European patients
who do not have Asian ancestry.61 On the other hand,
HLA-B*5801 was confirmed to be associated with
allopurinol-related EN in Japan59 and Europe,62 but the
strength of association was lower than in Taiwan.
Even in cases requiring immediate referral to specialized wards, the dermatologist will have a specific role
in the management of patients with EN (Fig. 40-1).
Decision tree for referral of a patient with EN
Diagnosis of epidermal necrosis
Involved BSA < 10%
Slow progression
No severity marker
Stable
Progression
Involved BSA > 10%
Serum bicarbonate < 20 mM

Serum urea level > 10 mM
Serum glucose level > 14 mM
Respiratory rate > 20
pO2 < 80 mm Hg
or rapid progression
Transfer to specialized center
Usual medical wards
Systemic follow-up
High risk of serious sequelae
(skin, eyes, genitalia, mouth, psychic...)
Figure 40-1 Decisional tree for referral of a patient with

EN. (Adapted from Ellis MW: A case report and a proposed algorithm for the transfer of patients with StevensJohnson syndrome and toxic epidermal necrolysis to a
burn center. Mil Med 167:701, 2002)
441
HISTORY
Section 6
::
EN clinically begins within 8 weeks (usually 4 to 30

days) after the onset of drug exposure for the first
time. Only in very rare cases with prior reaction and
inadvertent rechallenge with the same drug does it
appear more rapidly, within a few hours. Nonspecific
symptoms such as fever, headache, rhinitis, cough,
or malaise may precede the mucocutaneous lesions
by 1 to 3 days. Pain on swallowing and burning or
stinging of the eyes progressively develop, heralding
mucous membrane involvement. About one-third of
cases begin with nonspecific symptoms, one-third
with symptoms of mucous membrane involvement,
and one-third with an exanthema. Whatever the initial symptoms are, their rapid progression, the addition of new signs, severe pain, and constitutional
symptoms should alert one to the onset of a severe
disease.
CUTANEOUS LESIONS
The eruption is initially symmetrically distributed
on the face, the upper trunk, and the proximal part
of limbs.63 The distal portions of the arms as well as
the legs are relatively spared, but the rash can rapidly extend to the rest of the body within a few days
and even within a few hours. The initial skin lesions
are characterized by erythematous, dusky red, purpuric macules, irregularly shaped, which progressively
coalesce. Atypical target lesions with dark centers are
often observed (Fig. 40-2A). Confluence of necrotic
lesions leads to extensive and diffuse erythema.
Nikolskys sign, or dislodgement of the epidermis by
lateral pressure, is positive on erythematous zones (Fig.
40-3 and eFig. 40-3.1 in online edition). At this stage,
the lesions evolve to flaccid blisters, which spread with
pressure and break easily (see Fig. 40-2B). The necrotic
epidermis is easily detached at pressure points or by
frictional trauma, revealing large areas of exposed, red,
sometimes oozing dermis (see Figs. 40-2C and 40-2D).
In other areas, epidermis may remain.
Patients are classified into one of three groups
according to the total area in which the epidermis is
detached or detachable (positive Nikolsky): (1) SJS,
less than 10% of body surface area (BSA); (2) SJS/TEN
overlap, between 10% and 30%; (3) TEN, more than
30% of BSA (eFig. 40-3.2 in online edition). Correct
evaluation of the extent of lesions is difficult, especially
in zones with spotty lesions. It is helpful to remember
that the surface of one hand (palm and fingers) represents a little less than 1% of the BSA.
MUCOUS MEMBRANE INVOLVEMENT
442
Mucous membrane involvement (nearly always on

at least two sites) is observed in approximately 90%
of cases and can precede or follow the skin eruption.
It begins with erythema followed by painful erosions
of the oral, ocular, and genital mucosa. This usually
leads to impaired alimentation, photophobia, con-
junctivitis, and painful micturition. The oral cavity

and the vermilion border of the lips are almost invariably affected and feature painful hemorrhagic erosions coated by grayish white pseudomembranes and
crusts of the lips (Fig. 40-4). Approximately 80% of
patients have conjunctival lesions,64,65 mainly manifested by pain, photophobia, lacrimation, redness,
and discharge. Severe forms may lead to epithelial
defect corneal ulceration, anterior uveitis, and purulent conjunctivitis. Synechiae between eyelids and
conjunctiva often occur. There may be shedding of
eyelashes (see Fig. 40-4B). Genital erosions are frequent, often overlooked in women, and may lead to
synechiae.66
Shedding of nails occurs in severe forms.
EXTRACUTANEOUS SYMPTOMS
EN is associated with high fever, pain, and weakness.
Visceral involvement is also possible, particularly
with pulmonary and digestive complications. Early
pulmonary complications occur in approximately 25%
of patients and are essentially manifested by elevated
respiratory rate and cough, which should prompt
strict surveillance.67,68 Bronchial involvement in EN is
not correlated with the extent of skin lesions or with
the offending agent. In most cases chest radiographs
are normal on admission but can rapidly reveal interstitial lesions that can progress to acute respiratory
distress syndrome (ARDS). In all reported cases, when
acute respiratory failure developed rapidly after the
onset of skin involvement, it was associated with poor
prognosis. In the case of respiratory abnormalities,
fiberoptic bronchoscopy may be useful to distinguish
a specific epithelial detachment in the bronchi from
an infectious pneumonitis, which has a much better
prognosis.
Gastrointestinal tract involvement is less commonly
observed, with epithelial necrosis of the esophagus,
small bowel, or colon manifesting as profuse diarrhea with malabsorption, melena, and even colonic
perforation.69,70 Renal involvement has been reported.
Proteinuria, microalbuminuria, hematuria, and azotemia are not rare. Proximal tubule damage can result
from necrosis of tubule cells by the same process that
destroys epidermal cells.71 Glomerulonephritis is
rare.72
LABORATORY TESTS
LABORATORY VALUES
There is no laboratory test to support the diagnosis of
EN. Laboratory examinations are essential to evaluation of severity and daily management as for all lifethreatening conditions in intensive care units.
Evaluation of respiratory rate and blood oxygenation are among the first steps to take in the emergency
room. Any alteration should be checked through measurement of arterial blood gas levels. Serum bicarbonate levels below 20 mM indicate a poor prognosis.14
Chapter 40
::
Figure 40-2 A. Early eruption. Erythematous dusky red macules (flat atypical target lesions) that progressively coalesce
and show epidermal detachment. B. Early presentation with vesicles and blisters, note the dusky color of blister roofs,
strongly suggesting necrosis of the epidermis. C. Advanced eruption. Blisters and epidermal detachment have led to large
confluent erosions. D. Full-blown epidermal necrolysis characterized by large erosive areas reminiscent of scalding.
They usually result from respiratory alkalosis related

to the specific involvement of bronchi and more rarely
from metabolic acidosis.
Massive transdermal fluid loss is responsible for
electrolyte imbalances, hypoalbuminemia, and hypoproteinemia, and mild and transient renal insufficiency
and prerenal azotemia are common. Raised blood urea
nitrogen level is one marker of severity. Anemia is
usual, and mild leukocytosis as well as thrombocytopenia may occur. Neutropenia is often considered to be
an unfavorable prognostic factor but is too rare to have

a significant impact on SCORTEN. Transient peripheral CD4+ lymphopenia is nearly always seen and is
associated with decreased T-cell function. Mild elevation in levels of hepatic enzymes and amylase (most
probably of salivary origin) are frequent but without
impact on prognosis. A hypercatabolic state is responsible for inhibition of insulin secretion or insulin resistance, which results in hyperglycemia and occasionally
overt diabetes. A blood glucose level above 14 mM is
443
full-thickness necrosis and subepidermal detachment

(Fig. 40-5). Apoptosis of epithelial cells may involve
sweat glands and hair follicles. A moderately dense
mononuclear cell infiltrate of the papillary dermis is
observed, mainly represented by lymphocytes, often
CD8+ and macrophages.73,74 Eosinophils seems to be
less common in patients with the most severe form of
EN. Results of direct immunofluorescence study are
negative. Histopathology of involved mucous membranes, rarely performed, would show similar alterations.75
Section 6
::
Figure 40-3 Early exanthematous phase with Nikolskys

sign.
one marker of severity.14 Other abnormalities in laboratory values may occur, indicating involvement of other
organs and complications such as sepsis.
HISTOPATHOLOGY
Skin biopsy for routine histologic and possibly immunofluorescence studies should be strongly considered, especially if there are alternative diagnoses to
consider. In the early stages, epidermal involvement
is characterized by sparse apoptotic keratinocytes
in the suprabasal layers, which rapidly evolves to a
444
(Box 40-1)
Milder presentations of EN must be distinguished
from erythema multiforme minor (EMM) (see Chapter 39). Early EN cases are often initially diagnosed as
varicella. The rapid progression of skin lesions and the
severity of mucous membrane involvement should
raise the probability of EN.
The absence of mucous membrane involvement or
its restriction to a single site must always raise the
suspicion of an alternative diagnosis: staphylococcal scalded skin syndrome in infants; purpura fulminans in children and young adults; acute generalized
exanthematous pustulosis, phototoxicity, or pressure
blisters in adults. Thermal burns or scalding are occasionally an issue when a transient loss of consciousness occurs.
Linear immunoglobulin (Ig) A bullous disease and
paraneoplastic pemphigus present with a less acute
progression. Pathologic findings and a positive result
on direct immunofluorescence testing are important
for these diagnoses.
In all aspects, including pathology, generalized bullous fixed drug eruption (GBFDE) resembles EN. It
Figure 40-4 A. Extensive erosions and necroses of the lower lip and oral mucosa. B. Massive erosions covered by crusts
on the lips. Note also shedding of eyelashes.
Chapter 40
::
Figure 40-5 Histologic appearance of toxic epidermal necrolysis. A. Eosinophilic necrosis of the epidermis in the peak
stage, with little inflammatory response in the dermis. Note cleavage in the junction zone. B. The completely necrotic
epidermis has detached from the dermis and folded like a sheet.

of Epidermal Necrolysis (EN)
Most Likely
Limited EN (StevensJohnson syndrome)
Erythema multiforme major
Varicella
Widespread EN
Acute generalized exanthematous pustulosis
Generalized bullous fixed drug eruption
Consider
Linear immunoglobulin A bullous disease
Pressure blisters after coma
Phototoxic reaction
Always Rule Out
Staphylococcal scalded skin syndrome
Thermal burns
Skin necrosis from disseminated intravascular
coagulation or purpura fulminans
Chemical toxicity (e.g., colchicine intoxication,
methotrexate overdose)
may have a similar drug-related mechanism. However, the distinction is worthwhile because GBFDE
has a reputation for much better prognosis, probably
because of the mild involvement of mucous membranes and the absence of visceral complications. Prior
attacks, rapid onset after drug intake, and very large,
well-demarcated blisters are the hallmarks of GBFDE.
Toxic destruction of epithelia, whether through contact (fumigants) or ingestion (colchicine poisoning,
methotrexate overdose), may result in clinical features of
EN, but with skin erosions often predominating in the
folds. In these rare cases, causality is generally obvious.
Overreporting of SJS is common. It usually arises
from confusion between desquamation and detachment of epidermis, and also between mucous membranes and periorificial skin. Because of such confusion,
patients with a desquamative rash and scaly lips are
not rarely diagnosed with and reported as having SJS.
COMPLICATIONS AND SEQUELAE

During the acute phase, the most common complication of EN is sepsis. The epithelial loss predisposes these patients to infections, which are the
main causes of mortality.4,63 Staphylococcus aureus
and Pseudomonas are the most frequent pathogens,
but about one-third of positive blood cultures contain enterobacteriae not present on the skin, a finding that suggests bacterial translocation from gut
lesions.76 Multisystem organ failure and pulmonary
445
Section 6
::
complications are observed in more than 30% and

15% of cases, respectively.77
A very important advance in EN is the recent understanding that sequelae are more frequent and more
severe than previously thought.78 After the well-known
risks of the acute stage, EN behaves as a chronic disease. More medical attention should be directed to that
phase to better understand the frequency, mechanisms,
and evolution of sequelae. Adequate management and
prevention of sequelae are as important as saving the
life during the acute phase.
A large European cohort has found that 90% of patients
who survived EN suffered from sequelae at 1 year, with
a mean of three different problems per patient and an
important negative impact on the quality of life for about
half of them (RegiSCAR group, unpublished data).
Symptoms suggesting posttraumatic stress disorder
are not rare. Psychiatric consultation and/or psychological support are probably necessary in a majority
of cases. Late ophthalmic complications are reported
in 20% to 75% of patients with EN, with a credible
figure of about 50% (Fig. 40-6).64,65,78 The relationship
between the initial severity of ocular involvement and
the development of late complications seems now to
be well established. Late ophthalmic complications are
mainly due to functional alteration of the conjunctival
epithelium with dryness and abnormal lacrimal film.
This leads to chronic inflammation, fibrosis, entropion,
trichiasis, and symblepharon. Long-term irritation
and deficiency of stem cells in the limbus may result
in metaplasia of corneal epithelium with painful ulcerations, scarring, and altered vision. Such severe eye
lesions occasionally develop in patients who had no
patent ocular signs during the acute phase of EN.64
Hypopigmentation and/or hyperpigmentation are
most frequent; residual hypertrophic or atrophic scars
rarely occur. Nail changes, including change in pigmentation of the nail bed, ridging, dystrophic nails,
and permanent anonychia, occur in more than 30% of
cases (Fig. 40-7). Mouth sequelae are present in about
Figure 40-7 Abnormal regrowth of nails after SJS.

one-third of patients who complain of dryness, altered
taste, and late alterations of teeth.79
Vulvar and vaginal complications of EN are reported
by about 25% of patients.66 Dyspareunia is not rare and
is related to vaginal dryness, itching, pain, and bleeding. Genital adhesions may lead to the requirement
for surgical treatment. Esophageal, intestinal, urethral,
and anal strictures may also develop in rare cases.
Chronic lung disease can be observed after EN, often
attributed to bronchiolitis obliterans, and occasionally
requires lung transplantation.68,80 Because these late
complications and sequelae may develop insidiously,
it is strongly suggested that all patients surviving EN
have a clinical follow-up a few weeks after discharge
and 1 year later, including examination by an ophthalmologist and by other organ specialist(s) as indicated
by abnormal signs and symptoms.

The epidermal detachment progresses for 5 to 7 days.
Then, patients enter a plateau phase, which corresponds
to progressive reepithelialization. This can take a few
days to a few weeks, depending on the severity of the
disease and the prior general condition of the patient.
During this period, life-threatening complications such
as sepsis or systemic organ failure may occur. The
overall hospital mortality rate of EN is 2225%, varying from 5% to 12% for SJS to more than 30% for TEN.
The prognosis is not affected by the type or dose of the
responsible drug or the presence of human immunodeficiency virus infection (see Table 40-1).12,14,63,77
Prospective follow-up has shown an additional
abnormally increased mortality in the 3-month period
following hospital discharge, which seems to result
from the negative impact of EN on prior severe chronic
conditions, for example, malignancies (RegiSCAR,
unpublished data).
TREATMENT
446
Figure 40-6 Late ocular complications of SJS. Note

opaque corneal epithelium, neovessels, and irritating eyelashes on lower eyelids. (Photograph provided by Julie
Gueudry MD and Marc Muraine MD, PhD, Hpital Charles
Nicolle, Rouen, France.)
EN is a life-threatening disease that requires optimal

management: early recognition and withdrawal of the
offending drug(s) and supportive care in an appropriate hospital setting.
Prompt withdrawal of offending agent(s) is associated with an increased rate of survival in patients
with EN induced by drugs with short elimination halflives.81 On the other hand, it is preferable to continue
every important and nonsuspected medication. That
will avoid reluctance on the part of the patients physicians to prescribe them in the future. In case of doubt, all
nonlife-sustaining drugs should be stopped, and particularly those administered within the previous 8 weeks.
SYMPTOMATIC TREATMENT
SPECIFIC TREATMENT IN ACUTE STAGE

Because of the importance of immunologic and cytotoxic mechanisms, a large number of immunosuppressive and/or anti-inflammatory therapies have been
tried to halt the progression of the disease. None has
clearly proved its efficacy. The low prevalence of the disease makes randomized clinical trials hard to perform.
INTRAVENOUS IMMUNOGLOBULIN. The

proposal to use high-dose intravenous Ig was based
on the hypothesis that Fas-mediated cell death can be
abrogated by the anti-Fas activity present in commercial batches of normal human Ig .45 Benefits have been
claimed by several studies and case reports,45,8890 but
refuted by several others.16,87,91,92 Thus, intravenous Ig
cannot be considered the standard of care,5 especially
after recent findings that the Fas-L/Fas pathway was
not, or only marginally, involved in the mechanisms of
EN.50 If used, a minimal precaution is to avoid preparations that are potentially nephrotoxic.
::
CORTICOSTEROIDS. The use of systemic corticosteroids is still controversial. Some studies found
that such therapy could prevent the extension of the
disease when administered during the early phase,
especially as intravenous pulses for a few days.86
Other studies concluded that steroids did not stop the
progression of the disease and were even associated
with increased mortality and adverse effects, particularly sepsis. Thus, systemic corticosteroids cannot be
recommended as the mainstay treatment of EN,5 but
a large cohort study has suggested a possible benefit
that should be explored by a prospective study.87
Chapter 40
Only patients with limited skin involvement, a

SCORTEN score of 0 or 1, and a disease that is not
rapidly progressing can be treated in nonspecialized
wards. Others should be transferred to intensive care
units or burn centers.82 There is no specific treatment
of demonstrated efficacy and supportive measures are
the most important.5 Supportive care consists of maintaining hemodynamic equilibrium and preventing lifethreatening complications. The aims are basically the
same as for extensive burns.
EN is associated with significant fluid loss from erosions, which results in hypovolemia and electrolyte
imbalance. Fluid replacement must be started as soon
as possible and adjusted daily. Volumes of infusions are
usually less than for burns of similar extent, because
interstitial edema is absent. Peripheral venous lines are
preferred when possible, because the sites of insertion of
central lines are often involved in detachment of epidermis and prone to infection. The environmental temperature should be raised to 28C to 30C (82.4F to 86F). The
use of an air-fluidized bed improves patient comfort.
Early nutritional support is preferentially provided by nasogastric tube to promote healing and to
decrease the risk of bacterial translocation from the
gastrointestinal tract. To reduce the risk of infection,
aseptic and careful handing is required. Skin, blood,
and urine specimens should be cultured for bacteria
and fungi at frequent intervals. Prophylactic antibiotics are not indicated. Patients should receive antibiotics when clinical infection is suspected. Prophylactic
anticoagulation is provided during hospitalization.
We do not recommend extensive and aggressive
debridement of necrotic epidermis in EN because the
superficial necrosis is not an obstacle to reepithelialization, and might even accelerate the proliferation
of stem cells due to the inflammatory cytokines. This
is the single noticeable divergence between authors
of this chapter and the recommendations of US Burn
centers.5 A few recent series suggest that debridement is necessary neither in superficial burns81 nor in
EN. 84,85 There is no standard policy on wound dressings
and the use of antiseptics. It is a matter of experience
for each center. Skillfulness on the part of specialized
nurses, careful manipulation, and an aggressive protocol of prevention and treatment of pain are essential.
Eyes should be examined daily by an ophthalmologist. Preservative-free emollients, antibiotic or antiseptic eye drops, and vitamin A are often used every
2 hours in the acute phase, and mechanical disruption
of early synechiae is indicated. Early graft of cryo-
preserved amniotic membrane has been proposed as

capable to decrease the rate of severe eye sequelae.64
The mouth should be rinsed several times a day
with antiseptic or antifungal solution.
CYCLOSPORINE A. Cyclosporine is a powerful

immunosuppressive agent associated with biologic
effects that may theoretically be useful in treatment of
EN: activation of T helper 2 cytokines, inhibition of CD8+
cytotoxic mechanisms, and antiapoptotic effect through
inhibition of Fas-L, nuclear factor-B, and TNF-. Several case reports and series suggested some efficacy of
cyclosporine A in halting the progression of EN without
worrisome side effects when administered early.93,94
PLASMAPHERESIS OR HEMODIALYSIS. The
rationale for using plasmapheresis or hemodialysis is
to prompt the removal of the offending medication, its
metabolites, or inflammatory mediators such as cytokines. A small series reported their efficacy and safety
in treating EN.9598 However, considering the absence
of evidence and the risks associated with intravascular
catheters, these treatments cannot be recommended.
ANTITUMOR NECROSIS FACTOR AGENTS.
Anti-TNF monoclonal antibodies have been successfully used to treat a few patients. Because a prior
447
randomized controlled trial of thalidomide, an antiTNF agent, had to be interrupted due to significantly
increased mortality,99 extreme caution is suggested in
the use of anti-TNF agents to treat EN.
TREATMENT OF SEQUELAE
Section 6
Very promising treatments have now been developed

for the ocular sequelae of EN, including gas permeable
scleral lenses100,101 and grafting of autologous stem cells
from contralateral limbus or mouth mucosa.102,103 With
the exception of ocular sequelae, the literature contains
only case reports related to treating sequelae. Photoprotection and cosmetic lasers may help resolve the
pigmentation changes on the skin.
PREVENTION
::
448
Primary prevention is only feasible in populations where

a strong association has been established between a simple genetic maker and the risk of EN. That is the case
for HLAB*1502 and EN induced by carbamazepine. The
FDA has issued the recommendation to test patients
from Asian ancestry for HLAB*1502 before prescribing carbamazepine. This recommendation should be
refined to exclude persons of Japanese or Korean origin.
In individuals of Han Chinese origin, alternative antiepileptic drugs can be carefully prescribed, although
there may be an association of EN with phenytoin and
HLAB*1502 as well.57 The present status of research on
the pharmacogenetics of EN (RegiSCAR unpublished
data) makes unlikely the finding of other genetic markers useful for primary prevention.
Secondary prevention is important for patients who
experienced EN and are reluctant to take any medication. The most important issue is to evaluate drug
causality. In vitro tests or patch tests to medications
occasionally can be useful in the exploration of drug
allergy. When used in EN patients, their sensitivity is
low.104,105 Careful inquiry into all exposures to medications in the few weeks preceding the onset of the reaction leads to the identification of a probable culprit
drug in approximately 70% of cases. The most useful
clinical criteria are duration of treatment before onset
(typically 4 to 30 days), absence of prior intake, and
use of a drug known for being associated with a high
risk.39
The few published cases of recurrent SJS or TEN
were always due to inadvertent readministration of
the same or a very closely related medication. Epidemiology and in vitro studies suggest that the list of
possible cross-reactive medications is rather narrow,
based on close chemical similarities. As an example,
there is no evidence that patients who experienced SJS
or TEN in reaction to an anti-infectious sulfonamide
are at increased risk for reaction to sulfonamiderelated diuretics or antidiabetic medications. Only
anti-infectious sulfonamides should be contraindicated in this situation.
A list of the suspected medication(s) and molecules

of the same biochemical structure must be given to the
patient on a personal allergy card. It is also very useful to provide a list of drugs of common use that cannot
be suspected. Because of recent indications of genetic
susceptibilities to the development of EN, prescription
of the offending agent to family members should also
be avoided.
KEY REFERENCES
3. Bastuji-Garin S et al: Clinical classification of cases of
toxic epidermal necrolysis, Stevens-Johnson syndrome,
and erythema multiforme. Arch Dermatol 129:92, 1993
5. Endorf FW et al: Toxic epidermal necrolysis clinical
guidelines. J Burn Care Res 29:706, 2008
22. Mockenhaupt M et al: Stevens-Johnson syndrome and toxic
epidermal necrolysis: Assessment of medication risks with
emphasis on recently marketed drugs. The EuroSCARstudy. J Invest Dermatol 128:35, 2008
23. Auquier-Dunant A et al: Correlation between clinical
patterns and causes of erythema multiforme major, Stevens Johnson and toxic epidermal necrolysis. Arch Dermatol 138:1019, 2002
25. Halevy S et al: Allopurinol is the most common cause of
Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 58:25, 2008
36. Ting W et al: Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus and the spectrum of the
acute syndrome of apoptotic pan-epidermolysis (ASAP):
A case report, concept review and proposal for new classification of lupus erythematosus vesiculobullous skin
lesions. Lupus 13:941, 2004
44. Nassif A et al: Drug specific cytotoxic T-cells in the skin
lesions of a patient with toxic epidermal necrolysis. J
50. Chung WH et al: Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 14:1343,
2008
54. Takahashi R et al: Defective regulatory T cells in patients
with severe drug eruptions: Timing of the dysfunction
is associated with the pathological phenotype and outcome. J Immunol 182:8071, 2009
55. Chung WH et al: Medical genetics: A marker for Stevens
Johnson syndrome. Nature 428:486, 2004
56. Hung SI et al: HLA-B*5801 allele as a genetic marker for
severe cutaneous adverse reactions caused by allopurinol.
Proc Natl Acad Sci U S A 102:4134, 2005
62. Lonjou C et al: A European study of HLA-B in StevensJohnson syndrome and toxic epidermal necrolysis
related to five high-risk drugs. Pharmacogenet Genomics
18:99, 2008
64. Shay E et al: Amniotic membrane transplantation as a
new therapy for the acute ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis.
Surv Ophthalmol 54:686, 2009
87. Schneck J et al: Effects of treatments on the mortality of
Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the
prospective EuroSCAR Study. J Am Acad Dermatol 58:33,
2008
101. Tougeron-Brousseau B et al: Vision-related function after
scleral lens fitting in ocular complications of StevensJohnson syndrome and toxic epidermal necrolysis. Am J
Ophthalmol 148:852, 2009
Chapter 41 :: Cutaneous Reactions to Drugs

:: Neil H. Shear & Sandra R. Knowles
CUTANEOUS ADVERSE DRUG
ERUPTIONS AT A GLANCE
Drug-induced cutaneous eruptions are
common.
They range from common nuisance rashes to
rare life-threatening diseases.
Drug reactions may be limited solely to skin

or may be part of a severe systemic reaction,
such as drug hypersensitivity syndrome or
toxic epidermal necrolysis.
Complications of drug therapy are a major cause of

patient morbidity and account for a significant number of patient deaths.1 Drug eruptions range from
common nuisance eruptions to rare or life-threatening drug-induced diseases. Drug reactions may
be solely limited to the skin, or they may be part of
a systemic reaction, such as drug hypersensitivity
syndrome or toxic epidermal necrolysis (TEN) (see
Chapter 40).
Drug eruptions are often distinct disease entities and
must be approached systematically, as any other cutaneous disease. A precise diagnosis of the reaction pattern can help narrow possible causes, because different
drugs are more commonly associated with different
types of reactions.
EPIDEMIOLOGY
A systematic review of the medical literature, encompassing nine studies, concluded that cutaneous reaction rates varied from 0% to 8% and were highest for
antibiotics.2 Outpatient studies of cutaneous adverse
drug reactions (ADRs) estimate that 2.5% of children
who are treated with a drug, and up to 12% of children
treated with an antibiotic, will experience a cutaneous
reaction.3
PATHOGENESIS OF DRUG
ERUPTIONS
Constitutional factors influencing the risk of cutaneous eruption include pharmacogenetic variation in
drug-metabolizing enzymes and human leukocyte
antigen (HLA) associations. Acetylator phenotype
alters the risk of developing drug-induced lupus due
to hydralazine, procainamide, and isoniazid. HLADR4 is significantly more common in individuals with
hydralazine-related drug-induced lupus than in those
with idiopathic systemic lupus erythematosus.4 HLA
factors may also influence the risk of reactions to nevirapine, abacavir, carbamazepine, and allopurinol.57
Many drugs associated with severe idiosyncratic
drug reactions are metabolized by the body to form
reactive, or toxic, drug products.8 These reactive products comprise only a small proportion of a drugs
metabolites and are usually rapidly detoxified. However, patients with drug hypersensitivity syndrome,
TEN, and StevensJohnson syndrome (SJS) resulting
from treatment with sulfonamide antibiotics and the
aromatic anticonvulsants (e.g., carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine)
show greater sensitivity in in vitro assessments to the
oxidative, reactive metabolites of these drugs than do
control subjects.9
Acquired factors also alter an individuals risk of
drug eruption. Active viral infection and concurrent
use of other medications have been shown to alter
the frequency of drug-associated eruptions. Reactivation of latent viral infection with human herpes virus
6 also appears common in drug hypersensitivity syndrome and may be partially responsible for some of
the clinical features and/or course of the disease.10,11
Viral infections may act as, or generate the production of, danger signals that lead to damaging immune
responses to drugs, rather than immune tolerance.
Drugdrug interactions may also alter the risk
of cutaneous eruption. Valproic acid increases the
risk of severe cutaneous adverse reactions to lamotrigine, another anticonvulsant.12 The basis of these
Cutaneous Reactions to Drugs
Fixed drug eruptions are usually solitary

dusky macules that recur at the same site.
In the evaluation of a patient with a history of a suspected ADR, it is important to obtain a detailed
medication history, including use of over-the-counter
preparations and herbal and naturopathic remedies.
New drugs started within the preceding 3 months,
especially those within 6 weeks, are potential causative agents for most cutaneous eruptions (exceptions
include drug-induced lupus, drug-induced pemphigus, and drug-induced cutaneous pseudolymphoma),
as are drugs that have been used intermittently.
::
These reactions may mimic other cutaneous

diseases such as acne, porphyria, lichen
planus, and lupus.
ETIOLOGY
Chapter 41
The spectrum of clinical manifestations

includes exanthematous, urticarial, pustular,
and bullous eruptions.
449
Section 6
::
450
interactions and reactions is unknown, but they may

represent a combination of factors, including alterations in drug metabolism, drug detoxification, antioxidant defenses, and immune reactivity.
The course and outcome of drug-induced disease are
also influenced by host factors. Older age may delay
the onset of drug eruptions and has been associated
with a higher mortality rate in some severe reactions. A
higher mortality rate is also observed in patients with
severe reactions who have underlying malignancy.13
The pathogenesis of most drug eruptions is not understood, although the clinical features of most drug reactions are consistent with immune-mediated disease.
The immune system may target the native drug, its
metabolic products, altered self, or a combination of
these factors.14
MORPHOLOGIC APPROACH
TO DRUG ERUPTIONS
Although there are many presentations of cutaneous
drug eruptions, the morphology of many cutaneous
eruptions may be exanthematous, urticarial, blistering, or pustular. The extent of the reaction is variable.
For example, once the morphology of the reaction has
been documented, a specific diagnosis [e.g., fixed drug
eruption (FDE) or acute generalized exanthematous
pustulosis (AGEP)] can be made. The reaction may
also present as a systemic syndrome [e.g., serum sickness-like reaction or hypersensitivity syndrome reaction (HSR)]. Fever is generally associated with such
systemic cutaneous ADRs.
EXANTHEMATOUS ERUPTIONS
Exanthematous eruptions, sometimes referred to as
morbilliform or maculopapular, are the most common
form of drug eruptions, accounting for approximately
95% of skin reactions2 (Fig. 41-1). Simple exanthems
are erythematous changes in the skin without evidence of blistering or pustulation. The eruption typically starts on the trunk and spreads peripherally in a
symmetric fashion. Pruritus is almost always present.
These eruptions usually occur within 1 week of initiation of therapy and may appear 1 or 2 days after drug
therapy has been discontinued.15 Resolution, usually
with 714 days, occurs with a change in color from
bright red to a brownish red, which may be followed
by desquamation. The differential diagnosis in these
patients includes an infectious exanthem (e.g., viral,
bacterial, or rickettsial), collagen vascular disease, and
infections.
Exanthematous eruptions can be caused by many
drugs, including -lactams (the penicillins), sulfonamide antimicrobials, nonnucleoside reverse transcriptase inhibitors (e.g., nevirapine), and antiepileptic
medications. Studies have shown that drug-specific T
cells play a major role in exanthematous, bullous, and
pustular drug reactions.16 In patients who have concomitant infectious mononucleosis, the risk of devel-
Figure 41-1 Exanthematous drug eruption: ampicillin.

Symmetrically arranged, brightly erythematous macules
and papules, which are discrete in some areas and confluent in others on the trunk and discrete on the extremities.
oping an exanthematous eruption while being treated

with an aminopenicillin (e.g., ampicillin) increases
from 3%7% to 60%-100%.17 A similar drugviral interaction has been observed in 50% of patients infected
with human immunodeficiency virus (HIV) who are
exposed to sulfonamide antibiotics.14
An exanthematous eruption in conjunction with
fever and internal organ inflammation (e.g., liver, kidney, central nervous system) signifies a more serious
reaction, known as the hypersensitivity syndrome reaction, drug-induced hypersensitivity reaction (DIHS) or
drug reaction with eosinophilia and systemic symptoms (DRESS) (Table 41-1). It occurs in approximately
1 in 3,000 exposures to agents such as aromatic anticonvulsants, lamotrigine, sulfonamide antimicrobials, dapsone, nitrofurantoin, nevirapine, minocycline,
metronidazole, and allopurinol (Fig. 41-2). HSR occurs
most frequently on first exposure to the drug, with
initial symptoms starting 16 weeks after exposure.
Fever and malaise are often the presenting symptoms.
Atypical lymphocytosis with subsequent eosinophilia
may occur during the initial phases of the reaction in
some patients. Although most patients have an exanthematous eruption, more serious cutaneous manifestations may be evident (Fig. 41-3). Internal organ
involvement can be asymptomatic.11 Some patients
may become hypothyroid due to an autoimmune thyroiditis approximately 2 months after the first symptoms appear.18
The formation of toxic metabolites of the aromatic
anticonvulsants may play a pivotal role in the development of HSR.9 In most individuals, the chemically
reactive metabolites that are produced are detoxified
by epoxide hydroxylases. However, if detoxification
is defective, one of the metabolites may act as a hapten
and initiate an immune response, stimulate apoptosis,
TABLE 41-1
Clinical Features of Selected Cutaneous Reactions to Drugs
Present
Present
Absent
Present
Aromatic
anticonvulsants
(e.g., phenytoin,
phenobarbital,
carbamazepine),
sulfonamide antibiotics,
dapsone, minocycline,
allopurinol, lamotrigine
Serum sicknesslike reaction
Urticaria,
exanthem
Present
Absent
Present
Present
Cefaclor, cefprozil,
bupropion, minocycline,
infliximab, rituximab
Drug-induced
lupus
Usually absent
Present/
absent
Present/absent
Present
Absent
Procainamide,
hydralazine, isoniazid,
minocycline, acebutolol
Drug-induced
subacute
cutaneous lupus
erythematosus
Papulosquamous
or annular
cutaneous
lesion (often
photosensitive)
Absent
Absent
Absent
Absent
Thiazide diuretics,
calcium channel
blockers, ACE inhibitors
Acute
generalized
exanthematous
pustulosis
Nonfollicular
pustules on
an edematous
erythematous
base
Present
Absent
Absent
Absent
Blockers, macrolide
antibiotics, calcium
channel blockers
ACE = angiotensin-converting enzyme; SJS = StevensJohnson syndrome; TEN = toxic epidermal necrolysis.
or cause cell necrosis directly. Approximately 70%

75% of patients who develop anticonvulsant HSR in
response to one aromatic anticonvulsant show crossreactivity to the other aromatic anticonvulsants. In
addition, in vitro testing shows that there is a pattern
of inheritance of HSR induced by anticonvulsants.
Thus, counseling of family members and disclosure of
risk are essential.
Sulfonamide antimicrobials are both sulfonamides

(contain SO2-NH2) and aromatic amines (contain a
benzene ring-NH2). Aromatic amines can be metabolized to toxic metabolites, namely, hydroxylamines and
nitroso compounds.19 In most people, the metabolite is
detoxified. However, HSRs may occur in patients who
either form excess oxidative metabolites or are unable
to detoxify such metabolite. Because siblings and other
Figure 41-2 Drug hypersensitivity syndrome: phenytoin. Symmetric, bright red, exanthematous eruption,
confluent in some sites; the patient had associated
lymphadenopathy.
Figure 41-3 Hypersensitivity syndrome reaction, characterized by fever, a pustular eruption, and hepatitis, in
a 23-year-old man after 18 days of treatment with
minocycline.
Exanthem,
exfoliative
dermatitis,
pustular
eruptions, SJS/
TEN
Hypersensitivity
syndrome
reaction
::
Lymphadenopathy Implicated Drugs
Drug
Eruption
Chapter 41
Fever
Internal
Organ
Involvement Arthralgia
Clinical
Presentation
451
Section 6
::
452
first-degree relatives may be at an increased risk (perhaps as high as 1 in 4) of developing a similar adverse
reaction, counseling of family members is essential.
Other aromatic amine-containing drugs, such as
procainamide, dapsone, and acebutolol, may also be
metabolized to chemically reactive compounds. It is recommended that patients who develop symptoms compatible with a sulfonamide-induced HSR avoid these
aromatic amines, because the potential exists for crossreactivity. However, cross-reactivity is much less likely
to occur between sulfonamides antimicrobials and drugs
that are not aromatic amines (e.g., sulfonylureas, thiazide
diuretics, furosemide, celecoxib, and acetazolamide).20
Allopurinol is associated with the development of
serious drug reactions, including HSR. Active infection
or reactivation of HHV-6 has been observed in patients
who develop allopurinol HSR.21 Allopurinol-induced
severe adverse reactions, specifically HSR and SJS/
TEN spectrum, have been strongly associated with a
genetic predisposition in Han Chinese and Thai populations; presence of the HLA-B*5801 allele was found
to be an important genetic risk factor.6,22
URTICARIAL ERUPTIONS
Urticaria is characterized by pruritic red wheals of various sizes. Individual lesions generally last for less than
24 hours, although new lesions can commonly develop.
When deep dermal and subcutaneous tissues are also
swollen, the reaction is known as angioedema. Angioedema is frequently unilateral and nonpruritic and lasts
for 12 hours, although it may persist for 25 days.21
Urticaria and angioedema, when associated with
drug use, are usually indicative of an immunoglobulin
(Ig) E-mediated immediate hypersensitivity reaction.
This mechanism is typified by immediate reactions to
penicillin and other antibiotics (see Chapter 38). Signs
and symptoms of IgE-mediated allergic reactions typically include pruritus, urticaria, cutaneous flushing,
angioedema, nausea, vomiting, diarrhea, abdominal
pain, nasal congestion, rhinorrhea, laryngeal edema,
and bronchospasm or hypotension. Urticaria and
angioedema can also be caused by non-IgE-mediated
reactions that result in direct and nonspecific liberation of histamine or other mediators of inflammation.15 Drug-induced non-IgE-mediated urticaria and
angioedema are usually related to nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin converting
enzyme (ACE)-inhibitors and opioids.
Serum sickness-like reactions (see Table 41-1) are
defined by the presence of fever, rash (usually urticarial), and arthralgias 13 weeks after initiation of drug
therapy. Lymphadenopathy and eosinophilia may also
be present; however, in contrast to true serum sickness,
immune complexes, hypocomplementemia, vasculitis,
and renal lesions are absent.
Cefaclor is associated with an increased relative risk
of serum sickness-like reactions. The overall incidence
of cefaclor-induced serum sickness-like reactions has
been estimated to be 0.024%0.2% per course of cefaclor prescribed. In genetically susceptible hosts, a reactive metabolite is generated during the metabolism of
cefaclor that may bind with tissue proteins and elicit

an inflammatory response manifesting as a serum sickness-like reaction.23
Other drugs that have been implicated in serum
sickness-like reactions are cefprozil, bupropion, minocycline, and rituximab24 as well as infliximab.25 The
incidence of serum sickness-like reactions caused by
these drugs is unknown.
PUSTULAR ERUPTIONS
Acneiform eruptions are associated with the use of
iodides, bromides, adrenocorticotropic hormone, glucocorticoids, isoniazid, androgens, lithium, actinomycin D, and phenytoin. Drug-induced acne may appear
in atypical areas, such as on the arms and legs, and is
most often monomorphous. Comedones are usually
absent. The fact that acneiform eruptions do not affect
prepubertal children indicates that previous hormonal
priming is a necessary prerequisite. In cases in which
the offending agent cannot be discontinued, topical
tretinoin may be useful.26 An acneiform eruption often
occurs during treatment with epidermal growth factor
receptor inhibitors (e.g., gefitinib, erlotinib, cetuximab).
The acneiform rash is often accompanied by paronychia,
dry skin, and skin fissures. The eruption is dose dependent, with respect to both incidence and severity.27 In a
systemic review and meta-analysis encompassing over
1,000 patients receiving cetuximab as a single-agent, the
incidence of an acneiform eruption was 81.6%.28
AGEP is an acute febrile eruption that is often associated with leukocytosis (Fig. 41-4 and Table 41-1).
After initiation of the implicated drug, 13 weeks
Figure 41-4 Acute generalized exanthematous pustulosis in a 48-year-old man who developed nonfollicular
pustules and fever after 7 days of treatment with diltiazem.
PSEUDOPORPHYRIA. Pseudoporphyria is a cutaneous phototoxic disorder that can resemble either

porphyria cutanea tarda in adults or erythropoietic
protoporphyria in children (see Chapter 132). Pseudoporphyria of the porphyria cutanea tarda variety is
characterized by skin fragility, blister formation, and
scarring in photodistribution; it occurs in the presence
of normal porphyrin levels. The other clinical pattern
mimics erythropoietic protoporphyria and manifests
(Table 41-2)
DRUG-INDUCED LINEAR IgA DISEASE. Both

idiopathic and drug-induced linear IgA diseases (see
Chapter 58) are heterogeneous in clinical presentation.
Cases of the drug-induced type have morphologies
resembling erythema multiforme, bullous pemphigoid, and dermatitis herpetiformis. The drug-induced
disease may differ from the idiopathic entity in that
mucosal or conjunctival lesions are less common, spontaneous remission occurs once the offending agent is
withdrawn, and immune deposits disappear from the
skin once the lesions resolve.
Biopsy specimens are necessary for diagnosis. Histologically, the two entities are similar. A study suggests
that, as in the idiopathic variety, the target antigen is
not unique in the drug-induced disease. Although
13%30% of patients with sporadic linear IgA have circulating basement membrane zone antibodies, these
antibodies have not been reported in drug-induced
cases.34 In patients with linear IgA bullous disease
::
BULLOUS ERUPTIONS
as cutaneous burning, erythema, vesiculation, angular chicken pox-like scars, and waxy thickening of the
skin. The eruption may begin within 1 day of initiation
of therapy or may be delayed in onset for as long as
1 year. The course is prolonged in some patients, but
most reports describe symptoms that disappear several weeks to several months after the offending agent
is withdrawn. Because of the risk of permanent facial
scarring, the implicated drug should be discontinued
if skin fragility, blistering, or scarring occurs.31 In addition, the use of broad-spectrum sunscreen and protective clothing should be recommended. Drugs that
have been associated with pseudoporphyria include
naproxen and other NSAIDs, and voriconazole.32,33
Chapter 41
may elapse before skin lesions appear. The lesions

often start on the face or major skin creases. Generalized desquamation occurs approximately 2 weeks
later. The estimated incidence of AGEP is approximately 15 cases per million per year. AGEP is most
commonly associated with -lactam and macrolide
antibiotics, anticonvulsants, and calcium channel blockers.29 Differential diagnosis includes pustular psoriasis,
HSR with pustulation, subcorneal pustular dermatosis
(SneddonWilkinson disease), pustular vasculitis, or in
severe cases of AGEP, TEN. The typical histopathologic
analysis of AGEP lesions shows spongiform subcorneal and/or intraepidermal pustules, an often marked
edema of the papillary dermis, and perivascular infiltrates with neutrophils and exocytosis of some eosinophils. Discontinuance of therapy is usually the extent
of treatment necessary in most patients, although some
patients may require the use of corticosteroids. Patch
tests have been used in the diagnosis of AGEP.30
TABLE 41-2
Drug Eruptions Mimicry

Clinical
Presentation
Pattern and
Distribution of
Skin Lesions
Mucous
Membrane
Involvement
StevensJohnson
syndrome
Atypical targets,
widespread
Toxic epidermal
necrolysis
Implicated Drugs
Treatment
Present
Aromatic anticonvulsants,a
lamotrigine, sulfonamide
antibiotics, allopurinol, piroxicam,
dapsone
IVIg, cyclosporine,
supportive care
Epidermal necrosis with

skin detachment
Present
As above
IVIg, cyclosporine,
supportive care
Pseudoporphyria
Skin fragility,
blister formation in
photodistribution
Absent
Tetracycline, furosemide,
naproxen
Supportive care
Linear IgA disease
Bullous dermatosis
Present/absent
Vancomycin, lithium, diclofenac,

piroxicam, amiodarone
Supportive care
Pemphigus
Flaccid bullae, chest
Present/absent
Penicillamine, captopril,
piroxicam, penicillin, rifampin,
propranolol
Supportive care
Bullous pemphigoid
Tense bullae, widespread
Present/absent
Furosemide, penicillamine,
penicillins, sulfasalazine, captopril
Supportive care
IVIg = intravenous immunoglobulin.

a
Aromatic anticonvulsants = phenytoin, carbamazepine, phenobarbital, oxcarbazepine, primidone.
453
proven by direct immunofluorescence, the index of suspicion of drug induction should be higher in cases with
only IgA and no IgG in the basement membrane zone.
Several drugs can induce linear IgA bullous dermatosis, the most frequently reported being vancomycin.35
Section 6
::
DRUG-INDUCED PEMPHIGUS. Pemphigus

may be considered as drug-induced or drug-triggered
(i.e., a latent disease that is unmasked by the drug
exposure; see Chapter 54). Drug-induced pemphigus
caused by penicillamine and other thiol-containing
drugs (e.g., piroxicam, captopril) tends to remit spontaneously in 35%50% of cases, presents as pemphigus
foliaceus, has an average interval to onset of 1 year,
and is associated with the presence of antinuclear antibodies in 25% of patients.
Most patients with nonthiol drug-induced pemphigus manifest clinical, histologic, immunologic, and
evolutionary aspects similar to those of idiopathic
pemphigus vulgaris with mucosal involvement and
show a 15% rate of spontaneous recovery after drug
withdrawal. Treatment of drug-induced pemphigus begins with drug cessation. Systemic glucocorticoids and other immunosuppressive drugs are often
required until all symptoms of active disease disappear. Vigilant follow-up is required after remission to
monitor the patient and the serum for autoantibodies
to detect an early relapse.36
DRUG-INDUCED BULLOUS PEMPHIGOID.
Drug-induced bullous pemphigoid (see Chapter 56)

can encompass a wide variety of presentations, ranging from the classic features of large, tense bullae
arising from an erythematous, urticarial base with
moderate involvement of the oral cavity, through mild
forms with few bullous lesions, to scarring plaques
and nodules with bullae. Medications that have been
reported to cause bullous pemphigoid include furosemide, amoxicillin, and spironolactone. In contrast to
patients with the idiopathic form, patients with druginduced bullous pemphigoid are generally younger. In
addition, the histopathologic findings are of a perivascular infiltration of lymphocytes with few eosinophils
and neutrophils, intraepidermal vesicles with foci of
necrotic keratinocytes, thrombi in dermal vessels, and
a possible lack of tissue-bound and circulating antibasal membrane zone IgG.37
In the acute, self-limited condition, resolution occurs
after the withdrawal of the culprit agent, with or without glucocorticoid therapy. However, in some patients
the drug may actually trigger the idiopathic form of
the disease.
determinants may influence the likelihood of a reaction and variability in innate and adaptive immunity
may influence the clinical presentation.38 In addition,
the detection of drug-specific T-cell proliferation provides evidence that T cells are involved in severe skin
rashes.39
Treatment of SJS/TEN includes discontinuance of
the suspected drug(s) and supportive measures such
as careful wound care, hydration, and nutritional support. The use of corticosteroids in the treatment of SJS
and TEN is controversial.40,41 Intravenous Ig (IVIg, up
to 34 g over 3 days) has been shown in some reports
to halt progression of TEN, especially when IVIg is
started early. However, some studies have not found
an improved outcome in patients with TEN who are
treated with IVIg.38 A recent study concluded that neither corticosteroids nor intravenous Ig had any significant effect on mortality in comparison to supportive
care only.42 Other treatment modalities include cyclosporine,43 cyclophosphamide, and plasmapharesis.
Patients who have developed a severe cutaneous ADR
should not be rechallenged with the drug. Desensitization therapy with the medication may also be a risk.
FIXED DRUG ERUPTIONS

FDEs usually appear as solitary, erythematous, bright
red or dusky red macules that may evolve into an
edematous plaque; bullous-type lesions may be present, widespread lesions may be difficult to differentiate from TEN. FDEs are commonly found on the
genitalia and in the perianal area, although they can
occur anywhere on the skin surface (Fig. 41-5). Some
STEVENSJOHNSON SYNDROME AND

TOXIC EPIDERMAL NECROLYSIS. SJS and TEN
454
or the SJS/TEN spectra represent variants of the same

disease process. Differentiation between the two patterns depends on the nature of the skin lesions and the
extent of body surface area involvement (see Chapters
39 and 40).
Recently, the understanding of the pathogenesis of
severe cutaneous ADRs has expanded greatly. Various
factors including pharmacogenetic and immunogentic
Figure 41-5 Fixed drug eruption: tetracycline. A welldefined plaque on the knee, merging with three satellite
lesions. The large plaque exhibits epidermal wrinkling, a
sign of incipient blister formation. This was the second
such episode after ingestion of a tetracycline. No other
lesions were present.
DRUG-INDUCED LICHENOID
ERUPTIONS
Drug-induced lichen planus produces lesions that are
clinically and histologically indistinguishable from
those of idiopathic lichen planus (see Chapter 26); however, lichenoid drug eruptions often appear initially as
eczematous with a purple hue and involve large areas
of the trunk. Usually, the mucous membranes and
nails are not involved. Histologically, focal parakeratosis, cytoid bodies in the cornified and granular layers, the presence of eosinophils and plasma cells in the
inflammatory infiltrate, and an infiltrate around the
deep vessels favor a diagnosis of lichenoid drug eruption. Many drugs, including -blockers, penicillamine,
and ACE-inhibitors, especially captopril, reportedly
produce this reaction. Lichen planus-like eruptions
have also been reported with tumor necrosis factor-
(TNF) antagonists, such as infliximab, etanercept, and
adalimumab.48,49 The mean latent period is between 2
months and 3 years for penicillamine, approximately 1
year for -adrenergic blocking agents, and 36 months
for ACE-inhibitors. For anti-TNF treatments, the time
to reaction is similar with onset occurring between 3
weeks and 62 weeks. The latent period may be shortened if the patient has been previously exposed to
the drug. Resolution usually occurs with 24 months.
Rechallenge with the culprit drug has been attempted
in a few patients, with reactivation of symptoms within
415 days.50
Anticoagulant-induced skin necrosis begins 35 days

after initiation of treatment. The majority of cases of
anticoagulant-induced skin necrosis have been attributed to coumarin congeners (bishydroxycoumarin,
phenprocoumon, acenocoumarol, and warfarin) (Fig.
41-6). Early red, painful plaques develop in adiposerich sites such as breasts, buttocks, and hips. These
plaques may blister, ulcerate, or develop into necrotic
areas. It is estimated that 1 in 10,000 persons who
receive the drug is at risk of this adverse event. The
incidence is four times higher in women, especially
in obese women, with a peak incidence in the sixth
and seventh decades of life. Affected patients often
have been given a large initial loading dose of war-
::
ANTICOAGULANT-INDUCED
SKIN NECROSIS
farin in the absence of concomitant heparin therapy.

An accompanying infection such as pneumonia, viral
infection, or erysipelas may be seen in up to 25% of
patients. An association with protein C and protein S
deficiencies exists, but pretreatment screening is not
warranted. An association with heterozygosity for factor V Leiden mutation has been reported.
The pathogenesis of this adverse event is the paradoxical development of occlusive thrombi in cutaneous
and subcutaneous venules due to a transient hypercoagulable state. This results from the suppression of the
natural anticoagulant protein C at a greater rate than
the suppression of natural procoagulant factors.
Treatment involves the discontinuation of warfarin,
administration of vitamin K, and infusion of heparin
at therapeutic dosages. Fresh frozen plasma and purified protein C concentrates have been used. Supportive measures for the skin are a mainstay of therapy.
The morbidity rate is high; 60% of affected individuals require plastic surgery for remediation of fullthickness skin necrosis by skin grafting. These patients
may be treated with warfarin in the future, but small
dosages (25 mg daily) are recommended, with initial
treatment under heparin coverage.46,47
Chapter 41
patients may complain of burning or stinging, and

others may have fever, malaise, and abdominal symptoms. FDE can develop from 30 minutes to 816 hours
after ingestion of the medication. After the initial acute
phase lasting days to weeks, residual grayish or slatecolored hyperpigmentation develops. On rechallenge,
not only do the lesions recur in the same location, but
also new lesions often appear.
More than 100 drugs have been implicated in
causing FDEs, including ibuprofen, sulfonamides,
naproxen, and tetracyclines. A haplotype linkage in
trimethoprimsulfamethoxazole-induced FDE has
been documented.
A challenge or provocation test with the suspected
drug may be useful in establishing the diagnosis. Patch
testing at the site of a previous lesion yields a positive
response in up to 43% of patients. Results of prick and
intradermal skin tests may be positive in 24% and 67%
of patients, respectively.44,45 Food-initiated fixed eruptions also exist and are important to consider when
assessing causation.
DRUG-INDUCED CUTANEOUS
PSEUDOLYMPHOMA
Figure 41-6 Skin necrosis in a patient after 4 days of warfarin therapy.
Pseudolymphoma is a process that simulates lymphoma but has a benign behavior and does not meet
455
the criteria for malignant lymphoma. Drugs are a wellknown cause of cutaneous pseudolymphomas (see
Chapter 146), but the condition may also be induced
by foreign agents such as insect bites, infections (e.g.,
HIV), and idiopathic causes.51
Anticonvulsant-induced pseudolymphoma generally occurs after 1 week to 2 years of exposure to the
drug. Within 714 days of drug discontinuation, the
symptoms usually resolve. The eruption often manifests as single lesions but can also be widespread erythematous papules, plaques, or nodules. Most patients
also have fever, marked lymphadenopathy and hepatosplenomegaly, and eosinophilia. Mycosis fungoideslike lesions are also associated with these drugs.52
Section 6
DRUG-INDUCED VASCULITIS
::
Drug-induced vasculitis represents approximately

10% of the acute cutaneous vasculitides and usually
involves small vessels (see Chapter 163). Drugs that
are associated with vasculitis include propylthiouracil,
hydralazine, granulocyte colony-stimulating factor,
granulocyte-macrophage colony-stimulating factor,
allopurinol, cefaclor, minocycline, penicillamine, phenytoin, isotretinoin, and anti-TNF agents, including
etanercept, infliximab, and adalimumab.49 The average interval from initiation of drug therapy to onset
of drug-induced vasculitis is 721 days; in the case of
rechallenge, lesions can occur in less than 3 days.15
The clinical hallmark of cutaneous vasculitis is palpable purpura, classically found on the lower extremities. Urticaria can be a manifestation of small vessel
vasculitis, with individual lesions remaining fixed in
the same location for more than 1 day. Other features
include hemorrhagic bullae, ulcers, nodules, Raynaud
disease, and digital necrosis. The same vasculitic process may also affect internal organs such as the liver,
kidney, gut, and central nervous system and can be
potentially life threatening.53
Drug-induced vasculitis can be difficult to diagnose
and is often a diagnosis of exclusion. In some cases,
serologic testing has revealed the presence of perinuclear-staining antineutrophil cytoplasmic autoantibodies against myeloperoxidase. Alternative causes for
cutaneous vasculitis such as infection or autoimmune
disease must be eliminated. Tissue eosinophilia may be
an indicator of drug induction in cutaneous small vessel vasculitis. Treatment consists of drug withdrawal.
Systemic glucocorticoids may be of benefit.
DRUG-INDUCED LUPUS
456
(See Chapter 155)

Drug-induced lupus is characterized by frequent
musculoskeletal complaints, fever, weight loss, pleuropulmonary involvement in more than half of patients,
and in rare cases renal, neurologic, or vasculitic
involvement (see Table 41-1). Many patients have no
cutaneous findings of lupus erythematosus. The most
common serologic abnormality is positivity for antinuclear antibodies with a homogenous pattern. Although
antihistone antibodies are seen in up to 95% of druginduced lupus, they are not specific for the syndrome
and are found in 50%80% of patients with idiopathic
lupus erythematosus. Unlike in idiopathic lupus erythematosus, antibodies against double-stranded DNA
are typically absent, whereas antisingle-stranded DNA
antibodies are often present.54 Genetic factors may
also play a role in the development of drug-induced
lupus. HLA-DR4 is present in 73% of the patients with
hydralazine-induced lupus and in 70% of patients
with minocycline-induced lupus.55 Evidence now suggests that abnormalities during T-cell selection in the
thymus initiate lupus-like autoantibody induction.56
In contrast, drug-induced subacute cutaneous lupus
erythematosus is characterized by a papulosquamous
or annular cutaneous lesion, which is often photosensitive, and absent or mild systemic involvement. Circulating anti-Ro (Sjgren syndrome A) antibodies have
also been identified in many patients.
Many drugs have been implicated in causing druginduced lupus syndromes, especially hydralazine, procainamide, isoniazid, methyldopa, and minocycline.57
Drugs that have been associated with subacute cutaneous lupus erythematosus include thiazide diuretics, calcium channel blockers, and ACE inhibitors. The
number of patients who develop subacute cutaneous
lupus erythematosus during treatment with these
medications is very low, and these drugs are thought
to have a low risk for causing or exacerbating cutaneous lupus.58 Other drugs that have been associated
with drug-induced lupus include terbinafine, proton
pump inhibitors, and anti-TNF treatments.58
The identification of minocycline as a cause of druginduced lupus makes it important for dermatologists
to recognize this syndrome. Minocycline-induced
lupus typically occurs after 2 years of therapy. The
patient presents with a symmetric polyarthritis. Hepatitis is often detected on laboratory evaluation. Cutaneous findings include livedo reticularis, painful nodules
on the legs, and nondescript eruptions. Antihistone
antibodies are seldom present. A study of HLA class II
alleles revealed the presence of HLA-DR4 or HLA-DR2
in many of the patients.55
DIAGNOSIS AND MANAGEMENT

The iatrogenic disorders described here are distinct
disease entities, although they may closely mimic
many infective or idiopathic diseases. A drug cause
should be considered in the differential diagnosis of a
wide spectrum of dermatologic diseases, particularly
when the presentation or course is atypical.
The diagnosis of a cutaneous drug eruption involves
the precise characterization of reaction type. A wide
variety of cutaneous drug-associated eruptions may
also warn of associated internal toxicity (Table 41-3).
Even the most minor cutaneous eruption should trigger a clinical review of systems, because the severity of
systemic involvement does not necessarily mirror that
of the skin manifestations. Hepatic, renal, joint, respiratory, hematologic, and neurologic changes should be
sought, and any systemic symptoms or signs investi-
TABLE 41-3
Clinical Features That Warn of a Potentially

Severe Drug Reaction
Systemic
Fever and/or other symptoms of internal organ
involvement such as pharyngitis, malaise, arthralgia,
cough, and meningismus
Lymphadenopathy
Cutaneous reactions to drugs are largely idiosyncratic

and unexpected; serious reactions are rare. However,
once a reaction has occurred, it is important to prevent
future similar reactions in the patient with the same
drug or a cross-reacting medication. For patients with
severe reactions, wearing a bracelet (e.g., MedicAlert)
detailing the nature of the reaction is advisable, and
patient records should be appropriately labeled.
Host factors appear important in many reactions.
Some of these can be inherited, which places firstdegree relatives at a greater risk than the general
population for a similar reaction to the same or a metabolically cross-reacting drug. This finding appears to
be important in SJS, TEN, and drug hypersensitivity
syndrome.
Reporting reactions to the manufacturer or regulatory authorities is important. Postmarketing voluntary
reporting of rare, severe, or unusual reactions remains
crucial to enhance the safe use of pharmaceutical
agents.
PREVENTION
::
gated. Fever, malaise, pharyngitis, and other systemic

symptoms or signs should be investigated. A usual
screen would include a full blood count, liver and
renal function tests, and a urine analysis.
Skin biopsy should be considered for all patients
with potentially severe reactions, such as those with
systemic symptoms, erythroderma, blistering, skin
tenderness, purpura, or pustulation, as well as in
cases in which the diagnosis is uncertain. Some cutaneous reactions, such as FDE, are almost always due
to drug therapy, and approximately 40%50% of SJS/
TEN cases are also drug related.59 Other more common
eruptions, including exanthematous or urticarial eruptions, have many nondrug causes.
There is no gold standard investigation for confirmation of a drug cause. Instead, diagnosis and assessment
of cause involve analysis of a constellation of features
such as timing of drug exposure and reaction onset,
course of reaction with drug withdrawal or continuation, timing, and nature of a recurrent eruption on
rechallenge, a history of a similar response to a crossreacting medication, and previous reports of similar
reactions to the same medication. Investigations to
exclude nondrug causes are similarly helpful.
Several in vitro investigations can help to confirm
causation in individual cases, but their exact sensitivity
and specificity remain unclear. Investigations include
the lymphocyte toxicity and lymphocyte transformation assays.60 The basophil activation test has been
reported to be useful to evaluate patients with possible
drug allergies to -lactam antibiotics, NSAIDs, and
muscle relaxants.14 Penicillin skin testing with major
and minor determinants is useful for confirmation of
an IgE-mediated immediate hypersensitivity reaction
to penicillin.14 Patch testing has been used in patients
with ampicillin-induced exanthematous eruptions,
AGEP reactions,61 abacavir-induced hypersensitivity,62
and in the ancillary diagnosis of FDEs. Patch testing
has greater sensitivity if performed over a previously
involved area of skin.
Cutaneous drug eruptions do not usually vary in
severity with dose. Less severe reactions may abate
with continued drug therapy (e.g., transient exan-
Chapter 41
Cutaneous
Evolution to erythroderma
Prominent facial involvement edema or swelling
Mucous membrane involvement (particularly if erosive or
involving conjunctiva)
Skin tenderness, blistering, or shedding
Purpura
thematous eruptions associated with commencement

of a new HIV antiretroviral regimen). However, a reaction suggestive of a potentially life-threatening situation should prompt immediate discontinuation of the
drug, along with discontinuation of any interacting
drugs that may slow the elimination of the suspected
causative agent. Although the role of corticosteroids
in the treatment of serious cutaneous reactions is controversial, most clinicians choose to start prednisone
at a dosage of 12 mg/kg/day when symptoms are
severe. Antihistamines, topical corticosteroids, or both
can be used to alleviate symptoms.63 Resolution of the
reaction over a reasonable time frame after the drug is
discontinued is consistent with a drug cause but also
occurs for many infective and other causes of transient cutaneous eruptions. Drug desensitization, also
known as induction of drug tolerance, has been used
primarily for IgE-mediated reactions caused by drugs
such as penicillin or more recently, monoclonal antibodies such as rituximab and infliximab.14,64 Patients
should not be rechallenged or desensitized if they have
suffered a potentially serious reaction.
KEY REFERENCES
11. Eshki M et al: Twelve-year analysis of severe cases of drug
reaction with eosinophilia and systemic symptoms. Arch
Dermatol 145:67-72, 2009
14. Khan D, Solensky R: Drug allergy. J Allergy Clin Immunol
125:S126-S137, 2010
39. Mockenhaupt M: Severe drug-induced skin reactions:
Clinical pattern, diagnostics and therapy. J Dtsch Dermatol
Ges 7:142-160, 2009
53. Justiniano H, Berlingeri-Ramos A, Sanchez J: Pattery analysis of drug-induced skin diseases. Am J Dermatopathol
30:352-369, 2008
457
Chapter 42 :: Pityriasis Rosea

:: Andrew Blauvelt
PITYRIASIS ROSEA AT A GLANCE
Common acute papulosquamous eruption
normally lasting 410 weeks.
Section 6
Most often begins as a single 2- to 4-cm thin

oval plaque with a fine collarette of scale
located inside the periphery of the plaque
(herald patch).
::
Similar-appearing, but smaller, lesions

appear several days to weeks later, typically
distributed along the lines of cleavage on the
trunk (Christmas tree pattern).
Usually asymptomatic, sometimes pruritic
with mild flu-like symptoms.
Occurs most commonly in teenagers and
young adults.
Probably a viral exanthem associated with
reactivation of human herpes virus (HHV)-7
and sometimes HHV-6.
Treatment is usually supportive, although
midpotency topical corticosteroids can
reduce pruritus; high-dose acyclovir for
1 week may hasten recovery.
The term pityriasis rosea (PR) was first used by Gibert in

1860 and means pink (rosea) scales (pityriasis).1 PR is a
common acute, self-limited skin eruption that typically
begins as a single thin oval scaly plaque on the trunk
(herald patch) and is typically asymptomatic. The
initial lesion is followed several days to weeks later
by the appearance of numerous similar-appearing
smaller lesions located along the lines of cleavage of
the trunk (a so-called Christmas tree pattern). PR most
commonly occurs in teenagers and young adults, and
is most likely a viral exanthem associated with reactivation of human herpes virus 7 (HHV-7) and sometimes HHV-6,25 the viruses responsible for rubeola
(see Chapter 192). Possible treatment may focus on
associated pruritus. One study suggests that administration of high-dose acyclovir for 1 week, if initiated
early in the disease course, hastens recovery from PR.6
EPIDEMIOLOGY
458
PR is reported in all races throughout the world, irrespective of climate.79 The average annual incidence
at one center was reported to be 0.16% (158.9 cases
per 100,000 person-years).9 Although PR is usually
considered to be more common in the spring and fall

months in temperate zones, seasonal variation has not
been borne out in studies performed in other parts of
the world. Clustering of cases can occur and has been
used to support an infectious etiology for PR, although
this is not a consistent feature observed in all communities.8 Most studies have shown a slight female
preponderance of approximately 1.5:1.7,9 PR most commonly occurs between the ages of 10 and 35 years.9 It
is rare before age 2 years and after age 65 years. Recurrences of PR are rare, which suggests lasting immunity
after an initial episode of PR.

Historically, PR has been considered to be caused by an
infectious agent, given (1) the resemblance of the rash to
known viral exanthems; (2) rare recurrences of PR that
suggest lifelong immunity after one episode; (3) occurrence of seasonal variation in some studies; (4) clustering
in some communities; and (5) the appearance of flu-like
symptoms in a subset of patients. Numerous studies
over the past 50 years have explored various pathogens
as possible causes of PR. These pathogens have included
bacteria, fungi, and, most notably, viruses. Beginning
with a study by Drago and colleagues in 1997,2 most
recent PR etiologic and pathogenic studies have been
focused on two ubiquitous viruses: (1) HHV-7 and (2)
HHV-6. Critical evaluation of the medical and scientific
literature on PR reveals neither credible nor reproducible evidence that PR is associated with any pathogen
other than HHV-7 and HHV-6.10
Indeed, the best scientific evidence suggesting that
PR is a viral exanthem associated with reactivation
of either HHV-7 or HHV-6 (and sometimes with both
viruses) is strong.25,1113 The most definitive and compelling study on HHVs and PR was by Broccolo and
colleagues in 2005.4 Using sensitive and quantitative
techniques, investigators have collectively shown that
(1) HHV-7 DNA, and less commonly HHV-6 DNA, can
be readily detected in cell-free plasma or serum samples from many patients with PR, but not in serum or
plasma from healthy individuals or patients with other
inflammatory skin diseases; (2) HHV-7 messenger RNA
and protein, and less commonly HHV-6 messenger
RNA and protein, can be detected in scattered leukocytes found in perivascular and perifollicular regions
within PR lesions, but not in normal skin or skin from
patients with other inflammatory skin diseases; (3)
HHV-7- and HHV-6-specific immunoglobulin (Ig) M
antibody elevations in the absence of virus-specific IgG
antibodies do not occur in PR patients, whereas in primary viral infections elevation of IgM antibodies alone
is typical; and (4) HHV-7 and HHV-6 DNA are present
in saliva of individuals with PR, which is not observed
in those with a primary infection with these viruses.
Taken together, these data strongly suggest that PR is
Chapter 42
::
Figure 42-1 A typical primary plaque (herald patch) of

pityriasis rosea, demonstrating an oval shape and fine
scale inside the periphery of the plaque.
later by the onset of numerous smaller lesions on the
trunk. Pruritus is severe in 25% of patients with uncomplicated PR, slight to moderate in 50%, and absent in
25%. In a minority of patients, flu-like symptoms have
been reported, including general malaise, headache,
nausea, loss of appetite, fever, and arthralgias.
Pityriasis Rosea
a viral exanthem associated with systemic reactivation

of HHV-7 and, to a lesser extent, HHV-6. Patients are
viremic, which may explain associated flu-like symptoms in some patients, and they generally do not have
infected epithelial cells or large viral loads within skin
lesions, which explains the difficulty in detecting these
viruses by electron microscopy and by nonnested
polymerase chain reaction testing.
Despite these findings, there is still controversy over
the role of HHV-7 and HHV-6 in the etiology of PR,
because a number of studies with negative results
have failed to support a causative role for HHV-7 and
HHV-6 in this disease.1416 Whereas the studies with
positive results have used the most sensitive, specific,
and calibrated techniques for virologic studies and
reports have been published in high-quality journals,
the studies with negative results either used laboratory
methods that were not particularly sensitive, calibrated,
or quantifiable, or focused on peripheral blood mononuclear cells rather than cell-free plasma or serum.
Correct interpretation of the recent viral literature on
PR also requires proper understanding of the biology
of HHV-7 and HHV-6. HHV-7 and HHV-6 are closely
related -herpes viruses, and the clinical diseases and
biology associated with this group of HHVs are not
as well studied as those of the -herpes viruses (herpes simplex virus 1 and 2, varicella-zoster virus) and
the -herpes viruses (EpsteinBarr virus and Kaposi
sarcoma-associated herpes virus). HHV-6 and HHV-7
are ubiquitous, with 90% of the US population infected
with HHV-6 by the age of 3 years17 and 90% of the US
population infected with HHV-7 by the age of 5 years.18
Unlike the -herpes viruses, HHV-7 and HHV-6 do
not infect keratinocytes, but instead infect CD4+ T
cells within blood and are retained within these cells
in a latent form in most individuals.10,1719 These cells
are the likely source of cell-free viral DNA found in
plasma or serum samples of patients with PR. They
are also the likely source of the scattered perivascular
and perifollicular virus-positive cells observed within
some lesions of PR.3,4
It is important to note that the concept that PR represents a reactive viral exanthem containing few infected
cells within skin lesions and viral reactivation within
circulating blood CD4+ T cells is perfectly analogous
to that of the disease roseola, which is well accepted
to be caused by primary infection with either HHV-6
or HHV-720,21 (see Chapter 192). Children with roseola
are viremic and skin lesions generally do not contain
infected cells.22 Complete understanding of the role of
HHV-7 and HHV-6 in the pathogenesis of PR is lacking at this time. For example, the mechanisms by which
HHV-7 and HHV-6 are reactivated are unknown. As
well, the characteristic distribution of lesions and differences in lesional and nonlesional skin are unexplained.
CUTANEOUS LESIONS
The primary plaque of PR, or herald patch (Figs. 42-1
42-3 and see eFigs. 42-3.1 and 42-3.2 in online edition),
is seen in 50%90% of cases. It is normally well demarcated; 24 cm in diameter; oval or round; salmon
CLINICAL FINDINGS
HISTORY
In classic PR, patients usually describe the onset of a single truncal skin lesion followed several days to weeks
Figure 42-2 A nonscaly purpuric primary plaque (herald

patch) of pityriasis rosea.
459
Primary and secondary plaques
Herald
patch
Section 6
::
460
Figure 42-4 Schematic diagram of the primary plaque

(herald patch) and the typical distribution of secondary plaques along the lines of cleavage on the trunk in a
Christmas tree pattern.
Figure 42-3 A double herald patch of pityriasis rosea.
c olored, erythematous, or hyperpigmented (especially

in individuals with darker skin); and demonstrates a
fine collarette of scale just inside the periphery of the
plaque. When the plaque is irritated, it may have an
eczematous papulovesicular appearance (eFig. 42-3.3 in
online edition). The primary plaque is usually located
on the trunk in areas covered by clothes, but sometimes
it is on the neck or proximal extremities. Localization on
the face or penis is rare. The site of the primary lesion
does not differ between males and females.
The interval between the appearance of the primary
plaque and the secondary eruption can range from 2
days to 2 months, but the secondary eruption typically
occurs within 2 weeks of the appearance of the primary
plaque. At times, the primary and secondary lesions
may appear at the same time. The secondary eruption
occurs in crops at intervals of a few days and reaches
its maximum in approximately 10 days. Occasionally,
new lesions continue to develop for several weeks. The
symmetric eruption is localized mainly to the trunk
and adjacent regions of the neck and proximal extremities (Fig. 42-4). The most pronounced lesions extend
over the abdomen and anterior surface of the chest as
well as over the back (Figs. 42-542-7 and eFigs. 42-7.1
and 42-7.2 in online edition). Lesions distal to the
elbows and knees can occur. Two main types of secondary lesions occur: (1) small plaques resembling the
primary plaque in miniature, aligned with their long
axes along lines of cleavage and distributed in a Christmas tree pattern, and (2) small, red, usually nonscaly
papules that gradually increase in number and spread
peripherally. The two types of lesions may coexist.
In approximately 20% of patients, the clinical picture

diverges from the classic one described above. The primary plaque may be missing or present as double or
multiple lesions (Fig. 42-3 and see eFig. 42-3.1 in online
edition), often close together. The primary plaque may be
the sole manifestation of the disease or only one of the two
lesions (eFig. 42-3.2 in online edition). The distribution of
the secondary eruption may be exclusively peripheral.
Facial and scalp involvement occurs more commonly in
black children. Localized forms of disease may involve
Figure 42-5 Typical distribution of secondary plaques

along the lines of cleavage on the back in a Christmas tree
pattern.
Chapter 42
Figure 42-8 Typical nonspecific histologic features of

pityriasis rosea, including patchy parakeratosis, absence
of a granular cell layer, slight acanthosis, spongiosis, and a
lymphohistiocytic infiltrate in the superficial dermis.
::
certain body regions such as the palms, soles, axillae,

vulva, and groin (eFigs. 42-3.3 and 42-7.1 in online edition) and also may be localized to one side of the body.
The morphology of the secondary lesions may also
be atypical, and in these cases, the diagnosis of PR can
be more challenging. Macules lacking scales may occur,
papules may be follicular, and typical plaques may be
absent or resemble psoriasis (eFig. 42-7.3 in online edition). The palms and soles are involved at times, and
the clinical picture in these patients may simulate a
widespread eczematous eruption. A vesicular type of
PR (eFig. 42-3.3 in online edition) uncommonly affects

children and young adults. Urticarial, pustular, purpuric (Fig. 42-2 and eFig. 42-7.4 in online edition), and erythema multiforme-like variants of PR also exist. Many
patients will have classic PR plaques admixed with the
atypical vesicles, follicular papules, and purpura.
Pityriasis Rosea
Figure 42-6 Typical distribution of secondary plaques

along the lines of cleavage on the chest of a black individual.

In rare cases enanthema may occur with hemorrhagic
macules and patches, bullae on the tongue and cheeks,
or lesions that resemble aphthous ulcers. Nail dystrophy after PR has also been reported. Lymphadenopathy may occur in patients with PR, especially early
in the course of the disease and in association with
flu-like symptoms.
In cases of classic PR, most patients do not require
skin biopsies because the diagnosis is straightforward
on clinical grounds and the histologic findings are nonspecific. Typical histopathologic features include focal
parakeratosis, a reduced or absent granular cell layer,
mild acanthosis, mild spongiosis, papillary dermal
edema, a perivascular and superficial dermal interstitial infiltrate of lymphocytes and histiocytes, and focal
extravasation of erythrocytes (Fig. 42-8).23,24 Similar
histologic findings are observed in both primary and
secondary plaques. The histologic picture is indistinguishable from that of superficial gyrate erythema. In
older lesions, the perivascular infiltrate is often both
superficial and deep, with less spongiosis and more
pronounced acanthosis. These late lesions may be difficult to distinguish from psoriasis and lichen planus.
LABORATORY TESTS
Figure 42-7 Vesicular pityriasis rosea, showing typical

primary plaque and secondary papulovesicles. Note
Christmas tree distribution.
Routine blood studies usually give normal results and

are not recommended. However, leukocytosis, neutrophilia, basophilia, lymphocytosis, and slight increases
in erythrocyte sedimentation rate and levels of total
protein, 1- and 2-globulins, and albumin have been
reported.
461
Section 6
::
462
(Box 42-1)
Secondary syphilis may present with slightly scaly
lesions and can mimic papular PR with no primary
plaque. Mucosal lesions and lymphadenopathy may
occur in both PR and syphilis, but as with involvement
of the palms and soles, these findings are much more
common in the latter. Serologic tests for syphilis will
differentiate the two. Tinea corporis may resemble PR,
especially when PR occurs as only a primary plaque
or when it is localized to the groin area. Scaling will
be at the periphery of the plaques in tinea corporis
as opposed to inside the periphery of plaques in PR.
Mycologic investigation is often necessary to rule out
dermatophyte infection. The lesions of nummular
dermatitis are usually round, not oval, and pinpoint
papules and vesicles are more prominent than in PR.
Guttate psoriasis may be difficult to distinguish from
PR when only a few lesions are present, when lesions
follow lines of cleavage, and when the disease course
is chronic. Histologic examination may be useful in
these cases. Pityriasis lichenoides chronica may present with a Christmas tree pattern on the trunk, but as
a rule, typical lesions will be found on the extremities.
Many drugs have been reported to cause PR-like
rashes. Thus, it is always important to obtain a drug
history to investigate this possibility. These include
arsenic, barbiturates, bismuth, captopril, clonidine,

of Pityriasis Rosea (PR)
Secondary syphilis: history of primary chancre, no
herald patch is present, lesions typically involve
palms and soles, condyloma lata may be present,
usually more systemic complaints and lymphadenopathy, presence of plasma cells on histology,
positive serologic test for syphilis [e.g., a Venereal
Disease Research Laboratory (VDRL) test].
Tinea corporis: scale is usually at periphery of
plaques, plaques usually not oval and distributed
along lines of cleavage, positive KOH examination.
Nummular dermatitis: plaques usually circular and
not oval, no collarettes of scale, tiny vesicles common. When in doubt, perform a biopsy.
Guttate psoriasis: plaques usually smaller than PR
plaques and do not follow lines of cleavage, scales
are thick and not fine. When in doubt, perform a
biopsy.
Pityriasis lichenoides chronica: longer disease
course, smaller lesions, thicker scale, no herald
patch, more common on extremities. When in
doubt, perform a biopsy.
PR-like drug eruption: see text for extensive list.
When in doubt, obtain a drug history.
gold, interferon-, isotretinoin, ketotifen, labetalol,

organic mercurials, methoxypromazine, metronidazole, omeprazole, d-penicillamine, salvarsan, sulfasalazine, terbinafine, lithium, and tripelene amine
hydrochloride. Of note, more recent additions to this
list include imatinib,25 a drug used in the treatment
of chronic myeloid leukemia, and tumor necrosis factor (TNF)- blockers used to treat psoriasis.26,27 Druginduced PR may closely resemble classic PR, but it
often shows atypical features, a protracted course,
large lesions, subsequent marked hyperpigmentation,
and transformation to lichenoid dermatitis.
COMPLICATIONS
Patients may experience flu-like symptoms, but these
are relatively mild if they occur. About one-third of
patients with PR experience significant levels of anxiety
and depression, mostly centered around uncertainty
over the cause of the disease and the length of disease
recovery.28 Reassurance is important for these individuals. No serious complications occur in otherwise
healthy PR patients. However, PR during pregnancy
is of concern. In one series of 38 pregnant women with
PR, Drago and colleagues reported nine premature
deliveries, although all babies born to women who had
PR during their pregnancy showed no birth defects.29
Five women had miscarriages, which was most common in the first trimester. Thus, pregnant women who
develop PR should warrant careful evaluation and
follow-up.

COURSE
All patients with PR have complete spontaneous
resolution of their disease. The disease duration normally varies between 4 and 10 weeks, with the first
few weeks associated with the most new inflammatory skin lesions and the greatest likelihood of flu-like
symptoms. Both postinflammatory hypopigmentation
and hyperpigmentation can follow PR. As with other
skin diseases, this occurs more commonly in individuals with darker skin color, with hyperpigmentation predominating.30 Treatment with ultraviolet light
phototherapy may also worsen postinflammatory
hyperpigmentation and should be used with caution.
Otherwise, patients have no residual effects secondary
to the occurrence of PR. Recurrent disease is possible,
but it is rare.
TREATMENT
Because PR is self-limited, there is no need to treat
uncomplicated cases.31 Patient education and reassurance is warranted in all cases. Midpotency topical
corticosteroids may be used for symptomatic relief
of pruritus. Interestingly, Drago and colleagues have
BOX 42-2 Treatment of Pityriasis

Rosea
PREVENTION
There are no data on how PR can be prevented.
KEY REFERENCES
Chapter 43 :: E
rythema Annulare Centrifugum and
Other Figurate Erythemas

:: Walter H.C. Burgdorf
ERYTHEMA ANNULARE
CENTRIFUGUM AT A GLANCE
Clinical pattern of annular expanding
erythematous rings, which enlarge rapidly,
fade, and then disappear, as new lesions
appear.
Diagnosis of erythema annulare centrifugum
is one of the exclusions.
Superficial and deep variants can be
separated clinically and histologically. Deep
form is usually lupus tumidus or erythema
migrans.
Erythema Annulare Centrifugum and Other Figurate Erythemas
2. Drago F et al: Human herpesvirus 7 in pityriasis rosea.

Lancet 349:1367, 1997
3. Watanabe T et al: Pityriasis rosea is associated with systemic active infection with both human herpesvirus-7 and
human herpesvirus-6. J Invest Dermatol 119:793, 2002
4. Broccolo F et al: Additional evidence that pityriasis rosea
is associated with reactivation of human herpesvirus-6
and -7. J Invest Dermatol 124:1234, 2005
6. Drago F, Vecchio F, Rebora A: Use of high-dose acyclovir
in pityriasis rosea. J Am Acad Dermatol 54:82, 2006
10. Drago F, Broccolo F, Rebora A: Pityriasis rosea: an update
with a critical appraisal of its possible herpesviral etiology. J Am Acad Dermatol 61:303, 2009
29. Drago F et al: Pregnancy outcome in patients with pityriasis rosea. J Am Acad Dermatol 58:S78, 2008
::
reported that patients given high-dose acyclovir (i.e.,

800 mg five times daily for 1 week) experienced more
rapid resolution of PR than patients treated with placebo for 1 week.6 Specifically, 79% of 42 patients had
complete resolution of PR within 2 weeks of starting
acyclovir therapy, whereas 4% of 45 patients treated
with placebo experienced resolution of their disease at
2 weeks. Although patients were blinded to the type of
treatment they received, the trial was limited in that the
investigators were not blinded and the patients were
not randomly assigned to one of the two treatment
groups. Given that acyclovir and its derivatives are relatively inexpensive and well-tolerated drugs, this form
of therapy should be considered in PR patients presenting early in their disease course who demonstrate
Chapter 43
For all patients, education about the disease process and reassurance.
For patients with associated pruritus, topical corticosteroids.
For patients early in the disease course who demonstrate associated flu-like symptoms and/or
extensive skin disease, oral acyclovir 800 mg five
times daily for 1 week (or equivalent acyclovir derivative) may hasten recovery from disease.
For selected patients, phototherapy may be useful.
associated flu-like symptoms and/or extensive skin

disease. Erythromycin was reported to be of benefit
to patients with PR,32 but clinical experience and more
recent reports have not confirmed this initial result.3335
Some patients with PR may benefit from phototherapy,36 although this should be used with caution given
that it can increase the risk of postinflammatory hyperpigmentation after disease resolution (Box 42-2).
The figurate erythemas include a variety of eruptions

characterized by annular and polycyclic lesions. Classification of this group has always been controversial;
the literature abounds with contradictions, uncertainties, and a bewildering array of synonyms. Darier in
1916 was the first to use the term erythema annulare
centrifugum1 (EAC), although similar lesions had been
described previously under other names. Table 43-1
lists the figurate erythemas and the differential diagnoses to consider.
EPIDEMIOLOGY
EAC is an uncommon disorder. No epidemiologic data
are available. There are only three large series in the
literature: (1) 66 cases identified clinically,2 (2) 73 first
463
TABLE 43-1
Migratory Erythemas
Section 6
::
464
Disorder
Key Features
Erythema annulare centrifugum (EAC)
Slowly migrating lesions; often idiopathic.
This chapter
Erythema gyratum repens
Rapidly moving; usually cancer marker.
153
Erythema chronicum migrans
Annular lesions originating from tick bite; skin sign of Lyme borreliosis.
187
Lupus erythematosus
Most deep EAC is lupus tumidus. Annular lesions common in neonatal

and subacute cutaneous LE; Ro/La antibodies should be sought;
overlaps with Sjgren syndrome (especially in Asians).
155
Urticaria
Giant urticaria is often annular and migratory; patients have ordinary

urticaria elsewhere and more pruritus.
38
Pityriasis rosea
Individual lesions closely resemble superficial EAC but pattern and

course different
42
Bullous pemphigoid
Early lesions often urticarial and may be annular.
56
Erythema multiforme
Target lesions, usually acral, often mucosal disease; some lesions

annular.
39
Dermatophyte infections and tinea

versicolor
Many fungal infections are annular (ringworm); the scale contains

hyphae or spores.
188
Psoriasis
Pustular and occasionally ordinary psoriasis may have annular lesions.
18
Erythema marginatum
Transient, rapidly spreading annular erythema; specific for rheumatic

fever.
160
Marker for glucagonoma; erosive perioral and acral lesions, but truncal
lesions may be polycyclic.
153
Carrier state chronic granulomatous

disease
Female carriers may have annular lupus erythematosus-like rash.
143
Hereditary lactate dehydrogenase

M-subunit deficiency
Rare genodermatosis with annular erythematous and scaly lesions.
This chapter
Familial annular erythema
Extremely rare.
This chapter
Annular erythema of infancy
Many different disorders; must rule out neonatal lupus erythematosus.
This chapter
diagnosed histologically,3 and (3) 90 carrying either a

clinical or histological diagnosis.4 EAC appears to have
no predilection for either sex or for any age group.
and often returning as the tumor recurs.1416 This paraneoplastic marker must be distinguished from metastatic tumors with an annular pattern.17,18
CLINICAL FINDINGS
Both the annularity and the peripheral spread of EAC

have attracted speculation as to a possible mechanism.
Most hypotheses have centered on interactions among
inflammatory cells, their mediators, and ground substance as foreign antigens diffuse through the skin.5,6
While many possible triggers have been suggested,
all are common problems and EAC is very rare, so a
direct causality is impossible to prove. It is better to
view EAC as idiopathic. In one series, 24 patients were
closely evaluated, and in none of the cases was any
definite cause found.7 Suspected triggers include bacterial8 and candidal9 infections, autoimmune diseases,10
menses,11 pregnancy,12 and even stress.13 Although
medications are often identified as causing EAC in
case reports, none regularly induces such lesions. EAC
may be coupled with malignant neoplasms, with the
eruption disappearing after treatment of the tumor
HISTORY
The history is most important in exploring the differential diagnostic considerations. In general, the lesions
are asymptomatic but may be cosmetically disturbing.
CUTANEOUS LESIONS
EAC presents as one or more lesions that begin as erythematous macules or urticarial papules and enlarge
by peripheral extension to form ringed, arcuate, or
polycyclic figures. They are usually asymptomatic.
EAC has traditionally been divided into superficial and
deep forms. In the superficial form, the bands have fine
scales, which are more prominent on the inner aspect
rather than the advancing edge. The lesions spread
Figure 43-3 Superficial erythema annulare centrifugum

showing perivascular lymphocytic infiltrates in papillary dermis. (Used with permission from Heinz Kutzner,
Friedrichshafen, Germany.)
Superficial EAC has epidermal changes of parakeratosis and spongiosis, with a superficial perivascular infiltrate (eFig. 43-2.1 in online edition, Figs. 43-3 and Fig.
43-4). There is minimal papillary dermal edema and
no spongiosis. Thus, there are histological similarities
to pityriasis rosea. The deep form has superficial and
deep perivascular infiltrates (Fig. 43-5). Histopathology is important in excluding common differential
diagnostic considerations; interface change or mucin
helps identify lupus erythematosus; a plasma cell
infiltrate suggests erythema chronicum migrans; and
eosinophils are a possible clue to drug reactions.
Figure 43-4 Higher view of superficial erythema annulare

centrifugum with parakeratosis and focal spongiosis.
(Used with permission from Heinz Kutzner, Friedrichshafen, Germany.)
Erythema Annulare Centrifugum and Other Figurate Erythemas
Figure 43-2 Superficial erythema annulare centrifugum.

Multiple lesions, once again demonstrating scale. (Used
with permission from Wilfried Neuse and Thomas Ruzicka,
Dsseldorf, Germany.)
HISTOPATHOLOGY
::
Figure 43-1 Superficial erythema annulare centrifugum.

A large annular plaque with trailing scale behind the
advancing erythematous edge.
Chapter 43
gradually to form large rings with central clearing,

with the edges of the lesions often advancing several
millimeters a day (Fig. 43-1 and Fig. 43-2). After a variable period of time, the lesions disappear, often to be
replaced by new ones. In some cases annual recurrence
has been described.
In the deep form of EAC, there is no scale and the rings
are infiltrated (eFig. 43-2.1 and eFig. 43-2.2 in online edition); almost all these cases represent either lupus erythematosus or erythema migrans caused by infection
with Borrelia burgdorferi.4 A few may be drug-induced.
465

of Erythema Annulare
Centrifugum (EAC)
Most Likely
Dermatophyte infections
Tinea versicolor
Erythema migrans
Annular urticaria
Lupus erythematosus
Annular psoriasis
Section 6
::
Figure 43-5 Deep erythema annulare centrifugum with

normal epidermis and lymphocytic infiltrates about
vessels of superficial and deep dermis. Many such lesions
are lupus tumidus, so a careful search for mucin is mandatory. None is seen here. (Used with permission from Heinz
Kutzner, Friedrichshafen, Germany.)

There are no other laboratory tests diagnostic for EAC.
(Box 43-1)
The differential diagnostic challenge in EAC is multiple. First, one must exclude lupus erythematosus
and erythema migrans. We view superficial EAC as a
specific entity; the annular variants of diseases such as
dermatophyte infections, psoriasis, urticaria, bullous
diseases, leukocytoclastic vasculitis, secondary syphilis, and sarcoidosis are not EAC. While a relationship
to chronic pityriasis rosea has been suggested,4 there
are so many clinical differences that we prefer not to
make this association.
There also are a number of rare figurate erythemas
that cause problems. Erythema gyratum repens, which
is generally more rapidly moving, usually reflects
an underlying malignancy (see Chapter 153). Annular erythemas are seen in the carrier state of chronic
granulomatous disease or a lactate dehydrogenase Msubunit deficiency. Annular lichenoid dermatitis of
youth is clinically similar. Familial EAC, originally
described as erythema gyratum perstans, is rare.
Finally, there is the broad spectrum of annular erythemas of infancy,19 including neonatal lupus erythematosus, Malassezia furfur infections, and the idiopathic
variants which themselves may show eosinophilic or
neutrophilic infiltrates, as well as atrophy.

466
EAC tends to be a chronic disease, which waxes and

wanes.
Consider
Erythema multiforme
Pityriasis rosea
Granulomatous diseases (granuloma annulare,
actinic granuloma, sarcoidosis)
Bullous pemphigoid (urticarial phase)
Leukocytoclastic vasculitis (especially in children)
Erythema marginatum
Erythema gyratum repens
Hypereosinophilic syndrome
Carrier state chronic granulomatous disease
Hereditary lactase dehydrogenase M-subunit
deficiency
Familial annular erythema
Annular erythemas of infancy
Always Rule Out
Lupus erythematosus
Lyme borreliosis
Underlying tumor or annular metastasis
TREATMENT
Only symptomatic relief is available. Systemic glucocorticoids usually suppress EAC, but recurrence
is common when these drugs are stopped. Systemic
therapy with antipruritics may help. Topical vitamin
D analogs, perhaps combined with ultraviolet irradiation, are another option.20,21 Empiric use of antibiotic,
antifungal, or anticandidal agents has sometimes been
useful. Biologics may represent yet another option.22
KEY REFERENCES
2. Kim KJ et al: Clinicopathologic analysis of 66 cases of erythema annulare centrifugum. J Dermatol 29:61, 2002
3. Weyers W, Diaz-Cascajo C, Weyers I: Erythema annulare
centrifugum: Results of a clinicopathologic study of 73
patients. Am J Dermatopathol 25:451, 2003
4. Ziemer M, Eisendle K, Zelger B: New concepts on erythema annulare centrifugum: A clinical reaction pattern that
does not represent a specific clinicopathological entity. Br
J Dermatol 160:119, 2009
7. Mahood JM: Erythema annulare centrifugum: A review
of 24 cases with special reference to its association with
underlying disease. Clin Exp Dermatol 8:383, 1983
10. Watkins S, Magill JM Jr, Ramos-Caro FA. Annular eruption preceding relapsing polychondritis: Case report and
review of the literature. Int J Dermatol 48:356, 2009
18. Patrizi A et al: Neutrophilic figurate erythema of infancy.
Pediatr Dermatol 25:255, 2008
GRANULOMA ANNULARE
AT A GLANCE
The cause is unknown, and the pathogenesis

is poorly understood.
Pathologic features consist of granulomatous
inflammation in a palisaded or interstitial
pattern associated with varying degrees of
connective tissue degeneration and mucin
deposition.
Most cases resolve spontaneously within
2 years.
Granuloma annulare is a benign self-limited disease,

first described by Colcott-Fox1 in 1895 and RadcliffeCrocker2 in 1902.
EPIDEMIOLOGY
Granuloma annulare is a relatively common disorder.3
It occurs in all age groups, but is rare in infancy.35 The
localized annular and subcutaneous forms occur more
frequently in children and young adults. The generalized variant is more common in adults. Many studies
report a female preponderance,3 but some have found a
higher frequency in males.6 Granuloma annulare does
not favor a particular race or geographic area, with the
possible exception of the perforating type, which may
be more common in Hawaii.7
Most cases of granuloma annulare are sporadic.
Occasional familial cases are described with occur-
The etiology of granuloma annulare is unknown, and

the pathogenesis is poorly understood. Most cases
occur in otherwise healthy children. A variety of predisposing events and associated systemic diseases is
reported, but their significance is unclear. It is possible
that granuloma annulare represents a phenotypic reaction pattern with many different initiating factors.12
Granuloma Annulare
A localized ring of beaded papules on

the extremities is typical; generalized,
subcutaneous, perforating, and patch
subtypes also occur.
::
Relatively common disorder; exact

prevalence is unknown; favors children and
young adults.
rence in twins, siblings, and members of successive

generations.3,8,9 Attempts to identify an associated
HLA subtype have yielded disparate results in different population groups.10,11
Chapter 44
Chapter 44 :: Granuloma Annulare

:: Julie S. Prendiville
PREDISPOSING EVENTS
Nonspecific mild trauma is considered a possible triggering factor because of the frequent location of lesions
on the distal extremities of children. An early study of
subcutaneous granuloma annulare found a history of
trauma in 25% of children,3 but this observation has not
been replicated. Trauma is also a suspected factor in
auricular lesions.13 Granuloma annulare has occurred
after a bee sting,14 a cat bite,15 and an octopus bite,16
and insect bite reactions have also been implicated.3
There is a report of perforating granuloma annulare
in long-standing tattoos.17 Widespread lesions have
developed after waxing-induced pseudofolliculitis18
and erythema multiforme minor,19 and in association
with systemic sarcoidosis.3,20 Severe uveitis without
other evidence of sarcoidosis has occurred in a few
patients with granuloma annulare.21,22,23
INFECTIONS AND IMMUNIZATIONS. There

are several reports of the development of granuloma
annulare within herpes zoster scars, sometimes many
years after the active infection.24 It is also described
after chickenpox.25 Generalized, localized, and perforating forms of granuloma annulare may occur
in association with human immunodeficiency virus
(HIV) infection (see eFig. 44-0.1 in online edition).2631
Adenovirus was isolated from a lesion in one HIVpositive patient.32 EpsteinBarr virus was excluded as
a causative agent in these cases.26,27 However, in other
467
Section 6
::
468
instances generalized granuloma annulare has been

linked to viral infections, including EpsteinBarr virus
infection,33 chronic hepatitis B,34 and hepatitis C.35 Vaccinations for tetanus,36 diphtheria toxoid,37 and hepatitis B vaccination38 have been implicated as triggering
factors, although vaccination sites were spared in one
case of generalized granuloma annulare.39
Lesions compatible with granuloma annulare may
occur in patients with active tuberculosis.12 There are
also reports of granuloma annulare after tuberculin
skin tests3 and Bacille Calmette-Gurin immunization.40
Evidence of Borrelia burgdorferi infection was detected in
two reports,41,42 but this association was not confirmed
in a serologic study.43 A case in which chronic relapsing
granuloma annulare flared during scabies infestation
was attributed to the Koebner phenomenon.44
SUN EXPOSURE. Granuloma annulare with a pre-
dilection for sun-exposed areas4548 and seasonal recurrence45 has been described. Photosensitive granuloma
annulare has been observed in patients with HIV
infection.49 One patient developed generalized disease
after psoralen plus ultraviolet A (UVA) light therapy,50
but it is of note that phototherapy and psoralen/UVA
phototherapy have also been used to treat generalized
granuloma annulare.5154
Actinic granuloma, also known as annular elastolytic
giant cell granuloma, develops on photodamaged skin
and is believed to represent a granulomatous reaction to actinic elastosis.55 Its relationship to granuloma
annulare is debated.
DRUGS. Granuloma annulare-like drug reactions are

reported for gold therapy and treatment with allopurinol, diclofenac, quinidine, intranasal calcitonin, and
amlodipine.56
An interstitial granulomatous drug reaction linked
to the use of angiotensin-converting enzyme inhibitors, calcium channel blockers, and other medications
is considered a distinct entity but may mimic granuloma annulare.5759
DIABETES MELLITUS AND THYROID DISEASE. Development of granuloma annulare in
patients with diabetes mellitus is extensively documented. Whether this is a true relationship has long
been debated. The link is primarily with type 1 insulindependent diabetes,60 but cases are also reported with
type 2 noninsulin-dependent disease.6163 Localized60
and generalized46,63,64 as well as subcutaneous nodular61,65,66 and perforating5,7 forms of granuloma annulare have been observed. Granuloma annulare rarely
predates the onset of diabetes.60,66 The histopathologic
similarity between granuloma annulare and necrobiosis lipoidica diabeticorum and the coexistence of both
conditions in occasional diabetic patients62 suggest a
true association. However, most patients with granuloma annulare do not have diabetes mellitus. Studies attempting to establish a causal correlation have
yielded conflicting results.60,67,68
Granuloma annulare has also occurred in a number
of patients with thyroiditis, hypothyroidism, and thyroid adenoma.64,6972
MALIGNANCY. An association between granuloma

annulare and malignancy in adult patients is reported
primarily with Hodgkin and non-Hodgkin lymphoma,
including mycosis fungoides, Lennert lymphoma,
B-cell disease,7376 T-cell leukemia/lymphoma,77,78
and angioblastic T-cell lymphoma.79 It is reported less
commonly with myeloid leukemias80 and with solid
tumors, particularly of the breast.46,73 The skin lesions
of cutaneous lymphoma and other hematologic malignancies can mimic granuloma annulare both clinically
and histopathologically.81,82 It may be difficult to distinguish whether they represent true granuloma annulare
with atypical lymphocytes, or cutaneous lymphoma
obscured by a granulomatous infiltrate.75,76
PATHOGENETIC MECHANISMS
The pathogenetic mechanisms that result in foci of
altered connective tissue surrounded by a granulomatous inflammatory infiltrate are not understood.
Proposed mechanisms include (1) a primary degenerative process of connective tissue initiating granulomatous inflammation,83 (2) a lymphocyte-mediated
immune reaction resulting in macrophage activation
and cytokine-mediated degradation of connective
tissue,30,8488 and (3) a subtle vasculitis or other microangiopathy leading to tissue injury.84
CLINICAL FINDINGS
HISTORY
The typical history is of one or more papules with
centrifugal enlargement and central clearing. These
annular lesions are often misdiagnosed as tinea corporis and treated unsuccessfully with topical antifungal
agents. Subcutaneous nodules may raise suspicion
about malignancy or rheumatoid disease.89
Granuloma annulare is usually asymptomatic.
Mild pruritus may be present, but painful lesions are
rare.90,91 Nodular lesions on the feet may cause discomfort from footwear.92 Cosmesis is often a concern for
adolescent and adult patients, particularly with generalized disease.
CUTANEOUS LESIONS
Clinical variants of granuloma annulare include the
localized, generalized, subcutaneous, perforating, and
patch types. Linear granuloma annulare,93,94 a follicular pustular form,95 and papular umbilicated lesions
in children96 have also been described. There is overlap between the different variants, and more than one
morphologic type may coexist in the same patient.
LOCALIZED TYPE. The most common form of

granuloma annulare is an annular or arcuate lesion.
It may be skin colored, erythematous, or violaceous.
It usually measures 15 cm in diameter.3 The annular
margin is firm to palpation and may be continuous or
SUBCUTANEOUS TYPE. The subcutaneous form

of granuloma annulare occurs predominantly in children,89,99,100 but is also described in adult patients.101103
It is characterized by firm to hard, usually asymptomatic nodules located in the deep dermis and subcutaneous tissues. They may extend to underlying muscle,
and nodules on the scalp and orbit are often adherent
to the underlying periosteum.
Individual lesions measure from 6 mm to 3.5 cm in
diameter.100,104 They are distributed most often on the
anterior lower legs in a pretibial location.99 Other sites
of predilection are the ankles, dorsal feet, buttocks, and
hands.103,105 Nodules on the scalp,104,106 eyelids,107109
and orbital rim65,110,111 may present a diagnostic challenge. Subcutaneous granuloma annulare may also be
found on the penis.112114
Granuloma Annulare
GENERALIZED TYPE. The generalized form of

granuloma annulare is said to comprise 8%15% of
cases.3,46 The majority of patients are adults, but it may
also be seen in childhood.46,98 Unlike in localized disease, the trunk is frequently involved, in addition to
the neck and extremities. The face, scalp, palms, and
soles may also be affected.46
Generalized granuloma annulare presents as widespread papules (Fig. 44-3A), some of which coalesce
to form small annular plaques or larger discolored

patches with raised arcuate and serpiginous margins
(see Fig. 44-3B). Lesions may be skin colored, pink,
violaceous, tan, or yellow. An annular or nonannular morphology may predominate.46 A generalized
form of perforating granuloma annulare has also been
described.5,7
::
consist of discrete or coalescent papules in a complete

or partial circle (Fig. 44-1). The epidermis is usually
normal, but surface markings may be attenuated over
individual papules. Within the annular ring, the skin
may have a violaceous or pigmented appearance. Solitary firm papules or nodules may also be present. Papular lesions on the fingers may appear umbilicated.
The dorsal hands and feet, ankles, lower limbs, and
wrists are the sites of predilection (see Figs. 44-1 and
44-2). Less commonly, lesions occur at other sites,
including the eyelids.97 The palms and soles are occasionally involved.90,91 Localized annular lesions may
coexist with the subcutaneous or patch forms.
Chapter 44
Figure 44-1 A. Typical annular lesion of granuloma annulare on a finger. B. A larger annular lesion of granuloma annulare
on the dorsum of the hand.
PERFORATING TYPE. The perforating type of

granuloma annulare is a rare variant characterized by
transepidermal elimination of the necrobiotic collagen.
It may be localized, usually to the dorsal hands and fingers (see eFig. 44-3.1 in online edition), or generalized
over the trunk and extremities.5,7 It has been described
on the ears,115 on the scrotum,116 and within herpes
zoster scars and tattoos.16 Superficial small papules
develop central umbilication or crusting, and there
may be discharge of a creamy fluid. Lesions heal with
atrophic or hyperpigmented scars. In one series, 24%
of patients complained of pruritus and 21% of pain.117
Papular umbilicated granuloma annulare on the hands
of children96 and a generalized follicular pustular type
of granuloma annulare95 may be clinical variants.
Figure 44-2 Localized granuloma annulare with nodule

on the hand of a child.
PATCH TYPE. Macular lesions that present as erythematous, redbrown, or violaceous patches without
an annular rim are reported in adult women.88,118 An
arcuate dermal erythema is also observed. General-
469
::
ized confluent erythema has been described in an HIVpositive patient.30
Section 6
Figure 44-3 A. Generalized granuloma annulare. Small papular lesions that are too small to exhibit annular configuration.
B. Multiple annular lesions on the lower arm.

Most patients with granuloma annulare are healthy
and have no other abnormal physical findings. Arthralgia is reported in association with painful lesions on
the hands.91 Granuloma annulare-like skin lesions
and joint disease characterize a multisystem disorder
described as interstitial granulomatous dermatitis
with arthritis.119
Oral involvement was observed in one patient with
HIV-associated disease.27
LABORATORY TESTS
A diagnosis of localized granuloma annulare is made
on clinical examination, and further evaluation is
rarely indicated. Biopsy to obtain a specimen for histopathologic examination is necessary when the presentation is atypical, when lesions are symptomatic, and
when the diagnosis is otherwise in doubt. Histopathologic analysis may be required to confirm a diagnosis
of generalized granuloma annulare or subcutaneous
nodular disease on the head and orbital region.
tiocytes (Fig. 44-4). The necrobiotic centers are usually

oval, slightly basophilic, devoid of nuclei, and marked
by a loss of definition of the collagen bundles and
diminished or absent elastic tissue fibers. Stains for
mucin and lipid often give positive results.
An interstitial, nonpalisaded pattern of inflammation with histiocytes infiltrating among fragmented
collagen bundles may be predominant, particularly in
the generalized form. This interstitial pattern is also
observed in the absence of apparent connective tissue
change. Stains for mucin may be helpful in detecting
connective tissue alteration within the infiltrate.
Lymphocytes are admixed with histiocytes in the
granuloma and in a perivascular distribution. Multinucleated giant cells may be present but are not as
numerous as in actinic granuloma.123 Neutrophils and
eosinophils are occasionally seen, but plasma cells are
rare. Evidence of vascular reactivity includes variable
endothelial cell swelling, red cell extravasation, fibrin,
leukocytoclasis, and neutrophilic infiltration in blood
vessel walls.124 When leukocytoclastic vasculitis or
nuclear debris is a prominent finding, a diagnosis of
palisaded neutrophilic and granulomatous dermatitis
of immune complex disease should be considered.124
HISTOPATHOLOGIC FINDINGS
470
The diagnosis is best made at low magnification.

Changes are usually observed in the upper and middle dermis, although any part of the dermis or subcutis can be involved. The characteristic histopathologic
finding is a lymphohistiocytic granuloma associated
with varying degrees of connective tissue degeneration and mucin deposition. The inflammatory infiltrate
may have a palisaded or interstitial pattern, or a mixture of both patterns.120122 Occasionally, a sarcoid-like
pattern with large epithelioid histiocytes is seen.120
The typical appearance is of single or multiple foci
of inflammation with a central core of altered collagen
(necrobiosis) surrounded by a wall of palisaded his-
Figure 44-4 Palisading granulomatous inflammation surrounding degenerating collagen within the dermis. (Hematoxylin and eosin stain, 200.) (Used with permission
from Dr. Richard Crawford.)
tural changes in the connective tissue and capillaries

have been described.83
SPECIAL TESTS
A diagnosis of granuloma annulare is made clinically
or by skin biopsy. Special investigations are usually
not necessary. Further evaluation to rule out systemic
disease such as infection, sarcoidosis, or malignancy
may be required in atypical cases of granuloma annulare.12,77,81,82,118 Investigation for endocrine disease is
indicated if the patient has signs or symptoms of diabetes or thyroid dysfunction.
Imaging studies may be performed in subcutaneous granuloma annulare when the clinical features are
not recognized or when the presentation is atypical
with rapid enlargement or pain.126 Radiographs show
a nonspecific soft tissue mass without calcification
Chapter 44
In subcutaneous granuloma annulare the foci of

necrobiosis are larger and lie within the deep dermis
and subcutaneous fat. They may be distinguished
from rheumatoid nodules by the presence of mucin
in the necrobiotic zone.107 Central ulceration and communication between the area of necrobiosis and the
surface are characteristic of perforating granuloma
annulare. Examination of serial sections may be necessary to demonstrate the necrobiotic plug. An interstitial pattern of inflammation with diffuse necrobiosis is
reported in the patch type of granuloma annulare.119
Palisaded granulomas have also been observed in
macular lesions.88
Immunofluorescence testing may show deposition
of fibrin, immunoglobulin (Ig) M, and C3 as a variable
finding around vessel walls or at the basement membrane zone; IgM cytoid bodies are also reported.119
Immunohistochemistry may be useful to confirm the
histiocytic nature of equivocal disease.125 Ultrastruc-
::
ANNULAR TYPE
Consider
Tinea corporis
Subacute cutaneous lupus erythematosus
Neonatal lupus erythematosus
Annular lichen planus
Acute febrile neutrophilic dermatosis
Erythema chronicum migrans
Actinic granuloma/annular elastolytic giant cell
granuloma
Necrobiosis lipoidica diabeticorum
Rule Out
Infections (e.g., tuberculosis, atypical mycobacteria,
syphilis)
Interstitial granulomatous dermatitis with arthritis
Annular sarcoidosis
Lymphoma
GENERALIZED TYPE
Consider
Lichen planus
Lichen nitidus
Rule Out
Lichenoid and granulomatous dermatitis of acquired
immunodeficiency syndrome
Infections (e.g., tuberculosis, atypical mycobacteria,
syphilis)
Sarcoidosis
Blau syndrome (familial granulomatous arthritis, skin
eruption, and uveitis)
Lymphoma
SUBCUTANEOUS TYPE
Consider
Erythema nodosum
Dermoid cyst
Rheumatoid nodules
Granuloma Annulare
Box 44-1 Differential Diagnosis of Granuloma Annulare
Rule Out
Epithelioid sarcoma
Benign or other malignant tumors
Deep infections
PERFORATING TYPE
Consider
Insect bites
Perforating collagenosis and other perforating
disorders
Foreign body granuloma
Papulonecrotic tuberculid
Palisaded neutrophilic and granulomatous dermatitis
of immune complex disease
PATCH TYPE
Consider
Morphea
Erythema annulare centrifugum
Parapsoriasis
Rule Out
Lymphoma
471
Box 44-2 Treatment Options for

Granuloma Annulare
Await spontaneous resolution
Apply topical corticosteroid with or without occlusion
Administer intralesional triamcinolone 2.5 mg/mL129
Section 6
::
ANECDOTAL REPORTS OF BENEFIT

Topical
Tacrolimus 0.1% ointment130
Pimecrolimus cream131
Imiquimod 5% cream132,133a
Intralesional
Interferon-135
Interferon-135
Sterile water or saline129
Systemic
Antimalarials98
Retinoids136140
Antibiotics141,142
Corticosteroids92,108
Cyclosporine77,143
Zileuton with vitamin E144
Fumaric acid esters145,146
Hydroxyurea,147 chlorambucil, niacinamide,
potassium iodide, dapsone3,46,92
Etanercept148b
Infliximab150b
Efalizumab151b
Adalimumab152154
Other
Phototherapy5154
Photodynamic therapy155,156
Skin biopsy157
Cryotherapy158
Pulsed dye, Nd:YAG or CO2 laser159162
a
Application of 5% imiquimod cream has been reported to

worsen granuloma annulare in a child.134
b
Development of granuloma annulare has been reported during
therapy with etanercept, infliximab, and adalimumab.149
or bone involvement. Ultrasonographic examination

reveals a hypoechoic area in the subcutaneous tissues.126,127 Magnetic resonance imaging shows a mass
with indistinct margins, isointense or slightly hyperintense to muscle with T1-weighted images and with
a heterogeneous but predominantly high signal intensity on T2-weighted images.126,128
472
See Box 44-1.
TREATMENT
The usual treatment options include awaiting spontaneous resolution, topical steroids and intralesional
steroids. These and more anecdotal reports are summarized in Box 44-2.
CLINICAL COURSE AND

PROGNOSIS
Most cases of localized granuloma annulare resolve
spontaneously without sequelae. Lesions may clear
within a few weeks or persist for several years. The
majority disappear within 2 years.92 Recurrent lesions
may develop months or even years later, frequently at
the same site. Generalized granuloma annulare often
runs a more protracted course.46 Perforating granuloma annulare results in scarring.117 There are a number of reports of anetoderma or middermal elastolysis
following generalized granuloma annulare and annular elastolytic giant cell granuloma.47,163166 One case of
generalized granuloma annulare in a photosensitive
distribution healed with scarring and milia formation.167
KEY REFERENCES
3. Muhlbauer JE: Granuloma annulare. J Am Acad Dermatol
3:217, 1980
43. Halkier-Sorensen L, Kragballe K, Hansen K: Antibodies to the Borrelia burgdorferi flagellum in patients with
scleroderma, granuloma annulare and porphyria cutanea tarda. Acta Derm Venereol 69:116, 1989
83. Hanna WM, Moreno-Merlo F, Andrighetti L: Granuloma
annulare: an elastic tissue disease? Case report and literature review. Ultrastructural Pathol 23:33, 1999
84. Dahl MV: Speculations on the pathogenesis of granuloma annulare. Australas J Dermatol 26:49, 1985
85. Mempel M et al: T-cell receptor repertoire and cytokine
pattern in granuloma annulare: defining a particular
type of cutaneous granulomatous inflammation. J Invest
Dermatol 118:957, 2002
86. Fayyazi A et al: Expression of IFN, coexpression of
TNF and matrix metalloproteinases and apoptosis of T
lymphocytes and macrophages in granuloma annulare.
Arch Dermatol Res 292:384, 2000
100. Felner EI, Steinberg JB, Weinberg AG: Subcutaneous
granuloma annulare: a review of 47 cases. Pediatrics
100:965, 1997
Disorders of Epidermal Differentiation

and Keratinization
Chapter 45 :: Epidermal Stem Cells

:: Rebecca J. Morris
EPIDERMAL STEM CELLS
AT A GLANCE
The epidermis is a continually renewing
tissue the function of which is maintained by
a hierarchy of stem cells, transit amplifying
cells, and terminally differentiating cells.
In the proliferative hierarchy, stem cells have
the highest proliferative potential.
Epidermal stem cells may be identified by
their functional characteristics, by distinctive
cell cycle patterns, or by characteristic
proteins.
Epidermal stem cells usually exist in
characteristic proliferative units with little
lateral migration.
The regulation of epidermal stem cells
comprises complex pathways many of which
are shared by embryonic, morphogenetic,
and homeostatic processes.
Epidermal diseases are associated with or
may arise from proliferative dysfunction
in the stem cell or transit amplifying cell
compartments.
Epidermal stem cells are attractive targets for
cell and gene therapies.
The cutaneous epithelium is a continually renewing

tissue maintained in a dynamic equilibrium of proliferation in the basal layer and loss through terminal
differentiation from the suprabasal layers. This process is orchestrated with great elegance by a hierarchy
of stem cells, transient amplifying cells, and terminally differentiating cells. These populations of cells
work together to maintain lifelong tissue function and
to bring about tissue repair. This chapter focuses on
the role of stem cells and their identification in the
epidermis.
CONCEPT OF STEM CELLS IN

RENEWING TISSUES
Proliferation in the cutaneous epithelium begins with
the stem cells.1,2 Stem cells in this regard lack many
characteristics of terminal differentiation, and have
an intrinsically high proliferative potential relative to
the other proliferating cells, but are generally capable
of lifelong proliferation.3 Upon division, a stem cell
produces off one daughter that remains a stem cell,
and one daughter that goes on to produce a series of
transit amplifying cells that serve to magnify or
amplify the stem cells division resulting in the production of many differentiated cells with minimal
input from the stem cell. This hierarchical system that
usually involves decreasing proliferative potential is
illustrated in Fig. 45-1. Stem cells typically interact
with their surroundings in a supportive, protective
niche.1
GENERAL METHODS FOR

STEM CELL IDENTIFICATION
AND ISOLATION
Stem cells may be studied by the presence or absence
of proteins on their surface that distinguish them from
other proliferative cells.2 Such proteins may be internal, or more desirably, proteins on the cell surface that
render the cells selective by various methods such as
by magnetic bead separation or by fluorescence activated cell sorting (FACS).2 Stem cells may also be studied by cellular kinetic characteristics such as in slowly
cycling label-retaining4 cells or through their patterns
of mitotic activity.5 Stem cells can sometimes be identified and isolated according to their special physical
properties such as cell size or buoyant density,6 or in
conjunction with other properties such as in the socalled side population cells7 that have active Abcg2
transporters. Candidate stem cells identified or isolated by any of these methods may then be characterized by functional tools such as in vitro colony forming
assays,810 or in an in vitro or in vivo skin reconstitution
assay.2
Proliferative hierarchy in epithelia
4
3
4
However, lateral migration is common during wound

healing where a tongue of proliferating epithelium
migrates over denuded dermis and reestablishes an
epithelium complete with vertical proliferative units
and terminal differentiation.18 In addition, Brash and
colleagues have suggested that following irradiation
of skin with ultraviolet light, clonal patches, each with
its own p53 mutation, might reflect epidermal cell proliferation and differentiation beyond the confines of
single proliferative units.19
2
4
Section 7
3
4
::
Disorders of Epidermal Differentiation and Keratinization
Stem
cells
Transit
amplifying
Terminally
differentiated
Figure 45-1 The proliferative hierarchy in epithelia: the

stem cell concept. The ultimate progenitor cells are termed
stem cells. They are slow cycling, long-lived, phenotypically
undifferentiated, reside in specialized microenvironments,
and constitute only a small percentage of the total epithelial cell population. Stem cell division produces transit
amplifying or committed progenitor cells, which cycle
rapidly and produce a clonal expansion of the offspring
arising from an initial stem cell division. These cells eventually become the mature, terminally differentiated cells
that constitute the bulk of a given epithelial population.
Numbers indicate generation.
ASYMMETRIC DIVISION
The hierarchical model for cell proliferation in the cutaneous epithelium implies some degree of cellular, genetic,
or population asymmetry.3,11 The model of the stem cell
hierarchy suggests a level of asymmetry that could be
due to infrequent cell division or to chromosomal segregation.3 As the stem cell mechanism is thought to provide
protection for the tissue as well as the cellular DNA,
Cairns12,13 hypothesized that perhaps stem cells have a
special mechanism for segregating their DNA and retaining an immortal strand at each division. Although
there is some fairly convincing evidence that stem cells of
the breast14 and intestinal epithelium15 may reserve an
immortal DNA strand, recent investigation of the multipotential stem cells of the mouse hair follicles suggest
that chromosome segregation does not occur.16,17 Moreover, the Tumbar laboratory developed a method to trace
the proliferation history of hair follicle bulge keratinocytes and thus provided direct evidence in support of the
infrequent division model for these particular stem cells.16
LATERAL MIGRATION
474
IDENTIFICATION OF STEM CELLS IN

THE CUTANEOUS EPITHELIUM
Cellular proliferation and terminal differentiation in

the epidermis are usually thought to occur in columns.
Slowly cycling epidermal stem cells were first identified by of their cell kinetic behavior in the context of
the epidermal proliferative units. Hence, Mackenzie
identified mitotic basal keratinocytes beneath the
edges of the hexagonal squames.20 In vertical cross
sections of skin, Christophers21 had found that some
basal cells in the shape of a hand mirror stained with
a fluorescent dye characteristic of suprabasal cells.
These studies were quantified by Potten in 197422
who called these units of structure epidermal proliferative units (EPUs). He focused on the central basal
cells, noting that they were rarely mitotic and also
rarely incorporated [3H]thymidine administered as a
single pulse, and conjectured that the quiescent central cells might have stem cell activity whereas the
peripheral cells may have transit amplifying cell
activity. The next major advance in understanding
the function of the EPU came with the identification
of slowly cycling label-retaining cells in the center of
the EPUs. Bickenbach4 and later Bickenbach and
Mackenzie,23 Morris,24 and Potten25 found that
administration of [3H]thymidine continuously for 3
days followed by a 48 week chase, could identify
these central cells in light microscopic autoradiographs. Further characterization of the central stem
cells and peripheral transit amplifying cells has been
performed by a variety of in vivo and in vitro techniques.2 The presence of EPUs in some areas of thin
human skin has also been noted, and may be as large
as 2 millimeters in diameter.20 The EPU concept in
skin is illustrated in Fig. 45-2.
The distribution of stem cells within the epidermis
has been a subject of debate. Hence, Lavker and Sun26
found that mitotic cells and cells that were rarely
mitotic (putative stem cells) were located respectively in the upper and lower aspects of the rete
ridges. These investigators postulated that the
deeper cells were physically more protected than
the superficial cells. In contrast, further studies have
demonstrated that cells with stem cell characteristics
in human epidermis can vary depending upon the
site.27 Ghazizadeh and Taichman28 used retrovirally
marked human epidermal keratinocytes followed by
grafting onto athymic nude mice to visualize proliferative units in human skin. These studies found presumptive stem cells to be distributed throughout the
epithelium.
Functional organization of inter-follicular epidermis
Compared with the plethora of markers and selectable

determinants for various hair follicle stem cells, few
such markers have been identified in the epidermis.
Notable exceptions are -1 integrin,10 CD71 (the transferrin receptor),29 and LRIG1 (Fig. 45-3).30 -1 integrin
is a cell adhesion molecule and can be used as a
selectable determinant to enrich for keratinocytes that
have a high proliferative potential in vitro and that can
Epidermal Stem Cells
MARKERS AND SELECTABLE

DETERMINANTS
::
Figure 45-2 Functional organization of interfollicular

epidermis: the epidermal proliferative unit (EPU) concept.
Interfollicular epidermis of the skin of certain body sites
is histologically organized into columns termed EPUs;
each consists of approximately ten basal cells, including
a single putative stem cell (yellow), its immediate transitamplifying cell progeny (blue), and early-differentiating
cells (purple). More differentiated keratinocytes (green)
and then mature enucleated squames lie directly above
them, in an ordered stack rising above the basal layer.
EPUs represent functionally independent packets of selfrenewing interfollicular epidermis that are ultimately
dependent on a single putative stem cell for lifelong cell
production. Constant self-renewal within the basal layer of
skin compensates for the continual loss of differentiated
squames from its surface. (Redrawn from Kaur P: Interfollicular epidermal stem cells: Identification, challenges, potential. J Invest Dermatol 126:1452, 2006.)
Chapter 45
Figure 45-3 A confocal microscopic image of human

scalp tissue stained for the EGFR (red) and LRIG1 (green).
Immunostaining such as this has provided valuable information on the role and function of stem cells in the epidermis. The significance of these two markers is reported
in Jensen KB, Watt FM: Single cell expression profiling of
human epidermal stem and transit amplifying cells. LRIG1
is a regulator of stem cell quiescence. Proc Natl Acad Sci
USA 103:11958-11963, 2006 and Jensen KB et al: LRIG1
expression defines a distinct multipotent stem ell population in mammalian epidermis. Cell Stem Cell 4:427-439,
2009. (Used with permission from Drs Kim Jensen and
Fiona Watt.)
reconstitute a graft. Cells staining brightly with a

fluorescently labeled antibody to -1 integrin keratinocytes are found in human epidermis situated at the
bottom of the rete ridges or atop the dermal papillae
depending on the location of the skin. CD71 is
expressed on all proliferating cells and can be used in
conjunction with -6 integrin (the external component
of the hemidesmosomes present on epidermal basal
cells) to enrich for a population that reacts with a fluorescently labeled antibody to -6 integrin, but does not
bind to fluorescently labeled CD71. This is enriched for
epidermal keratinocytes that have in vitro and in vivo
properties of stem cells. In the mouse, cells with this
phenotype are located in the hair follicle bulge. LRIG1
is a marker of human interfollicular stem cells and
helps to maintain stem cell quiescence.30 In the mouse,
LRIG1 immunoreactive cells are found in the hair follicle junctional zone between the sebaceous glands and
the infundibulum.31
ALTERNATIVE MECHANISMS
FOR REGULATING EPIDERMAL
PROLIFERATION
The stem cell concepts presented above have not gone
unchallenged. Clayton et al have studied clonal expansion in the mouse tail epidermis together with mathematical modeling.32 These investigators conclude that
the presence of stem cell/transit amplifying cell model
in the tails is incompatible with a long-lived stem cell
475
population and a short-lived transit amplifying cell

population. Moreover, this group infers that clones of
two basal cells in the tail can adopt any of the three
fates: (1) both cells can remain proliferative, (2) both
can differentiate and exit the cycle, or (3) that one cell
can remain proliferative and the other differentiates.
Thus, epidermis from different sites may have different mechanisms for proliferation and terminal differentiation. At the present time, there are no reports of
this model being applied to mouse dorsum or human
epidermis from any site.
Section 7
RELATIONSHIPS AMONG
VARIOUS EPITHELIAL STEM CELL
COMPARTMENTS
::
Cellular kinetic and labeling data suggest that there

are multiple stem and progenitor compartments
within the cutaneous epithelium. Under homeostatic
conditions, these compartments are stable over intervals with essentially no interactions.33 Hence, there are
multiple proliferative units within the hair follicles: the
infundibulum of the follicle, the bulge, the upper isthmus, and the sebaceous gland. The progeny of these
follicular and sebaceous proliferative units all appear
to be able to contribute to the repair of wounded epidermis.
REGULATION OF EPIDERMAL STEM

AND TRANSIT AMPLIFYING CELLS
Identification and functional characterization of molecules regulating epidermal stem cells and transit
amplifying cells is currently a subject of intense investigation.3437 Mediators under study comprise complex
pathways often shared by embryonic, morphogenetic,
and adult homeostatic and repair processes. Regula-
tory switches34 include (1) stimuli that direct progenitor cells toward a particular type of terminal
differentiation, (2) molecules and pathways characteristic of the niche and stem cell homeostasis, (3) molecules that differentially alter stem cell and transit
amplifying cell proliferation, and (4) positive and negative regulators involved in commitment to terminal
differentiation. Examples of such regulatory molecules
are given in Table 45-1.
SKIN DISEASES ARISING FROM

PROLIFERATIVE DYSFUNCTION
Skin cancer is thought to arise from aberrant proliferation of keratinocyte stem cells.3,38 In this regard, a
stem cell is a candidate for a tumor-initiating cell
because of its long-term persistence in the tissue and
because of its inherently high proliferative potential.
The relationship between the epidermal stem cell and
the so-called cancer stem cell is not known at the
present time; however, current thinking is that the tissue stem cells, when corrupted, may become cancer
stem cells that retain such stem cell properties as
long-term self renewal, an ability to cast off transit
amplifying cells, and production of terminally differentiated cells. Although stem cells are well protected
against carcinogen-induced damage by virtue of
being a rare and well-protected population, unlike
the relatively short-lived transit amplifying cells,
stem cells persist to endure the multiple mutations
that lead to malignancy.
Psoriasis is thought to be an example of hyperproliferation of transit amplifying cells, which among
inflammatory and dermal changes, is characterized
by increased numbers of -1 integrin dim cells in
the suprabasal layers.39 Additionally, markers of
proliferation such as Ki67 and C-myc are upregulated.
TABLE 45-1
Examples of Molecular Switches that Direct Epidermal Stem Cell Behavior

Stimuli that Direct Progenitor Cells toward a Particular Type of Terminal Differentiation
Epithelial to hair follicle: Wnt/-catenin; Negatively regulated by Dikk1 and Lef1/Tcf
Hair follicle stem cells to sebaceous cells: BLIMP1
Molecules and Pathways Characteristic of the Niche and Stem Cell Homeostasis
Maintenance of stem cell quiescence in hair follicles: NFATc1, Bmp6
Maintenance of stem cell quiescence in the epidermis: Lrig1
Molecules that Differentially Alter Stem Cell and Transit Amplifying Cell Proliferation
Stem cell to transit amplifying cell and stem cell renewal: Myc, p63, miR203 microRNA, histone modification
Positive and Negative Regulators involved in Commitment to Terminal Differentiation
Basal to spinous transition and barrier function: turn off K5/K14 and turn on K1/K10
Pathways: Notch, MAPK, NF-B, p63, AP2 family, EGF receptor signaling
Negative regulators of terminal differentiation: extracellular matrix repression, PcG repression
476
Please see Blanpain C, Fuchs E: Epidermal homeostasis: A balancing act of stem cells in the skin. Nat Rev Mol Cell Biol 10:207-217, 2009; Fuchs E:
Finding ones niche in the skin. Cell Stem Cell 4:499-502, 2009; and Watt FM, Jensen KB: Epidermal stem cell diversity and quiescence. EMBO Mol
Med 1:260-267, 2009 for more information and additional examples.
OUTLOOK

AND GENE THERAPY
The accessibility of skin makes it an attractive target
for gene therapy.42 Here, one goal is to correct mutant
genes in the stem cells ex vivo and transplant resulting normalized epithelium to patients.42 Another
goal is to correct defective expression of certain
secreted proteins in skin stem cells and to apply the
corrected epithelium to patients.43 Although the use
of epidermal cells including stem cells was proposed
more than a decade ago, these applications still have
not been developed for clinical practice. It is possible
that the predilection of epidermis to develop into
vertical proliferative units rather than to expand laterally precludes these applications. However, the
field of gene therapy is still considered to be in its
infancy, and identification and targeting of multipotential skin stem cells, as well identification of factors
resulting in the lateral migration of epithelium
during wound healing will increase therapeutic
In this chapter, I have discussed general properties of

epidermal stem cells and some of the techniques for
studying them. In this regard, keratinocyte stem cells
together with transit amplifying cells and terminally
differentiating cells play a role in the normal turnover
and repair of the epidermis. Additional studies, perhaps with novel approaches are needed for better identification of epithelial stem and transit amplifying
cells. Especially, more investigation is needed for an
understanding of the molecular switches that regulate stem cell and transit amplifying cell homeostases,
fate determination, and repair mechanisms. Moreover,
there is a great need for understanding stem cell targeting as well as the lateral migration in wound healing,
as these are key questions in making cell and gene
therapy a reality. Finally, it must be understood that
there will never be a pure population of stem cells.
Rather, each new marker or selectable determinant discovered, and each new functional assay developed is
essential for ultimately designing new treatments for
skin diseases and skin cancer.
Epidermal Stem Cells
Epidermal stem cells can be cultivated and expanded in

tissue culture.8,40 This has led to an application of epidermal cells in cell therapy of burn victims. Hence,
from a small biopsy from nonaffected skin, skin cells
including stem cells can be expanded ex vivo and then
reapplied to affected skin. The transplanted tissue
takes to debrided skin regions and ultimately forms a
new epithelium with the capacity to persist for many
years. This application is now standard therapy in
many burn units.40 In the transplanted epithelium, it is
noteworthy that epithelial appendages such as hair follicles, sebaceous glands, or eccrine glands are absent
because techniques for in vitro morphogenesis of these
tissues have not yet been developed. The lack of skin
appendages in the grafted epidermis results in fragility
as well as dryness due to lack of sebaceous glands, and
poor thermoregulation due to lack of eccrine glands in
the transplanted epithelium. These problems highlight
the urgent need to develop in vitro methods to recapitulate embryonic morphogenesis of the cutaneous
appendages. Ex vivo expanded epidermal keratinocytes
are also used for treating ulcers and other chronic
wounds.41
::
applications. Additionally, other related means of

manipulating the keratinocytes such as siRNA show
great promise.44
Chapter 45

AND CELL THERAPY
KEY REFERENCES
1. Blanpain C, Fuchs E: Epidermal homeostasis: A balancing
act of stem cells in the skin. Nat Rev Mol Cell Biol 10:207217, 2009
2. Kaur P: Interfollicular Epidermal stem cells: Identification, challenges, potential. J Invest Dermatol 126:1450-1458,
2006
3. Lajtha L: Stem cell concepts. Differentiation 14:23-34, 1979
13. Cairns J: Cancer and the immortal strand hypothesis. Genetics 174:1069-1072, 2006
25. Potten CS: Cell cycles in cell hierarchies. Int J Radiat Biol
49:257-258, 1986
34. Fuchs E: Finding ones niche in the skin. Cell Stem Cell
4:499-502, 2009
35. Watt FM, Jensen KB: Epidermal stem cell diversity and
quiescence. EMBO Mol Med 1:260-267, 2009
38. Watt FM, Driskell RR: The therapeutic potential of stem
cells. Philos Trans R Soc London B Biol Sci 365:155-163, 2010
40. Green H: The birth of therapy with cultured cells. BioEssays
30:897-903, 2008
477
Chapter 46 :: Epidermal Growth and Differentiation

:: Pierre A. Coulombe, Stanley J. Miller, &
Tung-Tien Sun
EPIDERMAL GROWTH AND DIFFERENTIATION AT A GLANCE
The interfollicular epidermis is maintained by
a population of stem cells.
Section 7
Slow-cycling stem cells give rise to transit

amplifying cells, which yield terminally
differentiated cells.
::
Abnormalities in epidermal stem cells may be

involved in pathogenesis of skin cancers and
other proliferative epidermal diseases.
INTRODUCTION
Although thin, human skin is a marvelously resilient
and multifunctional organ. It performs immunomodulatory and thermoregulatory functions, is involved in
social, cultural, and reproductive behaviors, and provides broad protection against water loss and environmental insults such as trauma, infection, and exposure
to radiation or chemicals. The outermost layer of skin,
termed the epidermis, consists of a stratified squamous
epithelium and its appendages, including hair follicles,
sebaceous, apocrine, and eccrine glands. This chapter
discusses epidermal differentiation, with the primary
focus placed on keratin filaments that are formed as
major structural elements within the epidermis.
Defects in epidermal keratins are known to play key
roles in a number of important blistering epidermal
diseases. Additional major epidermal differentiation
markers, including keratohyalin granules and the cornified envelope, are also discussed.
KERATINS AND EPIDERMAL

DIFFERENTIATION
KERATINS AND THEIR CLASSIFICATION
478
Keratins (also known as cytokeratins) are structural

proteins that belong to the superfamily of intermediate filament (IF) proteins. They are heterogeneous in
size (4070 kDa) and charge (pI 4.78.4), and notoriously insoluble. Sequencing the human genome
revealed the presence of 54 functional keratin genes
that are nearly perfectly conserved in other mammals.1 The tremendous diversity of keratin genes had
not been fully appreciated until the advent of database mining and genomics, and could not be accom-
Epidermal differentiation is accompanied by

orchestrated expression of keratins and subunits
of cornified envelope.
Keratins contribute to the mechanical stability
and pliability of the epidermis.
Mutations in major epidermal differentiation
products are underlying causes of important skin
diseases.
modated in the original nomenclature system aptly

devised by Roland Moll, Werner Franke and colleagues in 1982.2 In 2006, an international effort culminated in a revised nomenclature (Table 46-1) that
accommodates the newly discovered keratins, adheres
to the guidelines of the Human and Mouse Gene
Organization Gene Nomenclature Committee, and
maintains the original designation of keratins devised
by Moll and colleagues.1
Sequence homology and gene substructure (number
and position of introns) reveal two distinct groups of
keratins of roughly equal size, designated type I and II
IF genes1,3 (Fig. 46-1A). In Homo sapiens, functional type
I and type II keratin genes are clustered on the long
arms of chromosomes 17 (Fig. 46-1B) and 12 (Fig.
46-1C), respectively.1,4 Keratin genes are highly conserved across mammals, at the level of their organization, structure, sequence, and regulation.5 Mature
filaments contain type I and II keratins in a 1:1 molar
ratio.3,6 This requirement underlies the coordinated
transcription of type I and II keratin genes. Remarkably, most type I and II keratin genes are regulated in a
pairwise, tissue type-related, and differentiationrelated fashion.79 This is illustrated particularly well
in stratified epithelia such as epidermis (Fig. 46-2).
Given their large number, differential regulation, and
ease of detection (owing to abundance), keratin
mRNAs and proteins represent unparalleled markers
for staging the fate and differentiation of epithelial
cells, under healthy and diseased conditions.
KERATIN PROTEINS FORM

THE INTERMEDIATE FILAMENT
NETWORK OF EPITHELIAL CELLS
Despite sequence differences, all keratins display the
tripartite domain structure that is typical of IF-forming
Table 46-1
Human Keratins and Their Distributiona

Type I Keratins
Old Name
New
Name
Main Site(s) of
Expression
K9
K9
Epidermis (suprabasal)
K1
K1
K10
K10
K2e
K2
K12
K12
Cornea
K3
K3
Cornea (suprabasal)
K13
K13
Oral mucosa
K4
K4
Oral mucosa (suprabasal)
K14
K14
Complex epithelia
K5
K5
Complex epithelia
(basal layer)
K15
K15
Complex epithelia
K6a
K6a
Epithelial appendages
K16
K16
K6b
K6b
K17
K17
K6e/h
K6c
Skin (needs confirm.)
K18
K18
Simple epithelia
K7
K7
Simple epithelia
K19
K19
Broad distribution
K8
K8
Simple epithelia
K6irs14
K71K74
Inner root sheath (hair

follicles)
K6hf
K75
Companion layer (hair

follicles)
K2p
K76
Oral mucosa
K1b
K77
Sweat gland ducts
K5b
K78
Tongue
K6l
K79
Skin
Kb20
K80
Tongue
Hb1Hb6
K81K86
Hair shaft (hair follicles)
K20
K20
Gut epithelium
K23
K23
Pancreas (needs confirm.)
K24
K24
unknown
K25irs-4
K25K28
Inner root sheath (hair

follicles)
Ha1Ha8
K31K38
Hair shaft (Hair follicle)
K39
K39
K40
K40
Epidermal Growth and Differentiation
Main Site(s) of
Expression
::
Old Name New Name
Chapter 46
Type II Keratins
Note: A revised keratin nomenclature has been published: see Schweitzer et al., J Cell Biol (2006).
proteins (Fig. 46-1D). The central domain consists of an

extended helix featuring long-range heptad repeats
that mediate coiled-coil dimerization. This rod
domain is 310 amino acids long and is flanked by
highly variable sequences at the N- terminal head and
C-terminal tail domains (Fig. 46-1D).3 Neither terminal
domain exhibits known functional motifs other than
the glycine loops seen in epidermal keratins.10 The
head and tail domains are readily protease-accessible
at the surface of the filament, where they can foster
interactions with neighboring filaments, other proteins, or serve as substrates for posttranslational modifications involved in their regulation.11 Given their
heterogeneity of size and primary structure, the head
and tail domains are expected to make key contribu-
tions to the differential function and regulation of keratin proteins in vivo.12

The central rod domain of keratins is the main determinant of self-assembly, with important contributions
from the head domain as well.13 Assembly begins with
the formation of heterodimers in which the -helical
central rod domains of type I and II keratins are aligned
in parallel and perfect register. Heterodimers interact
along their lateral surfaces and in an end-to-end fashion to give rise to the 1012-nm wide filaments
(Fig. 46-2A) which, depending on IF protein type and
assembly conditions, may contain a variable number
of subunits in cross section.13 Mature IFs lack a structural polarity, a direct consequence of the antiparallel
orientation of their constituent coiledcoiled dimers.
479
The human keratin gene family
A
K84
K82
K85 K83 K81, 86

K7
K20
K18
K14
K17
K15
K13
K19
K8
K75
K5
K16
K6a-c
K4
K1
K28
Section 7
::
480
K3
0.1
K25
K2p
K72
K10
K36
K33a
K31
K33b
K12
K9
K34
K37
K23
K32
K38 K37
D
Head
K2e
C
Human chromosome 12q13.13
Cen ... KRT80 KRT7 pseudo pseudo KRT81
KRT86 KRT83 pseudo KRT85 KRT84 KRT82
pseudo KRT75 KRT6b KRT6c KRT6a KRT5
KRT71 KRT74 KRT72 KRT73 pseudo ... KRT2
KRT1 KRT77 pseudo pseudo pseudo KRT76
KRT3 KRT4 KRT79 KRT78 KRT8 ... KRT18
K73 K71 K74
K27
K26
Human chromosome 17q21.2

Cen ... pseudo KRT24 pseudo KRT25 KRT26
KRT27 KRT28 KRT10 KRT12 KRT20 KRT23
KRT39 KRT40 *several KAP genes* KRT33a
KRT34 KRT31 pseudo KRT37 KRT38 pseudo
KRT32 KRT35 KRT36 KRT13 KRT15 KRT19
KRT9 KRT14 KRT16 KRT17 pseudo ... Tel
-helical rod
1A 1B
2A
2B
Tail
Figure 46-1 The human keratin gene family. A. Comparison of the primary structure of human keratins using the publicly available ClustalW and TreeView software. Sequence relatedness is inversely correlated with the length of the lines
connecting the various sequences, and to the number and position of branch points. This comparison makes use of the
sequences from the head and central rod domain for each keratin. A few keratins were left out for clarity purposes. Two
major branches are seen in this tree display, corresponding to type I and type II sequences. Beyond this dichotomy, each
subtype is further segregated into major subgroupings (denoted by different colors). B. Organization of functional type I
keratin genes, all which are clustered on human chromosome 17, with the only exception being K18 (see * in C), which is
located at the telomeric (Tel) boundary of the type II gene cluster. (Cen = centromere.) A large number of genes encoding
keratin-associated proteins (KAP) interrupts the type I gene cluster, between KRT40 and KRT33A. [Pseudo = pseudogene
(nonfunctional).] C. Organization of functional type II keratin genes, which are clustered on human chromosome 12. The
K8 and K18 genes are separated by 450,000 bp. D. Schematic representation of the tripartite domain structure shared by
all keratin and other IF proteins. A central -helical rod domain acts as the major determinant of self-assembly. This rod
domain is partitioned into subdomains 1A, 1B, 2A, and 2B, and flanked by nonhelical head and tail domains at the Nand C-termini, respectively. Both ends of the rod domain contain 1520 amino acid regions (red) that are highly conserved
among all IF proteins.
The extraordinary stability of keratin subunits reflects

the tightness of interactions between type I and type II
keratins.14 Most of the intracellular pool of keratin proteins (>95%) is polymerized.4 There is evidence that
keratin IF assembly is initiated at the cell periphery,
near the cortical F-actin cytoskeleton, in cultured epithelial cells.15
Keratins form the major IF network in all epithelial
cells.2,3,9 The abundance and organization of keratin IFs
in vivo differ among epithelia. Keratin proteins are
highly abundant (10%80% of total cellular proteins)
in surface-exposed stratified squamous epithelia (e.g.,
epidermis, oral mucosa, corneal epithelium, etc.).7 In
epithelial cells of such tissues, keratin IFs are organized in a pancytoplasmic network extending from the
surface of the nucleus to the cytoplasmic periphery,
where they are membrane-anchored at sites of cell
matrix and cellcell adhesion (hemidesmosomes, desmosomes) (Fig. 46-2B). In simple epithelia (e.g., liver,
gut, pancreas, etc.), keratins are less abundant. In such
tissues, polarized epithelial cells often feature asymmetrically organized keratin IFs concentrated mostly
at the cytoplasmic periphery and, particularly, the apical pole.4 Several associated proteins contribute to the
organization and regulation of keratin IFs in these various settings.16 Some of these proteins promote the
bundling of keratin IFs (e.g., filaggrin, trichohyalin),
their association with microtubules and actin microfilaments (e.g., plectin, BPAG isoforms) and/or with
desmosomes or hemidesmosomes (desmoplakin,
plakophilin, BPAG isoforms, etc.) (Fig. 46-2). Other
partners, for example, TRADD, 143-3, Akt, reflect
the newly discovered participation of keratin IFs in
signaling roles.17
7
A
Skin provides a beautiful example of the tight relationship that has evolved between keratin gene regulation
and epithelial differentiation. More than half of all
known keratin genes are expressed in mature mammalian skin tissue alone. The architectural complexity of
adult skin epithelia is achieved through a temporally
and spatially regulated expression of keratin genes
and a number of other epithelial differentiation-related
genes.7,18 In the clinical setting, keratin typing is often
exploited in diagnosing cancer type, its differentiation
status (and therefore prognosis), as well as the origin
of the cells forming metastatic foci. This strategy is also
applied for diseases other than cancer (see below).4
In thin interfollicular epidermis (e.g., trunk; Fig.
46-2), mitotically active cells of the basal layer act as
progenitors, and consistently express K5 and K14 as
their main keratin pair, along with low levels of K15.
Onset of differentiation coincides with the appearance
of the K1/K10 pair through a robust transcriptional
induction that occurs at the expense of the K5/K14
genes, which are downregulated.7,18 Accordingly,
K1/K10 keratins are readily detectable in the lowermost suprabasal layer of epidermis (Fig. 46-2D). The
appearance of K1 and K10 correlates with a sudden
and dramatic shift in the organization of keratin IFs,

which now exhibit significant bundling.19 Another
type II gene, K2e, is expressed at a later stage of differentiation, i.e., the granular layer.20
The epidermis of palm and sole skin is specialized
for resisting a high degree of mechanical stress, and
thus is markedly thicker. This function is reflected in its
architecture of alternating stripes of primary and secondary ridges,21 and again, in keratin expression. In the
thick, stress-bearing, primary ridges, the major differentiation-specific (type I) K9 is presumed to foster a
more resilient cytoskeleton. In the thinner secondary
ridges, postmitotic keratinocytes preferentially express
the (type II) K6a and (type I) K16 and K17.22 Relative to
K1, K9, and K10, the properties of K6a, K16, and K17
likely foster greater cellular pliability, thereby providing flexible hinge regions between the more rigid,
K1/K9-rich primary ridges.22 While this attractive
model remains to be supported by direct experimentation, it is consistent with the dramatic upregulation of
K6a, K6b, K16, and K17 that occurs in keratinocytes
recruited from wound margins to participate in the restoration of the epidermal barrier following injury.23,24
Epidermal disease states are often accompanied by a
deviation from normal terminal differentiation and,
not surprisingly, they are almost always accompanied
by altered keratin gene expression. For instance, K6a,
K6b, K16, and/or K17, normally restricted to wound
repair in trunk epidermis, are ectopically induced in
KERATIN GENE EXPRESSION MIRRORS

EPITHELIAL DIFFERENTIATION: THE
CASE OF EPIDERMIS
::
Figure 46-2 Keratin filaments and interfollicular epidermis. A. Visualization of filaments, reconstituted in vitro from purified human K5 and K14, by negative staining and electron microscopy. (Bar = 150 nm.) B. Double-labeling for keratin
(red chromophore) and desmoplakin, a desmosome component (green chromophore), by indirect immunofluorescence
of human epidermal cells in culture. Keratin IFs are organized in a network that spans the entire cytoplasm and are attached at desmosomal cellcell contacts (arrowheads) between cells. (n = nucleus; bar = 50 m.) [Micrograph used with
permission from Dr Kathleen Green (Northwestern University).] C. Histological cross section of resin-embedded human
trunk epidermis, revealing the basal (B), spinous (S), granular (G), and cornified (C) cell layers. (Bar = 50 m; n = nucleus.)
D and E. Differential distribution of keratin epitopes on human skin tissue cross sections as visualized by an antibody-based
detection method. D. K10 is primarily concentrated in the differentiating, suprabasal layers of epidermis. E. K14 occurs in the
basal layer, where the epidermal progenitor cells reside. Dashed line indicates the basal lamina. (Bar = 50 m.) F. Ultrastructure of the boundary between the basal and suprabasal cells in mouse trunk epidermis, as seen by routine transmission
electron microscopy. The sample, from which this micrograph was taken, is oriented in the same manner as frame C. Organization of keratin filaments as loose bundles correlates with the expression of K5K14 in basal cells (brackets), whereas
the formation of denser, electron-dense filament bundles reflects the onset of K1K10 expression in early differentiating
cells (arrowheads). Arrows point to desmosomes connecting the two cells. (Bar = 2 m; n = nucleus.)
Chapter 46
481
Section 7
::
482
psoriasis and related hyperproliferative disorders,

nonmelanoma skin cancers, viral infections, and other
conditions accompanied by inflammation.23,25,26 Similar
replacement of the K1 and K10 keratin pair by K6,
K16, and K17 occurs when normal human keratinocytes are placed in culture.23,25,27 During early progression toward malignancy, cutaneous squamous cell
carcinoma progressively shifts from being K6/K16positive while maintaining some degree of K1/K10
expression, thus reflecting a differentiated state, to
being entirely negative for K1/K10 and positive for the
simple epithelial keratins K8/K18, indicative of a less
differentiated and more aggressive state.28 These variations in keratin gene expression likely impact the biological properties of keratinocyte in a significant way.
FUNCTION OF KERATIN IN THE

EPIDERMIS AND OTHER SKIN
EPITHELIA
A major function fulfilled by keratins and all other IF
proteins is to enhance the cells ability to withstand
trauma. This structural support function3,4 is made possible by the unique mechanical properties exhibited by
IF networks.24 This function is enhanced by attachment
of IFs to adhesion complexes (desmosomes, hemidesmosomes), and to F-actin and microtubules.3,4,16 Partial or
complete loss of this function, for example, through
inherited mutations, underlies a wide variety of rare diseases that render cells fragile and unable to sustain
mechanical stress (Table 46-2). In vivo, the mechanical
properties of IF networks likely need to be modulated, in
a dynamic fashion, to meet the demands placed on cells
by changing physiological circumstances. To a degree,
varying needs along a continuum of viscoelastic properties likely account, at least in part, for the dynamic regulation of keratin IF genes and their proteins in vivo.17,24
The recent discovery of nonmechanical functions for
keratin proteins has placed the field on an exciting new
path.17 In hair follicles, K17 promotes the anagen
(growth) phase by attenuating TNF--induced apoptosis in matrix keratinocytes.29 In the epidermis, the
suprabasally expressed K10 regulate proliferation in
the basal layer of epidermis and in sebaceous glands,
likely through a noncell-autonomous mechanism,30,31
while K17 cell autonomously regulates protein synthesis and cell size in wound-proximal keratinocytes.32
Keratins influence the melanin pigment distribution
and, thus, skin pigmentation.3335 In polarized epithelia, keratin IFs impact the distribution of organelles,
routing of specific outer membrane proteins, and
response to stress.36 These newly defined keratin functions, which are just beginning to be understood,
involve regulated interactions between keratin proteins and noncytoskeletal proteins, many exerting key
roles in specific signaling pathways.16,17,24,36 Interference with these functions could play a role in the
pathogenesis of disorders linked to IF gene mutations.4
The discovery of these novel keratin functions provides an opportunity to better understand the diversity and context-dependent regulation of IF genes and
their proteins.
MUTATIONS IN EPIDERMAL KERATINS

UNDERLIE SEVERAL INHERITED SKIN
BLISTERING DISEASES
In the 1980s, ultrastructural studies showed that
epidermal basal keratinocytes of patients with the
Dowling-Meara form of epidermolysis bullosa simplex (EBS) contained dense cytoplasmic aggregates,37,38
later shown to contain mispolymerized keratin.39,40 In
parallel, reverse genetic studies showed that expression of dominant-negative keratin mutations cause
keratin IF aggregation in cultured cells, and epithelial
fragility in vivo.41,42 In the early 1990s, the first mutations in keratins K5 and K14 were linked to EBS.39,43,44
In EBS, K5/K14-expressing basal layer keratinocytes
literally rupture in response to mild mechanical trauma
to the skin. Fragility is occasionally seen in other sites
of K5/K14 expression, such as the cornea and oral
mucosa.45 Similarly, dominant mutations in the suprabasally expressed K1, K10, and K2e were found to
cause epidermolytic hyperkeratosis (EHK),46,47 ichthyosis bullosa of Siemens,48 and related diseases (Table
46-2). Such efforts established that compromising keratin function engenders structural failure and fragility.
In specific instances, depending on the disorder, this
primary defect is accompanied by enhanced proliferation and hyperkeratosis,4,30 or aberrations in skin pigmentation.3335 Since then, a broad range of additional
diseases affecting either epidermal appendages (e.g.,
hair, nail) or nonskin epithelia (e.g., oral mucosa, cornea) have been linked to keratin mutations.4,49
The following general principles can be drawn from
the large body of data accumulated to date while studying keratin-based disorders. The majority of cases
involve single missense mutations acting in a dominantnegative fashion. Small insertions and deletions are also
seen with some frequency.49 In this setting, dominance
implies that disease-causing mutant keratin proteins do
not markedly alter the early stages of assembly (dimer,
tetramer formation) up to the step(s) involving subunit
incorporation in a growing IF polymer.4 Depending on
their nature and location within the keratin protein backbone, these mutations exert a wide range of effects on the
assembly or organization of IFs in keratinocytes, with a
corresponding impact on the severity of clinical presentation. This concept can be readily illustrated for EBS.50
Mutations altering residues that are highly conserved
within the central rod domain tend to dramatically alter
the structure of keratin IFs, foster the formation of aberrantly polymerized keratin aggregates, and cause severe
disease (as seen in the Dowling-Meara form of EBS).
Conversely, mutant proteins that elicit a clinically milder
version of the disease (e.g., Weber-Cockayne EBS) affect
keratin assembly more subtly, and do not cause keratin
aggregation.50 The extent to which a given keratin
mutant compromises the function of the entire IF network is also a function of the number and abundance of
potentially redundant IF proteins occurring in a given
cell, or its ability to overexpress an alternate IF protein.4
While it is assumed that these mutations elicit a cell fragility phenotype in part through their ability to alter cellular mechanics,5153 there is evidence that they alter
Table 46-2
Keratin-based, Inherited Skin Bullous Disease Affecting Primarily the Epidermisa

Disease
Relevant OMIM
Catalog Number(s)a
Target Genes
Affected Cell
Type
Comments
Basal keratinocyte
K, WC, and DM correspond to

different degrees of severity; the
position/nature of the mutation in
K5 0r K14 is a key determinant
Rare mutations in the same genes
result in recessive inheritance
(OMIM #60100)
Epidermolysis Bullosa
Simplex with mottled
pigmentation
131960
K5
Basal keratinocyte
A single dominant allele,

K5P28L, has been found in
multiple pedigrees. Typified by
hyperpigmentation of healed skin
blisters
Simplex with limb
girdle muscular
dystrophy
226670 (also,131950)
Plectin
Basal keratinocyte
Plectin is a cytolinker protein

attaching IFs to adhesive complexes
and F-actin/microtubules in
keratinocytes and myocytes
Dowling-Degos
disease
179850
K5 (null)
Basal keratinocyte
Inherited recessively; Features

multiple aberrations in skin
pigmentation
Epidermolytic
Hyperkeratosis
113800
K1 or K10
Spinous
keratinocyte
Same as Bullous congenital

ichthyosiform erythroderma. As
for EBS, there is wide variation in
severity of clinical presentation,
correlating with position and nature
of the mutation affecting either K1
or K10
Ichtyosis hystrix
(Curth-Macklin)
146490; 146600
K1 or K10
Spinous
keratinocyte
Characteristic ridges or spikes

present at the skin surface.
Ultrastructurally, presence of large
bundles of densely packed IFs
around nucleus
Ichtyosis Bullosa of
Siemens
Palmoplantar
keratodermas:
146800
K2e
Granular
keratinocyte
Epidermolytic
144200
K9
Non-epidermolytic
139350 (diffuse)
600962 (focal)
K1 K1 or K16
Spinous
keratinocyte
Spinous
keratinocyte
Striate
607654
DP, Dsg1 or K1
Affects primarily flexural areas;

Blistering confined to the upper
suprabasal layers; Can be confused
with mild EHK/BCIE
Confined to the epidermis of palms
and soles
Reflects the unique distribution of
this large type I keratin
This is one of the rare conditions
for which the pathogenesis is not
indicative of cell fragility; May
reflect a non-mechanical role for
keratins
Desmoplakin (DP) and desmoglein
1 (Dsg1) are structural components
of desmosomes, to which keratin
IFs are attached in epidermis
Spinous
keratinocyte
K5 or K14
::
131800 (Koebner subtype)

131800 (Weber-Cockayne)
131760 (Dowling-Meara)
Chapter 46
Simplex
Note: See the Intermediate Filament Database (www.interfil.org) and Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim/)
websites for further information.
483
keratin regulation, for example, via posttranslational

modifications,11 and elicit a cellular stress response.4,54
Treatment options for EBS are currently limited, and are
primarily palliative in nature.50 They consist of supportive care for skin, management of skin blisters as they
heal so as to prevent infection, and preventive avoidance
of mechanical trauma.
CORNIFIED ENVELOPE
Section 7
::
484
Alongside the substantial build up in keratin IFs inside

differentiating keratinocytes, two specializations allow
the epidermis to build a remarkably effective and
mechanically resilient barrier: (1) the cornified envelope
(CE), a covalently cross-linked protein polymer that
forms underneath the plasma membrane, and (2) an
extracellular hydrophobic phase that is made up of specialized lipids synthesized by terminally differentiating
keratinocytes.55 Epidermal lipids are discussed in detail
in Chapter 47, and will not be discussed further here.
The CE represents a complex assembly of covalently
cross-linked proteins that forms underneath, and eventually replaces, the outer keratinocyte membrane in the
granular layer of epidermis, as part of the final push to
complete terminal differentiation. This 20-nm thick
sheath, which is so insoluble and stable it resists
extended boiling in the presence of strong denaturants,
encases the cells interior, and significantly contributes
to the physicochemical properties of the stratum corneum compartment.56 The extraordinary stability of the
CE results in large part from the large number of -(-glutamyl)-lysine isopeptide bonds between its primary
constituents (see below), which are further reinforced
by disulfide bridges. These isopeptide bonds are catalyzed by transglutaminases, a family of calcium-dependent enzymes.57 The outer aspect of the CE is covalently
linked to ceramides and other specialized lipids that are
produced by, and secreted from, differentiated granular
keratinocytes, whereas large bundles of tightly packed
keratin IFs are cross-linked to its inner aspect.
The major protein constituents of the CE are loricrin,
involucrin, filaggrin, elafin, cystatin A, cornifelin, several small proline-rich (SPR) proteins and calciumbinding S100 proteins, and late-envelope proteins
(LEPs). In addition to these proteins, key components
of desmosomes (e.g., desmoplakin, envoplakin, and
periplakin) and several type II keratins (K1, K2, K5) are
also cross-linked into the CE5658 (Table 46-3). CE proteins have several interesting features in common.
First, many CE proteins are encoded by genes clustered as part of the epidermal differentiation complex
(EDC) locus on human chromosome 1q21. In addition
to obvious evolutionary implications, this genomic
clustering brings up the distinct possibility of coordinated regulation through cis-acting determinants.55,58
Second, many of these proteins are made as precursors
that are activated by proteolytic cleavage, calcium binding, or other modifications at the time of CE formation.
Third, many CE proteins are made of repeated units that
lack an intrinsically defined three-dimensional structure. Fourth, virtually all CE proteins are transglutaminase substrates.55,57
Involucrin, loricrin, and filaggrin, in particular, are

well-characterized components of the CE.56,57 Involucrin biosynthesis is initiated in the spinous compartment, soon after the onset of K1/K10 keratin expression,
in differentiating epidermal keratinocytes. It is the first
major component to be activated and cross-linked into
the emerging CE, possibly reflecting a scaffolding role,
and is concentrated in the outermost aspect of the
mature CE. Profilaggrin and loricrin are synthesized in
precursor forms and stored in keratohyalin granules.
Loricrin is the major structural component of the CE
(80% by weight)this largely unstructured but
highly flexible protein features glycine loops as
described for type II keratins. Once activated via
dephosphorylation and proteolytic cleavage, filaggrin
participates in the bundling of keratin IFs in the late
granular compartment of epidermis (hence accounting
for its incorporation into the CE) and also is degraded
to free amino acids that contribute to the cornified
cells ability to retain water. Basic information about
other CE components is provided in Table 46-3.56,57 The
protein composition and fine structure of the epidermal CE differs to a degree from those of the other stratified squamous epithelia; the underlying significance
of this CE heterogeneity is unclear.56,57
The important contribution of the CE toward proper
barrier function in epidermis is reflected in the clinical
symptoms associated with mutations altering their
primary constituents in the context of human diseases55 (Table 46-3). This is particularly well illustrated
by the recently documented role of filaggrin mutations
in ichtyosis vulgaris, atopic dermatitis (AD), and ADassociated hay fever or asthma (the so-called atopic
march; see Chapter 14).5961 The partial or complete loss
of filaggrin protein engendered by frameshift mutations in the corresponding gene compromises the epidermal barrier function and allows for the entry of
irritants and allergens into the skin,62 thereby eliciting
local (and even systemic) inflammation accompanied
by itching, erythema, and flaking reflecting improper
cornification (for further information see Chapter 14).
Barrier status in the epidermis thus sets our degree of
exposure to external elements and contributes to define
the relationship that we have with our environment.
CONCLUDING REMARKS
In this chapter, we have discussed epidermal differentiation viewed through the prism of keratin gene
regulation and CE formation. While it is well established that specific type I and type II keratins are
coexpressed as pairs associated with various stages of
normal and pathological epidermal differentiation,
and that mutations of major epidermal keratins cause
various forms of skin blistering diseases, the functional implications of these different keratins, not
only in terms of structural roles, but also in terms of
their novel involvements in signal transduction and
organelle transport, are just beginning to be understood. Additional studies are needed to better understand the roles of regulatory molecules in epidermal
proliferation, homeostasis, and disease; and how the
Table 46-3
Protein Composition of the Cornified Envelope (CE)a

Protein
Mol. Weight (kDa)

(Precursor Form)
Chromos
Location
CE Percent
Contribution
Loricrin
26
1q21
80
Rich in Gly, Ser, Cys residues; Contains glycine loops;

Flexible; Stored in keratohyalin granules; Mutated
in Vohwinkel syndrome, a mutilating keratoderma
with ichtyosis, and in progressive symmetric
erythrokeratodermia, a related condition.
Involucrin
65
1q21
Made up of repeated units; Highly -helical; Gly-,

Asp-rich; Early TG substrate; May act as a scaffold
during CE assembly
SPR
618
1q21
35
SPR: small proline-rich proteins; encoded by

15 genes that are differentially regulated in various
stratified epithelia; Great transglutaminases
substrates; Influence CEs mechanical properties
Cystatin A
12
3cen-q21
25
Cysteine protease inhibitor; Also stored in

keratohyalin granules; Mutations in cystatin M/E
cause Harlequin ichtyosis
LCEs
912
1q21
unknown
LCE: late cornified envelope proteins; Encoded by

18 genes; Synthesized and incorporated at a late
stage of CE formation
Profilaggrin/
Filaggrin
>400
36
1q21
<1
Also bundles keratin filaments; Degraded to single

amino acids, which markedly contribute to retain
H2O, in stratum corneum layers; Mutated in ichtyosis
vulgaris, a mild but very common condition; Risk
factor in individuals with atopic dermatitis and
asthma
S100A
1014
1q21
<1
Family of EF-hand containing, calcium binding

proteins; Believed to transmit calcium-dependent
signals
Proelafin
10
20q12-q13
<1
Elafin is the active entity, and acts as a serine

protease inhibitor
Annexin 1
36
9q12-q21
<1
Also known as lipocortin; Interacts with S100A11
Keratins (K1,
K2, (K5, K10,
K14)
5670
12q13
<1
Type II keratins are transglutaminase substrates;

Keratin IFs become covalently linked to the inner
aspect of the CE
Desmosomal
proteins
195330
Various
<1
Includes desmoplakin, envoplakin, periplakin, and

others. Assembly of CE is initiated at desmosome
cell-cell contacts
Comments/Disease Association
Chapter 46
::
Note: A review article by Eckert et al., J Invest Dermatol. 124:481-12 (2005) served as a direct inspiration for this Table.
keratin filaments function, at the atomic level, in normal and diseased epidermis. These future studies
should lead to new modalities, including cell and
gene therapies, for a better treatment of some of the
devastating skin diseases.
KEY REFERENCES
1. Schweizer J et al: New consensus nomenclature for mammalian keratins. J Cell Biol 174:169-174, 2006
2. Moll R et al: The catalog of human cytokeratins: Patterns

of expression in normal epithelia, tumors and cultured
cells. Cell 31:11-24, 1982
3. Fuchs E, Weber K: Intermediate filaments: Structure, dynamics, function, and disease. Annu Rev Biochem 63:345382, 1994
4. Omary MB, Coulombe PA, McLean WH: Intermediate
filament proteins and their associated diseases. N Engl J
Med 351:2087-2100, 2004
7. Fuchs E: Keratins and the skin. Annu Rev Cell Dev Biol
11:123-153, 1995
24. Kim S, Coulombe PA (2007): Intermediate filament scaffolds fulfill mechanical, organizational, and signaling
functions in the cytoplasm. Genes Dev 21(13):1581-97
56. Candi E, Schmidt R, Melino G: The cornified envelope:
A model of cell death in the skin. Nat Rev Mol Cell Biol 6:
328-340, 2005
485
Chapter 47 :: Skin as an Organ of Protection

:: Ehrhardt Proksch & Jens-Michael Jensen
SKIN BARRIER AT A GLANCE
The most important function of the skin is to
form a barrier between the organism and the
environment.
Section 7
The skin barrier prevents excessive water

loss (insideoutside barrier) and the entry of
harmful substances from the environment
(outsideinside barrier).
::
The physical barrier is predominantly

located in the stratum corneum.
The stratum corneum barrier is composed

of corneocytes and intercellular lipids,
cholesterol, free fatty acids, and ceramides.
Keratins and cornified envelope proteins are
important for the mechanical stability of the
corneocytes.
The cornified envelope protein involucrin
binds ceramides covalently, forming a
backbone for the subsequent attachment of
free ceramides.
The nucleated epidermis through tight
junctions and desmosomes also contributes
to the barrier.
Experimental barrier disruption increases
epidermal lipids and changes in epidermal
differentiation.
The signals for barrier recovery are cytokines
and the calcium ion gradient.
Several diseases are characterized by a
probably genetically disturbed barrier
function. The disturbed barrier function
contributes to disease pathology, in
particular in contact dermatitis, atopic
dermatitis, forms of ichthyosis, and psoriasis.
Lipid or lipid-like creams and ointments can
repair disturbed barrier function.
486
The skins most important function is to form an effective barrier between the inside and the outside of
the organism. Life on dry land requires the presence of
a barrier to regulate water loss and prevent desiccation, commonly referred to as the insideoutside
barrier. Additionally, skin provides an outside
inside barrier to protect against mechanical, chemical,
and microbial assaults from the external environment

(Fig. 47-1).1 To perform these functions the epidermis
undergoes keratinization, a process in which epidermal cells progressively mature from basal cells with
proliferative potential to the lifeless, flattened squames
of the stratum corneum (SC) (Fig. 47-2). Both the SC
and the deeper skin layers protect the skin from
mechanical forces, ultraviolet (UV) radiation, cold and
hot temperatures, and invasion of chemicals and
microbes. To effectively perform this multiplicity of
functions, the skin contains different types of barriers.
The physical barrier consists mainly of the SC, but the
nucleated epidermis, in particular the tight junctions,
provides another important barrier component. The
chemical/biochemical (antimicrobial) barrier consists
of lipids, acids, lysozymes, and antimicrobial peptides
(discussed in Chapter 10). The humoral and cellular
immune system provides a barrier to infectious disease, but immune hyperactivity may lead to allergy
(Table 47-1).
Although the skin is of central importance for preventing water loss in a dry environment, aquatic animals also require a skin barrier to protect them from
the high salinity of their surrounding environment.
Terrestrial mammals with dense fur have much thinner skin than animals without this protective coat,
demonstrating that fur itself is a considerable barrier.
The relatively hairless skin of pigs shows much
Functions of the epidermal inside-outside and

outside-inside barrier
Mechanical assaults
(irritation, UV irradiation, heat and cold shock)
Microbial assaults
(bacteria, fungus, virus)
Physical
skin barrier
Chemical assaults
(irritants, allergens)
Stratum
corneum
Epidermis
Prevention of excessive water loss and

dessication, disruption barrier leads to
increased transepidermal water loss
Figure 47-1 Functions of the epidermal insideoutside

and outsideinside barrier.
Progressive maturation of the epidermis
Scale desquamation
Cornified lipid envelope
Lipid bilayers
SC
Cornified cell envelope with

involucrin, loricrin, filaggrin
Tight junction
SG
Lamellar body
Keratohyalin granule
SS
Cytokeratin K1/K10
s imilarity to human skin and is therefore a good model

for skin research.
In addition to the SC the entire skin, as a whole,
serves a protective function. The innermost region of
human skin, the subcutaneous fat layer, offers mechanical shock protection, insulates the body against external heat and cold, and is active in general energy
metabolism and storage. The dermis is composed of
collagen bundles and elastic fibers and is very important for the mechanical strength of the skin. The epidermis, the skins outer layer, consisting primarily of
stratified nucleated keratinocytes and the SC, is most
important for skin protectionthe focus of this chapter.
Sweat glands and blood vessels regulate body temperature. Sebaceous glands secrete specialized lipids to protect the hair from the environmental stress (see Chapter
TABLE 47-1
Different Skin Barriers

Physical barrier
Stratum corneum (corneocytes,

lipid lamellae), nucleated
epidermis (desmosomes, tight
junctions)
Chemical/biochemical
(antimicrobial) barrier
(innate immunity)
Lipids, organic acids, lysozymes,

antimicrobial peptides
Immune barrier
humoral and cellular
immune systems
Lymphocytes, neutrophils,
monocytes, Langerhans cells
79). In animals, these lipids serve as a water repellent

for the fur, aiding in buoyancy and temperature regulation, and also preventing desiccation of the body and
UV damage. The role of sebaceous lipids for SC barrier
function and for dry skin is under active investigation.2,3 Sebaceous glands also transport glycerol to the
skin surface, which is important for SC hydration.4
Nerve fibers are chemosensitive and act as a warning
system against external trauma (see Chapter 102).
Skin as an Organ of Protection
Figure 47-2 The nucleus in the stratum granulosum (SG) should be flattened. In the basal cell layer please add a hemidesmosome towards the basal membrane (please review the former graphic). The lamellar bodies should be hatched (including the membrane fused bag shaped lamellar bodies).
::
Cytokeratin K5/K14
SB
Chapter 47
Desmosome
STRUCTURE OF THE STRATUM

CORNEUM: THE PHYSICAL
PERMEABILITY BARRIER
(Table 47-2)
Research from the 1940s and 1950s established that
the SC is the specific location of the physical barrier.5,6
The SC barrier structure visualized by electron microscopy and ruthenium tetroxide fixation (Fig. 47-3) is a
better indicator of its barrier function than the typical
basket-weave appearance of the SC in routine formalin-embedded tissue sections. Regulation of water
permeation is not absolute. The normal movement of
water from the SC into the atmosphere is known as
transepidermal water loss (TEWL), previously called
insensible water loss. The SC serves as the principal
barrier against the percutaneous penetration of chemicals and microbes1 as well.
The 1020 m thick SC forms a continuous sheet of
protein-enriched cells, embedded in an intercellular
matrix, enriched in nonpolar lipids, and organized as
487
TABLE 47-2
Protection Functions of the Stratum Corneum
Section 7
Structural Bases
Biochemical Mechanisms
Permeability barrier
Lamellar bilayers
Hydrophobic lipids
Mechanical integrity/resilience
Cornified envelope, cytosolic filaments
Cross-linked peptides; e.g., involucrin, loricrin.

Keratin filaments
Hydration
Lamellar bilayers; corneocyte cytosolic

matrix
Sebaceous gland-derived glycerol; filaggrin

breakdown amino acids; natural moisturizing
factors (NMFs), hornerin
Cohesion/desquamation
Corneodesmosomes
Serine proteases
Antimicrobial defense
Lamellar bilayers; extracellular matrix
Free fatty acids; antimicrobial peptides
UV protection
Corneocyte cytosol
Structural proteins; trans-urocanic acid (tUCA)
Antioxidant defense
Corneocytes and extracellular matrix
Keratins; sebaceous gland-derived vitamin E and

other antioxidants
Waterproofing/repellence
Lamellar bilayers
Keratinocyte and sebum-derived lipids
Cytokine signaling
Corneocyte cytosol
Storage and release of pro-IL-; serine proteases
Xenobiotic defense
Lamellar bilayers
Lipid solubility; cytochrome P450 system (outer

epidermis)
::
Functions
488
Figure 47-3 Electron microscopy reveals that in the stratum granulosum (SG)stratum corneum (SC) interface the lamellar bodies (LB) content is extruded to the intercellular space (A), thus forming continuous bilayers. (B then C). Desmosomes are becoming corneosomes in the process of cornification (D).
The lipid-depleted corneocyte
Lipid-enriched extracellular
matrix with lipid bilayers
Corneocyte-bound
Lipid-depleted
lipid envelope
corneocyte
Corneocyte-bound
protein envelope
Figure 47-4 The lipid-depleted corneocyte is surrounded

by an inner protein envelope and an outer lipid envelope.
Special ceramides are covalently bound to cornified envelope proteins, in particularly to involucrin.
::
Lipid layer
the SCs extracellular layers. The lamellar bodies may

also contain proteins such as human b-defensin 2.7 In
response to certain signals, for example, an increase in
calcium concentration during the transition from the
granular layers to the SC, the lamellar bodies move to
the apex of the uppermost granular cells, fuse with the
plasma membrane, and secrete their content into the
intercellular spaces through exocytosis. The lipids
derived from the lamellar bodies are subsequently
Progressive maturation of the epidermis
SC
Chapter 47
lamellar lipid layers. The viable epidermis is a stratified squamous epithelium, consisting of basal, spinous, and granular cell layers. Upon leaving the basal
layer, keratinocytes begin to differentiate and undergo
a number of changes in both structure and composition during the apical migration into the stratum spinosum and stratum granulosum (see Chapter 46).
Keratinocytes synthesize and express numerous structural proteins and lipids during their maturation. The
final steps in keratinocyte differentiation are associated with profound changes in their structure, resulting in their transformation into flat and anucleated
squamous cells of the SC, consisting mainly of keratin
filaments and surrounded by a cell envelope composed of cross-linked proteins (cornified envelope proteins) as well as a covalently bound lipid envelope
(Fig. 47-2). Extracellular nonpolar lipids surround the
corneocytes to form a hydrophobic matrix. The cornified envelope proteins as well as the covalently bound
lipid envelope are thought to be important for the
chemical resistance of the corneocytes (Fig. 47-4). Desmosomes, which interconnect adjacent keratinocytes,
are important for SC cohesion and are shed during the
desquamation process in the SC. In the upper spinous
and granular layers characteristic lamellar vesicles
appear, which are called epidermal lamellar bodies
(Figs. 47-3 and 47-5). These are enriched in polar lipids,
glycosphingolipids, free sterols, phospholipids, and
hydrolytic enzymes that deliver the lipids required for
Acid sphingomyelinase
-glucocerebrosidase
phospholipase
steroid sulfatase
SG
Differentiation
SS
SB
Lamellar body (containing

hydrolytic enzymes and
phospholipids, ceramides,
glycosyl ceramides,
and sterols)
Figure 47-5 During differentiation, the upper stratum spinosum (SS) and the stratum granulosum (SG) cells generate
lamellar bodies containing preformed lipid structures and hydrolytic enzymes. Their content is extruded into the SG
stratum corneum (SC) interface and undergoes profound remodeling. SB = stratum basale.
489
Section 7
::
490
modified and rearranged into intercellular lamellae

positioned approximately parallel to the cell surface.
The covalently bound lipid envelope acts as a scaffold
for this process. After the extrusion of the lamellar bodies into the stratum granulosumSC interface, the
polar lipids are enzymatically converted into nonpolar
products. Hydrolysis of glycosphingolipids generates
ceramides while phospholipids are converted into free
fatty acids. These changes in lipid composition and cell
structure result in the formation of a very dense structure packed into the interstices of the SC (Table 47-2).8
LIPID COMPOSITION AND ROLE OF

LIPIDS IN THE STRATUM CORNEUM
PERMEABILITY BARRIER
Confocal laser scanning microscopy and X-ray microanalysis studies have shown that the major route of
penetration results in a tortuous pathway between the
corneocytes, confirming that intercellular lipids play an
irreplaceable role in regulating skin permeability barrier function.8 The major lipid classes in the SC are cholesterol, free fatty acids, and ceramides (see eFig. 47-5.1
in online edition).911
CHOLESTEROL.
Cholesterol is probably the most

abundant lipid in the entire body and part of the
plasma membrane, but also part of the intercellular
lipid lamellae in the SC. Although basal cells are capable of resorbing cholesterol from circulation, most cholesterol in the epidermis is synthesized in situ from
acetate.12 The epidermal keratinocyte, the main cell
type in the epidermis, is highly active in the synthesis
of several lipids, including cholesterol and free fatty
acids. The rate-limiting step in cholesterol biosynthesis
is catalyzed by hydroxymethylglutaryl CoA (HMG
CoA) reductase (Fig. 47-6). Epidermal cholesterol synthesis is regulated by these enzymes and increases during permeability barrier repair.13
FREE FATTY ACIDS. The skin contains free fatty

acids as well as fatty acids bound in triglycerides,
phospholipids, glycosylceramides, and ceramides.
The chain length of free fatty acids in the epidermis
ranges from C12 to C24. The rate-limiting enzymes acetyl-CoA carboxylase and fatty acid synthase in the epidermis are largely autonomous (Figs. 47-6 and 47-7).14
Saturated and monounsaturated fatty acids are synthesized in the epidermis, in contrast to di- and polyunsaturated acids. The nomenclature of the fatty acids
is determined from the position of the first double
bond in the molecule, starting from the terminal
methyl group. In particular, the essential -6unsaturated acids are obtained from food and reach
the epidermis by the circulation but can also be
obtained by topical treatment. The nonessential monounsaturated fatty acid, the oleic acid, is an -9-fatty
acid. The most important double unsaturated fatty
acid, linoleic acid, is an -6 fatty acid. Also of importance is -linoleic acid (-3). No skin changes due to
-3-fatty acid deficiency are currently known; how-
Synthetic pathways and key enzymes for

stratum corneum free fatty acids and cholesterol
Acetyl-CoA
HMG-CoA
synthase
Acetyl-CoA
carboxylase
HMG-CoA
HMG-CoA
reductase
Mevelonic acid
Malonyl-CoA
Fatty acid
synthase
Farnesyl
pyrophosphate
synthase
Farnesol
Squalene
synthase
Squalene
Free fatty acid
Cholesterol
Figure 47-6 Synthetic pathways and key enzymes for

stratum corneum free fatty acids and cholesterol. CoA =
coenzyme A; HMG-CoA = hydroxymethylglutaryl CoA.
ever, it has been proposed that these fatty acids are

important for the resolution of inflammation. -3fatty acids are obtained from fish, whereas -6-fatty
acids are obtained from plant oils.15,16 Essential fatty
acid deficiency (EFAD) caused by unusual diets or
malabsorption in humans or experimentally induced
in rats and mice leads to the EFAD syndrome, characterized by profound changes in epithelia including the
epidermis.17 In this condition, the epidermis is rough,
scaly, and red and shows a severely disturbed permeability barrier function. In addition, severe bacterial
infection, impaired wound healing, and alopecia may
occur. Linoleic acid is part of phospholipids, glucosylceramides, ceramide 1, ceramide 4, and ceramide 9.18
It has been proposed that the linoleic acid metabolite
-linoleic acid is of special importance for atopic
eczema.
CERAMIDES. Ceramide is an amide-linked fatty

acid containing a long-chain amino alcohol called
sphingoid base. The carbon chain lengths of amidelinked fatty acids and sphingoid bases in most mammalian tissues are 16 to 26 and 18 to 20, respectively
(see eFig. 47-5.1 in online edition). Although sphingolipids, including glycosphingolipids and phos
phosphingolipids, are ubiquitously distributed in
mammalian tissues, tissue-specific molecular distribution has been described. Glucosylceramide is
Sphingomyelin, glucosylceramides, and phospholipids as percursors
Acid sphingomyelinase
Ceramides
Sphingomyelin
Phospholipase A2
Phospholipids
Free fatty
acids
Glucosylceramides
Ceramides
-Glucocerebrosidase
Generation and degradation of ceramides
addition, there are two protein-bound ceramides: (1)

ceramide A and (2) ceramide B (see eFig. 47-5.1 in
online edition).8 These ceramides are covalently bound
to cornified envelope proteins, most importantly to
involucrin.
Ceramides are synthesized by serine-palmitoyltransferase as rate-limiting enzyme and by hydrolysis of
both glucosylceramide (by -glucocerebrosidase)19 and
sphingomyelin (by acid sphingomyelinase) (Figs. 47-7
and 47-8).20 Whereas all kinds of ceramides are derived
by synthesis from serine-palmitoyltransferase and from
-glucocerebrosidase, only ceramide 2 and ceramide
::
enriched in the epidermis and spleen while galactosylceramide is enriched in the brain, but is not detected
in keratinocytes. Whereas ceramide is a minor lipid
component, comprising less than 10% of cholesterol or
phospholipids in other mammalian tissues, ceramide
is a major lipid component in the SC, accounting for
30%40% of lipids by weight. Moreover, such a high
content of ceramides in the SC is not observed in the
epidermal stratum granulosum, stratum spinosum, or
stratum basale. This also suggests that terminal differentiation is a key factor in accumulating ceramide.
The SC contains at least nine different ceramides.18 In
Chapter 47
Figure 47-7 Sphingomyelin and glycosylceramides are precursors for ceramide generation, while phospholipids are precursors of fatty acids.
Serine + Palmitoyl-CoA
Serine palmitoyl transferase
Reductase
Sphingomyelin
Sphingomyelin
synthase
Sphinganine
Sphingomyelinases
Ceramide synthase
Desaturase
OH
Phosphatase
NH
Ceramide
-Glucocerebrosidase
Glucosylceramide
synthase
Dihydroceramide
CH2OH
Ceramide 1-phosphate
Ceramide kinase
Ceramide
synthase
Sphingosine
Glucosylceramide
Sphingosine
1-phosphatase
Glycolipids
Gangliosides
Suphatides
Galactosylceramide
Sphingosine 1-phosphate
Lyase sphingosine kinase
Glycerolipids
Figure 47-8 Generation and degradation of ceramides.
491
TABLE 47-3
Additional Protective Functions of the

Nucleated Epidermis
Section 7
Biochemical Correlates
Antimicrobial systems
Antimicrobial peptides and

lipids, iron-binding proteins,
complement
Antioxidants
Glutathione, oxidases,
catalase, cytochrome P450
system, vitamins C and E
Inflammatory mediators
Prostaglandins, eicosanoids,
leukotrienes, histamine,
cytokines
UV-absorbing molecules
Melanin, trans-urocanic
acid, vitamin D, vitamin C
metabolites, filaggrin
metabolites
Xenobiotic-metabolizing
enzymes
Glucoronidation, sulfation,
hydroxylation mechanisms
::
Functions
5 are obtained from sphingomyelinase because sphingomyelinase contains nonhydroxy acids.21
LIPID TRANSPORT
Keratinocytes require abundant cholesterol for cutaneous permeability barrier function. ABCA1 is a membrane transporter responsible for cholesterol efflux
and plays a pivotal role in regulating cellular cholesterol levels. It was demonstrated that ABCA1 is
expressed in cultured human keratinocytes and
murine epidermis. Liver X receptor (LXR) activation
and activation of peroxisome proliferator-activated
receptor (PPAR)-, PPAR-ss/, and retinoid X receptor
(RXR) increased ABCA1 expression in keratinocyte
cultures. Thus, cholesterol levels for permeability barrier function are regulated by ABCA1, LXR, and
PPARs.22 The cellular fatty acid transport and metabolism is regulated by fatty acid-binding proteins
(FABPs).23,24
Additional protective functions of the epidermis are
not discussed in this chapter, but are listed in Table 47-3.
EPIDERMAL PROLIFERATION
AND DIFFERENTIATION IN SKIN
BARRIER FUNCTION
492
To provide the physical barrier of the SC, not only

intercellular lipids, but also corneocytes are of crucial
importance.25,26 The epidermis undergoes keratinization in which epidermal cells progressively mature
from basal cells with proliferative potential to lifeless
flattened squames of the SC (Fig. 47-2). Keratinocytes
arise from stem cells in the basal layers and transient
amplification cells and move to a series of differentiation events until they are finally brought to desquamation.27 Thus, in the normal epidermis, there is a balance
between the processes of proliferation and desquamation that results in a complete renewal approximately
every 28 days. In some forms of ichthyosis, the rate of
desquamation may be decreased, leading to epidermal
cell retention (retention hyperkeratosis).28 (See Chapter
49.) In inflammatory skin diseases like psoriasis there
is an increase in proliferation resulting in a disturbance
in differentiation and parakeratotic squames (hyperproliferative hyperkeratosis).29
Keratins are major structural proteins synthesized in
keratinocytes (see Chapter 46). They assemble into a
web-like pattern of intermediate filaments that emanate from a perinuclear ring, extend throughout the
cytoplasm, and terminate at junctional desmosomes
and hemidesmosomes. During the final stages of normal differentiation, keratins are aligned into highly
ordered and condensed arrays through interactions
with filaggrin, a matrix protein. In keratin disorders,
the filament networks collapse around the nucleus,
preventing attachment with the filament-matrix complex and the inner surface of squames, and alter interaction between neighboring cells, thereby affecting
desquamation. Filaggrin aggregates the keratin filaments into tight bundles. This promotes the collapse of
the cell into a flattened shape, which is characteristic of
corneocytes in the cornified layer. Together, keratins
and filaggrin constitute 80%90% of the protein mass
of mammalian epidermis.25,26
The structural proteins involucrin, loricrin, trichohyalin, and the class of small proline-rich proteins
(SPRRs) are synthesized and subsequently crosslinked by transglutaminases to reinforce the cornified
envelope just beneath the plasma membrane. The proteins of the cornified envelope constitute about
7%10% of the mass of the epidermis. These corneocytes provide the bulwark of mechanical and chemical
protection, and together with their intercellular lipid
surroundings, confer water-impermeability. The cornified cell envelope is a tough protein/lipid polymer
structure formed just below the cytoplasmic membrane and subsequently resides on the exterior of the
corneocytes (Fig. 47-4). It is resistant to 10% KOH and
is the rigid structure seen on KOH skin scrapings. It
consists of two parts: (1) a protein envelope and (2) a
lipid envelope. The protein envelope contributes to
the biomechanical properties of the CE as a result of
cross-linking of specialized cornified envelope structural proteins by both disulfide bonds and N()(-glutamyl)lysine isopeptide bonds formed by
transglutaminases.26,30 The isopeptide bonds are resistant to most common proteolytic enzymes. The corneocyte-bound lipid envelope is plasma membrane-like
structure, which replaces the plasma membrane on the
external aspect of mammalian corneocytes.31 Involucrin, envoplakin, and periplakin serve as substrates for
the covalent attachment of -hydroxyceramides with
very long-chained N-acyl fatty acids by ester linkage.32
These not only provide a coating to the cell, but
also interdigitate with the intercellular lipid lamellae
(Table 47-2).26
EXPERIMENTAL BARRIER
DISRUPTION AND GENE
MODIFICATION IN EPIDERMAL
DIFFERENTIATION
Barrier recovery
50%
Figure 47-9 Three phases of barrier recovery with distinct metabolic activities occurring after acute barrier
disruption. A = Secretion of preformed pool of lamellar
bodies (0 to 30 minutes). B = Increased lipid synthesis
(free fatty acids, ceramide, and cholesterol) (30 minutes to
6 hours), accelerated lamellar body formation and secretion (2 to 6 hours). C = Increased glucosylceramide processing (9 to 24 hours), increased keratinocyte proliferation and differentiation (16 to 24 hours).
100%
::
Three phases of barrier recovery
Chapter 47
Experimental barrier disruption leads to changes in

epidermal differentiation, epidermal lipid keratin, and
cornified envelope protein expression and, vice versa,
overexpression and deficiency of these lipids and proteins in mice result in barrier defects. A number of diseases displaying defective epidermal barrier function
are also the result of genetic defects in the synthesis
and metabolism of either lipids, keratins, cornified
envelope proteins, or the transglutaminase 1 crosslinking enzyme.
Inhibition of HMG CoA reductase by topical application of the lipid-lowering drug lovastatin in mice
resulted in a disturbed barrier function and in epidermal hyperproliferation. Therefore, the specific relationship between barrier function and epidermal DNA
synthesis was examined. After acute skin barrier disruption (local acetone treatment or by tape-stripping)
(Fig. 47-9) and in a model of chronic barrier disruption
(EFAD diet), an increase in DNA synthesis leading to
epidermal hyperplasia was noticed.33 The increase in
DNA, and in lipid synthesis, was partially prevented
by occlusion.15,33,34
Also, the described acute and chronic barrier disruption leads to specific changes in epidermal keratin and
cornified envelope protein expression. Increased
expression of the basal keratins K5 and K14 and a
reduction of the differentiation-related keratins K1 and
K10 were noted. In addition, there was expression of
the proliferation-associated keratins K6 and K16 as
well as the inflammation-associated keratin K17 (see
eFig. 47-9.1 in online edition).35 The importance of keratins for skin barrier function was supported by studies in K10-deficient mice. Heterozygotes and
homozygotes showed a mild or severe permeability
barrier disruption, respectively. Importantly, homozygous neonatal K10-deficient mice exhibited an
extremely delicate epidermis and died a few hours
after birth. Heterozygous littermates showed a normal
skin at birth but developed increasing hyperkeratosis
as they grew up.36 Barrier repair in heterozygous K10deficient mice was delayed and skin hydration was
impaired.37 Changes in ceramide composition, a
reduced amount of glucosylceramide and sphingomyelin, and reduced acid sphingomyelinase activity, as
well as increased involucrin content, were also noted.38
This shows that genetically determined changes in
structural proteins lead to an impaired skin barrier
function and changes in differentiation and lipid composition.
The importance of keratins for skin barrier function
is further supported by studies in diseases that are
caused by monogenetic defects of these structural proteins. Epidermolysis bullosa simplex (EBS) shows
mutation in the basal layer keratins K5 or K14 (details
in Chapter 62). Genetic defects in the suprabasal keratins results in hyperkeratosis and a mild barrier defect
(details in Chapters 49 and 59). Epidermolytic hyperkeratosis (EHK) has spinous layer K1 or K10 defects,
epidermolytic palmoplantar keratoderma (EPPK) has
granular layer K9 defects (because this keratin is
expressed only in palmar and plantar skin, the disease
is restricted to that area), and ichthyosis bullosa of Siemens (IBS) has granular layer defects K2 (formerly
K2e) defects.25
Experimental permeability barrier disruption leads
to a premature expression of involucrin, but not loricrin.35 Overexpression of filaggrin in mice in the suprabasal epidermis resulted in a delay of barrier repair.39
Loss of normal profilaggrin and filaggrin is the cause
for the flaky tail in an autosomal recessive mutation
in mice that results in a dry, flaky skin, and annular
tail and paw constrictions in the neonatal period. Targeted ablation of the murine involucrin gene did not
show changes in skin barrier function under basal
conditions40 but resulted in a reduced barrier repair.
In addition, knockdown of filaggrin was shown to
increase UV-sensitivity in a human skin model.41
Loricrin deficient mice do not show a disturbed barrier function, but a greater susceptibility to mechanical stress which may alter skin barrier function
secondarily.42,43
Changes in epidermal proliferation and differentiation are also seen in inflammatory skin diseases
with a disturbed skin barrier function (see eFig.
47-9.1 in online edition). Increased proliferation is
one of the main characteristics of psoriasis, but in
atopic dermatitis lesional skin also there is a considerable increase in epidermal proliferation. Also,
changes in keratins and cornified envelope proteins
occur in inflammatory skin diseases.44 Overall, this
shows that there is undoubtedly a connection
between epidermal proliferation, differentiation, and
skin barrier function.
493
FUNCTIONS OF THE SUBCORNEAL

EPIDERMAL LAYERS
Section 7
::
Although the SC is recognized as the most important

physical barrier, the lower epidermal layers are also
significant in barrier function. A low-to-moderate
increase in TEWL occurs after removal of the SC by
tape stripping, whereas loss of the entire epidermis
through suction blisters leads to a severe disturbance
in barrier function. Loss of the SC and parts of the
granular layers in staphylococcal scalded skin syndrome (SSSS) are not usually life-threatening.45 In contrast, the suprabasal and subepidermal blistering
diseases pemphigus vulgaris, toxic epidermal necrolysis and severe burns, respectively, are life-threatening
when large areas of the body are involved. Patients die
because of extensive water loss or sepsis induced by
external bacteria infectionoutcomes directly resulting from perturbed barrier function. Survival rates can
be greatly improved with application of an artificial
barrier in the form of a foil or a grease ointment, often
containing active antimicrobial substances. These clinical observations confirm the importance of the nucleated epidermal layers in skin barrier function in both
directions, both in preventing excessive water loss and
the entry of harmful substances into the skin.46
TIGHT JUNCTIONS: A SECOND-LINE

EPIDERMAL BARRIER
Tight junctions are cell-junctions connecting neighboring cells sealing the intracellular space and controlling
the paracellular movements of molecules (Fig. 47-2).
The most important tight junction proteins in the
human epidermis are occludin, claudins, and zonal
occluding proteins (ZOs). Localization of occludin is
restricted to the stratum granulosum, ZO-1 and claudin 4 are found in suprabasal layers, and claudins 1
and 7 are found in all epidermal layers. In various diseases with perturbed SC barrier function, for example,
psoriasis vulgaris, lichen planus, acute and chronic
eczema, and ichthyosis vulgaris, tight junction proteins that were formerly restricted to the stratum granulosum and upper stratum spinosum, were also found
in deeper layers of the epidermis. Claudin 1-deficient
mice die within 1 day of birth due to tremendous water
loss.47 Altered barrier function of the skin has also been
demonstrated in mice overexpressing claudin 6 in the
epidermis.48,49
DESMOSOMAL PROTEINS:
STRUCTURAL CELLCELL INTERFACES
494
A perturbation in SC barrier function has also been

found after the alteration of desmosomal proteins.
Desmogleins are desmosomal cadherins that play a
major role in stabilizing cellcell adhesion in the living
layers of the epidermis (Fig. 47-2, see Chapter 53).
Autoantibodies against these transmembrane glycoproteins cause blisters in pemphigus vulgaris due to
loss of keratinocyte adhesion. In acute eczema, which

shows disturbed skin barrier function a reduction in
keratinocyte membrane E-cadherin in areas of spongiosis has been found.50,51 In transgenic mice in which the
distribution of desmoglein 3 in epidermis was similar
to that in mucous membrane, a highly increased TEWL
resulted in lethality during the first week of life due to
dehydration.52 Mice with conditionally inactivated
E-cadherin in the epidermis died perinatally due to the
inability to retain a functional epidermal water barrier.
Absence of E-cadherin leads to improper localization
of key-tight junctional proteins and impermeable tight
junctions and thus altered epidermal barrier function.53,54
CONNEXINS: INTERCELLULAR
GATEKEEPERS
Connexins are transmembrane proteins that homo- or
heteromerize on the plasma membrane to form a connexon. Connexons on adjoining cells that associate to
form gap junctions and allow the passage of ions and
small molecules between cells. Connexin 26 is one of
the most highly upregulated genes in psoriatic plaques.
Missense mutations in connexin 26 result in five distinct ichthyosis-like skin disorders. In mice overexpressing connexin 26, a hyperproliferative state,
infiltration of immunocells, and a delayed epidermal
barrier recovery were noted.55
PROTEASES
Proteases are important for epidermal differentiation.
The characteristic resistance of the cornified envelope
is based on the formation of very stable isopeptide
bonds that are catalyzed by transglutaminase 1, 3, and
5. Transglutaminase 1-deficient mice showed a defective SC and early neonatal death.56 Mutations in transglutaminases 1 have been found to be the defect in
lamellar ichthyosis.57 Cathepsin D is involved in the
processing of transglutaminase 1. Cathepsin D-deficient mice expressed a defect in barrier function and
hyperproliferation.58 Evidence suggests that cystatin
M/E and cathepsin L may be upstream proteases of
the cathepsin Dtransglutaminase pathway and must
exist in a tightly regulated balance in order to ensure
tissue integrity in the epidermis, hair follicles, and corneal epithelium.59 There is further evidence that disruption of the cystatin M/Ecathepsin pathway
contributes to the underlying skin barrier dysregulation characteristic of inflammatory dermatoses, such
as psoriasis and atopic dermatitis.60
Netherton syndrome, a severe autosomal recessive
genodermatosis (see Chapter 49) is caused by mutations in SPINK5, encoding the serine protease inhibitor
LEKTI. In Netherton syndrome, there is often an atopic
eczema-like skin disease with a disrupted permeability barrier. SPINK5/ mice replicate key features of
Netherton syndrome, including altered desquamation,
impaired keratinization, hair malformation, and a skin
barrier defect. LEKTI deficiency causes abnormal des-
mosome cleavage in the upper granular layer through

degradation of desmoglein 1 due to SC chymotryptic
enzyme (SCCE)-like hyperactivity. This leads to defective SC adhesion and results in loss of skin barrier
function.61,62
Barrier insult
CYTOKINE SIGNALING: REGULATION

OF EPIDERMAL HOMEOSTASIS
AND REPAIR
Chemotactic
and activating
cytokines
(e.g., IL-8)
Generation and
release of new
IL-1, TNF,
GM-CSF, IL-6
Epidermis
Dermis
Migration and trapping of
inflammatory cells
Macrophage-derived
cytokines
Inflammation
Endothelial cell
activation
Capillary
formation
Fibroblast
activation
Scar tissue
formation
Proliferation,
collagen/
GAG synthesis
A perturbed barrier recovers normally when exposed

to an isotonic, hypertonic, or hypotonic external solution instead of air. If the solution contains both calcium
and potassium, the barrier recovery is inhibited. Inhibitor studies using both L-type calcium channels and
calmodulin and ultrastructural examination by ioncapture cytochemistry showed that there is a calcium
gradient in the epidermis. There is a relatively low calcium concentration in the basal epidermis, and an even
lower concentration in the spinous layers, while the
highest calcium concentrations are found in the granu-
Release of preformed IL-1
::
IONIC MODULATIONS: EPIDERMAL

CALCIUM AND POTASSIUM LEVELS
Epidermal injury
Chapter 47
Cytokines are very important for the regulation of

wound healing in which reepithelization and differentiation to form a competent barrier are the last steps63
(see Chapter 248). Besides the immune cells, keratinocytes are able to produce a large variety and amounts
of cytokines (Fig. 47-10). Of special importance are the
so-called primary cytokines tumor necrosis factor
(TNF), interleukin (IL)-1, and IL-6. IL-1, TNF, and IL-6
are potent mitogens and stimulators of lipid synthesis
in cutaneous and extracutaneous tissues. After acute
permeability barrier disruption, an increase in the
expression of TNF, IL-1, and IL-6 on the mRNA and the
protein level occurs.20,64,65,66 In mice deficient in TNF
receptor 1 or IL-1 receptor 1/TNF receptor 1-double
knockout mice and in IL-6-deficient mice, a delay in
permeability barrier occurs.20,66 Moreover, topical
application of TNF enhances permeability barrier
repair, and topical application of IL-6 in IL-6-deficient
mice restores the normal speed in permeability barrier
repair (Fig. 47-10). In TNF-receptor 1-deficient mice,
the generation of lipids for skin barrier repair was
delayed and the activity of acid sphingomyelinase that
generates ceramides for skin barrier repair was
reduced.20 STAT 3 tyrosine phosphorylation was
induced after barrier disruption in wild type, but
markedly reduced in IL-6-deficient mice. The acute
increase in TNF, IL-1, and IL-6 after barrier disruption
is crucial for skin barrier repair. However, if barrier
disruption is prolonged and a chronic increase in cytokine production occurs, it could have a harmful effect
leading to inflammation and epidermal proliferation.
This disrupted permeability barrier, epidermal hyperproliferation, and inflammation, and is well known in
several diseases like irritant and allergic contact dermatitis, atopic dermatitis, and psoriasis, and could
aggravate the disease.
Barrier insult
Figure 47-10 A barrier insult from the outside results not

only in the release of cytokines for epidermal cell signaling, but also interacts with dermal processes, which may
result in inflammation and ultimately scar tissue formation
in case of destructions of the dermis. GAG = glycosaminoglycan; GM-CSF = granulocyte macrophage-colony stimulating factor; IL = interleukin; TNF = tumor necrosis factor.
lar layers. Calcium in the SC is very low because the
relatively dry SC with extracellular lipids is not able to
solve the high polar ions. After disruption of the permeability barrier there is influx of water in the SC and
the ion gradient is lost (Fig. 47-11). This depletion of
calcium regulates lamellar body exocytosis.6769 Calcium is a very important regulator of protein synthesis
in the epidermis, including regulation of transglutaminase 1 activity.70 Furthermore, extracellular calcium
ions are important for cell-to-cell adhesion and epidermal differentiation. Intracellular calcium is controlled
by more than one mechanism as demonstrated by the
two genetic diseases discussed below.
Disturbed regulation of calcium metabolism and
increased TEWL71 occur in Darier disease, characterized by loss of adhesion between suprabasal epidermal cells associated with abnormal keratinization,
and in HaileyHailey disease which shows loss of
495
Changes in calcium gradient
Normal
Disturbed barrier
barrier repair. Many agonists or antagonists of neurotransmitter receptors are used clinically to treat nervous disorders. Some of them might also be effective
for treating skin diseases.75
PATHOLOGICAL SKIN BARRIERS:

SKIN BARRIER FUNCTION IN
DERMATOSES
Section 7
::
Very low calcium
High calcium
Low calcium
Very high calcium
Figure 47-11 Changes in calcium gradient after barrier

disruption regulates lamellar body secretion and epidermal differentiation.
epidermal cell-to-cell adhesion (see Chapter 51). The
gene for Darier disease (ATP2A2) encodes a calcium
transport ATPase of the sarco(endo)plasmic reticulum
(SERCA2),72,73 while the gene for HaileyHailey disease (ATP2C1) codes for a secretory pathway for calcium and manganese transport ATPase of the Golgi
apparatus (SPCA1).74
NEUROTRANSMITTERS IN THE
KERATINOCYTES: COMMON ORIGINS
OF THE BRAIN AND SKIN
496
Neurotransmitters are found in keratinocytes and may

regulate skin permeability barrier function. The receptors can be categorized in two groups: (1) ionotropic
(calcium or chloride ion) receptors and (2) G-proteincoupled receptors. Topical application of calcium
channel agonists delays the barrier recovery while
antagonists accelerate barrier repair.
The G-protein-coupled receptors modulate intracellular cAMP level, increase of intracellular cAMP in epidermal keratinocytes delays barrier recovery, while
cAMP antagonists accelerate the barrier recovery. Activation of dopamine 2-like receptors, melatonin receptors, or serotonin receptor (type 5-HT 1) decreases
intracellular cAMP and consequently accelerates barrier recovery, while activation of adrenergic b2 receptors increases intracellular cAMP and delays the
Mild impairment of the skin barrier is found in monogenetic diseases expressing an impaired epidermal differentiation or lipid composition without inflammation,
for example, ichthyosis vulgaris and X-linked recessive ichthyosis (XLRI).71 The diseases with a more pronounced barrier disruption are inflammatory diseases,
for example, irritant and allergic contact dermatitis,
atopic dermatitis, seborrheic dermatitis, psoriasis, and
T-cell lymphoma. Also, blistering diseases, most of
them inflammation-related, show an increase in TEWL,
especially after loosening of the blister roof and the
development of erosions (Table 47-4). Since HIV
patients are known to display a xerotic phenotype, it
seems likely that allergen penetration due to a disturbed skin barrier activates the Th2 pathway and consequently aggravates the underlying skin barrier
disturbance (Table 47-4).76
Most inflammatory skin lesions are covered with dry
scales or scale-crusts due to the disturbed epidermal differentiation and an SC with poor water-holding capacity. Inflammatory skin diseases can be produced by
either exogenous or endogenous causes. In contact dermatitis, disruption of the barrier by irritants and allergens (which can also be irritants) is the primary event,
TABLE 47-4
Potential Role of the Cutaneous Barrier in the

Pathophysiology of Skin Disorders
Barrier abnormality represents a primary or intrinsic process:
Burns
Ulcers (ischemic, vascular, diabetic)
Bullous disorders by friction or keratin abnormalities
Premature infants skin
Ichthyosis, Gauchers (II), NiemannPick (I)
A primary barrier abnormality triggers immunologic
reactions, but vice versa primary immunological reactions
may trigger barrier abnormalities in yet unknown subgroups
of the diseases:
Atopic dermatitis
Psoriasis
Immunologic abnormality triggers barrier abnormality:
T-cell lymphoma (mycosis fungoides)
Autoimmune bullous diseases
Lichen planus
Dry skin in HIV
TEWL
50
10
Hydration (units)
TEWL (g/m2/h)
20
Age
(very young or old)
Dry environment
(atopics)
Other epidermally
derived dermatoses
90
40
30
Hydration
100
Pyschological stress with high

endogenous steroids
Humid
environment
Atopic dermatitis
(See also Chapter 14)

The existence of a defective permeability barrier
function in atopic dermatitis is now widely accepted. A
genetically impaired skin barrier function is already
present in nonlesional and more pronounced in
lesional skin in atopic dermatitis. Increased epidermal
proliferation and disturbed differentiation, including
changes in keratins and cornified envelope proteins
involucrin, loricrin, and filaggrin, and in lipid composition, cause impaired barrier function in atopic dermatitis (AD) (Fig. 47-12 and see eFig. 47-9.1 in online
edition).81 Mutations in the filaggrin gene have been
described by several research groups.8385 Two loss-of-
::
ATOPIC DERMATITIS: THE

CONSEQUENCE OF A CHRONICALLY
DISTURBED BARRIER
function genetic variants in the gene encoding filaggrin are strong predisposing factors for atopic
dermatitis in atopic kindreds of European origin.86
Slightly different mutations are found in Asian patients
with atopic dermatitis and ichthyosis vulgaris.87 These
mutations were also significantly associated with
asthma, independent of atopic dermatitis, which
means that genetic factors that compromise the epidermal barrier could also underlie mucosal atopic diseases (filaggrin is a protein that is unique to keratinizing
epithelia). The atopic syndrome represents a genetically impaired skin barrier function as well as impaired
nasal, bronchial, and intestinal mucous membrane barriers leading to atopic dermatitis, allergic rhinitis,
bronchial asthma, or aggravation of atopic dermatitis.
Defective permeability barrier function enables penetration of environmental allergens into the skin and
initiates immunological reactions and inflammation
(Fig. 47-13). Filaggrin mutation is the first strong
genetic factor identified in this complex disease. Filaggrin hydrolysis generates amino acids in their deiminated products that probably serve, together with
hornerin, as endogenous humectants.88,89 This may
explain the dry skin of atopic dermatitis. Also, gene
polymorphisms in the gene for SPINK5, which encodes
the serine protease inhibitor LEKTI, have been
reported90 and variations within two serine proteases
of the kallikrein family, the SC chymotryptic enzyme
that degrades corneodesmosomal proteins, involved
in the cohesion between the corneocytes of the SC,
have been found in some cohorts with AD.
Chapter 47
followed by penetration of the chemicals into the living

epidermal layers, irritation of the cell membrane, contact with immune cells, sensitization, inflammation,
increased epidermal proliferation, and changes in differentiation. In T-cell lymphoma (mycosis fungoides),
an endogenous cause for barrier disruption, changes in
epidermal proliferation, and differentiation by expansion of clonal malignant CD4+ T-cells are obvious.77 In
atopic dermatitis and in psoriasis, it is debatable
whether permeability barrier disruption is followed by
inflammation or whether inflammation leads to epidermal changes including barrier dysfunction. The vast
majority of reports on the pathogenesis of atopic dermatitis and even more on psoriasis focused on the primary
role of abnormalities in the immune system.78 However,
others have proposed an outsideinside pathogenesis
for atopic dermatitis and other inflammatory dermatoses with barrier abnormalities,7981 as an alternative to
the previous insideoutside paradigm.82
80
70
Disturbed
skin barrier
60
50
Trauma
40
Cytokine
cascade
Exogenous
steroids
30
20
Disease expression
10
0
0
Healthy
Non-lesional
Lesional
Figure 47-12 Transepidermal water loss (TEWL) (A) and

stratum corneum hydration (B) are impaired in atopic
dermatitis. Reduced stratum corneum hydration and enhanced TEWL are already seen in nonlesional skin and are
more pronounced in lesional skin in atopic dermatitis.
Inflammation
Pruritus
Figure 47-13 Endogenous and exogenous insults lead to a

disturbance in skin barrier function, thus inducing or maintaining inflammatory skin diseases in atopic dermatitis.
497
The impaired skin barrier function in atopic dermatitis is also caused by a reduced lipid content or
impaired lipid composition in the epidermis atopic
dermatitis. In particular, a decreased content for the
total amount and for certain types of ceramides has
been described.80 A decrease in covalently bound
ceramides91 and a reduced sphingomyelinase activity
have been found in atopic dermatitis. Also, decreased
lamellar body secretion, which is predominantly composed of lipids, with subsequent entombment of lamellar bodies within corneocytes, has been reported.92
Section 7
PSORIASIS: EPIDERMAL
HYPERPROLIFERATION AND
THE SKIN BARRIER
::

Psoriasis is a chronic, generalized, and scaly erythematous dermatosis that is primarily localized in the
epidermis, showing highly enhanced proliferation and
disturbed differentiation, which leads to hyperkeratosis and parakeratosis. In addition, there is a neutrophilic infiltrate in the beginning and in particular in
severe cases of psoriasis; later on a moderate Tlymphocytic infiltrate is present. Because of this
severely disturbed proliferation and epidermal differentiation, there is an impaired barrier function.93 The
level of TEWL is directly related with the clinical severity of the lesion: high TEWL in acute exanthematous
psoriasis; a moderate increase in TEWL in the chronic
plaque type of the disease. Abnormalities in the SC
intercellular lipids, especially a significant reduction in
ceramide 1, have been found.94 Electron microscopy
studies disclosed severe structural alteration of the
intercellular lipid lamellae.95 A genetic linkage of psoriasis to the epidermal differentiation complex 1q21
has been found. Within the epidermal differentiation
complex, the SPRRs are highly upregulated in psoriasis plaques.96 Also, the association of psoriasis with
cytokeratin K17 has been discussed.
ICHTHYOSIS: THE PATHOLOGICAL

LACK OF MOISTURE IN THE EPIDERMIS
498
(See Chapter 49)

Ichthyosis comprises a group of monogenetic diseases expressing a disturbed desquamation resulting
in scales and a mild-to-moderate barrier defect. They
are caused either by changes in epidermal lipids or by
changes in epidermal differentiation. XLRI is a noncongenital ichthyosis, consisting of a generalized desquamation of large, adherent, and dark brown scales.
The metabolic basis of XLRI is an enzymatic lysosomal
deficiency of steroid sulfatase or arylsulphatase C.
Complete deletions of the STS gene mapped to the
Xp22.3-pter region have been found in up to 90% of
patients. The reduced cholesterol sulfatase activity
leads to accumulation of cholesterol sulfate and a
reduction of cholesterol and consequent abnormality
in the structural organization of the intercorneocyte
lipid lamellae.9799
Ichthyosis vulgaris is the most common monogenetic

skin disease. Recently, loss-of-function mutations in the
gene encoding filaggrin that cause ichthyosis vulgaris
have been described. During terminal differentiation,
profilaggrin is cleaved into multiple filaggrin peptides
that aggregate keratin filaments. The resultant matrix is
cross-linked to form a major component of the cornified
cell envelope. Reduction of this major structural protein leads to an impaired keratinization and to a moderate defect in skin barrier function.100
Transglutaminase 1 is responsible for the cross-linking of several cornified envelope proteins. Therefore,
deficiency in transglutaminases 157 leads to lamellar
ichthyosis which is a more severe disease than ichthyosis vulgaris with a defect in filaggrin only.
TREATMENT IMPLICATIONS AND

APPROACHES: RESTORING THE
SKINS PROTECTIVE FUNCTION
Treatment strategies in inflammatory diseases often
address immunogenic abnormalities and barrier
function. Treatments with cyclosporine, tacrolimus,
pimecrolimus, and UV light have been shown to
reduce cell inflammation as well as to improve barrier
function, thus helping to normalize proliferation and
differentiation. Topical steroids, although clinically
effective, do not lead to the repair of the disturbed skin
barrier function seen in AD.101 However, because of
their side effects, all of these treatments should be used
for a short time only. In contrast, application of bland
creams and ointments containing lipids and lipid-like
substances, hydrocarbons, fatty acids, cholesterol
esters, and triglycerides can be used without side
effects for long-term treatment of mild-to-moderate
inflammatory diseases. Creams and ointments partially correct or stimulate barrier repair and increase
SC hydration,44,102104 thus influencing epidermal proliferation and differentiation.15 It has been proposed
that a lipid mixture containing the three key lipid
groups [(1) ceramides, (2) cholesterol, and (3) free fatty
acids] is able to improve skin barrier function and SC
hydration in AD.105 Also, the efficacy of ceramide 3 in a
nanoparticle cream in atopic dermatitis has been
described.106 However, because several research
groups and companies report that creams containing
ceramides and a mixture of the three key lipids are not
superior to classical cream or ointment preparations,
such preparations have not yet been widely used.
KEY REFERENCES
8. Bouwstra JA, Pilgrim K, Ponec M: Structure of the skin
barrier. In: Skin Barrier, edited by PM Elias, KR Feingold.
New York, Taylor and Francis, 2006, p. 65
10. Elias PM: Epidermal lipids, barrier function, and desquamation. J Invest Dermatol 80:44s, 1983
25. Roop D: Defects in the barrier. Science 267:474, 1995
30. Candi E, Schmidt R, Melino G: The cornified envelope:

A model of cell death in the skin. Nat Rev Mol Cell Biol
6(4):328, 2005
44. Jensen JM, Proksch E, Elias PM: The stratum corneum of
the epidermis in atopic dermatitis. In: Skin Barrier, edited
by PM Elias, KR Feingold. New York, Taylor and Francis,
2006, p. 569
49. Brandner JM, Proksch E: Epidermal barrier function:
Role of tight junctions. In: Skin Barrier, edited by PM
Elias, KR Feingold. New York, Taylor and Francis, 2006,

p. 191
81. Proksch E, Foelster-Holst R, Jensen JM: Skin barrier function, epidermal proliferation and differentiation in eczema. J Dermatol Sci 43(3):159-169, 2006
86. Irvine AD, McLean WH: Breaking the(un)sound barrier:
Filaggrin is a major gene for atopic dermatitis. J Invest Dermatol 126:1200, 2006
Chapter 48
Chapter 48 :: Irritant Contact Dermatitis

:: Antoine Amado, Apra Sood, &
James S. Taylor
::
Irritant contact dermatitis (ICD) is a

nonimmunologic inflammation of the skin
caused by contact with a chemical, physical,
or biologic agent.
Up to 80% percent of contact dermatitis
is irritant and is commonly related to
occupation.
The most important exogenous factor for
ICD is the inherent toxicity of the chemical
for human skin.
Endogenous factors, such as skin barrier
function and preexisting dermatitis, play an
important role in the pathogenesis of ICD.
Atopic dermatitis is a major risk factor for
irritant hand dermatitis because of impaired
barrier function and a lower threshold for
skin irritation.
spectrum of presentation after contact with an irritant

varies from overt dermatitis to subjective symptoms,
contact urticaria, caustic and necrotic reactions as well
as pigmentary changes and other dermatoses.
EPIDEMIOLOGY
In contrast to allergic contact dermatitis (ACD), no previous exposure to the causative agent is necessary in
eliciting irritant reactions.1 ICD accounts for 80% of all
cases of contact dermatitis,2,3 and is often occupationrelated (occupational ICD is discussed in detail in
Chapter 211). ICD caused by personal care products
and cosmetics is also common; however, very few
patients with these irritant reactions seek medical help
because they manage by avoiding the offending agent.4
The incidence of ICD is difficult to determine because
the accuracy of the epidemiologic data is limited. European cross-sectional studies for eczema due to all
causes in the general population have shown point
prevalence rates of 0.7%40% and 1-year to lifetime
prevalence rates of 7.2%11.8%.5 Data from the U.S.
Bureau of Labor Statistics show that of the 257,800 cases
of nonfatal occupational illnesses reported in 2008 for
Irritant Contact Dermatitis
IRRITANT CONTACT DERMATITIS

AT A GLANCE
Patch testing should be performed in cases

with suspected chronic irritant dermatitis to
exclude an allergic contact dermatitis.
Identification and avoidance of the potential
irritant is the mainstay of treatment.
Dermatitis or eczema is a pattern of cutaneous inflammation that presents with erythema, vesiculation, and
pruritus in its acute phase. Its chronic phase is characterized by dryness, scaling, and fissuring. Irritant contact
dermatitis (ICD) is a cutaneous response to contact with
an external chemical, physical, or biologic agent; endogenous factors such as skin barrier function and preexisting dermatitis also play a role (Figs. 48-1 and 48-2). The
Figure 48-1 Irritant contact dermatitis in a welder.
499
EXOGENOUS FACTORS
Figure 48-2 Irritant pustular dermatitis from nickel salts.
Section 7
::
all industries including state and local government and

private industry, 18.9% (48,600 cases) were skin diseases, the second most frequent cause of all occupational illnesses reported.6 Based also on annual surveys
of the Bureau of Labor Statistics incidence rates of occupational diseases in the American working population,
contact dermatitis constitutes 90%95% of all occupational skin diseases, and ICD constitutes about 80% of
occupational contact dermatitis.7

Four interrelated mechanisms have been associated
with ICD: (1) removal of surface lipids and waterholding substances, (2) damage to cell membranes, (3)
epidermal keratin denaturation,811 and (4) direct cytotoxic effects.11 There is a clearly demonstrated immunologic-like component to the irritant response,12 which is
characterized by the release of proinflammatory mediators, particularly cytokines, from nonimmune cutaneous cells (keratinocytes) in response to chemical stimuli.
This is a process that does not require previous sensitization.10 Disruption of the skin barrier leads to release
of cytokines such as interleukin (IL) 1, IL-1, and
tumor necrosis factor- (TNF-). A tenfold increase in the
levels of TNF- and IL-6, and a threefold increase in the
levels of granulocyte-macrophage colony-stimulating
factor and IL-2 have been observed in ICD. TNF- is
one of the key cytokines in irritant dermatitis, leading
to the increased expression of major histocompatibility
complex class II and intracellular adhesion molecule 1
on keratinocytes.10,13 The chemokine CCL21 that hones
naive T-lymphocytes to the skin, has also been shown
to be elevated in the skin during irritant reactions.14
Loss of function polymorphisms in the filaggrin
gene, an important protein for skin barrier function,
have been associated with an increased susceptibility
to chronic ICD.15 At the same time, it is hypothesized
that upregulation of ceramide 1 synthesis in the epidermis plays a major role in inducing the hardening
phenomenon in cutaneous irritation.16
INFLUENCING FACTORS
500
ICD is a multifactorial disease where both exogenous

(irritant and environmental) and endogenous (host)
factors play a role.
(See Table 48-1)

Other than with strong acids and alkalis, it has not
been possible to predict the irritant potential of a
chemical based on molecular structure. The irritant
potential of compounded formulations may be more
difficult to predict. Factors to be considered include:
(1) chemical properties of the irritant: pH, physical
state, concentration, molecule size, amount, polarization,
ionization, vehicle, and solubility; (2) characteristics of
exposure: amount, concentration, duration and type
of contact, simultaneous exposure to other irritants,
and interval after previous exposure;4,17 (3) environmental factors: body region and temperature; (4)
mechanical factors such as pressure, friction, or abrasion;2 and (5) ultraviolet (UV) radiation. Low ambient
humidity and cold temperature decrease the water
content of the stratum corneum, making it more
permeable to irritants. Larmi et al18 demonstrated
that UVB radiation diminished the nonimmunological
reactions caused by sodium lauryl sulfate (SLS)induced irritation, probably as a result of antiinflammatory effects.
When one or more irritants are combined or used
simultaneously, a synergistic or antagonistic effect may
occur as a consequence of specific cellular interactions
between the compounds, or an alteration in the skin
permeability by one or more of the compounds, that
would not occur when an irritant is used alone.4,12 This
is known as the crossover phenomenon. In a study by
Wigger-Alberti et al,19 concurrent application of SLS
and toluene twice daily for 30 minutes to the volar forearms of healthy volunteers induced significantly stronger irritant reactions than those caused by twice-daily
application of each chemical alone. This study suggests
a crossover phenomenon between the two compounds
by which one irritant caused an increased susceptibility
to the other. On the other hand, McFadden and
TABLE 48-1
Exogenous Factors Influencing Cutaneous

Irritation
Type of irritant (pH, chemical activity)
Cutaneous penetration of irritant
Body temperature
Mechanical factors (pressure, friction, abrasion)
Environment (temperature, humidity)
Other exposure factors: duration, prior or simultaneous
exposures, direct versus airborne
Data from Denig NI, Hoke AW, Maibach HI: Irritant contact dermatitis.
Clues to causes, clinical characteristics, and control. Postgrad Med
103:199-200, 207-208, 212-213, 1998; Frosch PJ, Jhon SM: Clinical
aspects of irritant contact dermatitis. In: Contact Dermatitis, 4th edition, edited by PJ Frosh, T Menn, J-P Lepoittevin. Germany, SpringerVerlag Berlin Heidelberg, 2006, pp. 255-294; Weltfriend S, Maibach HI:
Irritant dermatitis: Clinical heterogeneity and contributing factors. In:
Marzulli and Maibachs Dermatotoxicology, 7th edition, edited by H
Zhai, K-P Wilhelm, HI Maibach. Boca Raton, CRC Press, 2008,
pp. 125-138.
c olleagues20 demonstrated the neutralizing effect of

benzalkonium chloride over the irritant effect of SLS.
ENDOGENOUS FACTORS
(See Table 48-2)
GENETIC FACTORS. It has been hypothesized that
ETHNICITY. There are no studies that demonstrate a

significant influence of skin types on the development
of ICD.2729 Because erythema is difficult to measure in
TABLE 48-2
Endogenous Factors Influencing Cutaneous

Irritation
Atopic dermatitis
Skin site
Skin permeability
Individual (genetic) susceptibility
Primary sensitive (hyperirritable) skin
Lack of hardening
Secondary hyperirritability of the skin (status eczematicus)
Data from Denig NI, Hoke AW, Maibach HI: Irritant contact dermatitis. Clues to causes, clinical characteristics, and control. Postgrad Med
aspects of irritant contact dermatitis. In: Contact Dermatitis, 4th edition,
edited by PJ Frosh, T Menn, J-P Lepoittevin. Germany, Springer-Verlag
Berlin Heidelberg, 2006, pp. 255-294, Weltfriend S, Maibach HI: Irritant
dermatitis: Clinical heterogeneity and contributing factors. In: Marzulli and Maibachs Dermatotoxicology, 7th edition, edited by H Zhai,
K-P Wilhelm, HI Maibach. Boca Raton, CRC Press, 2008, pp. 125-138.
ATOPY. A history of atopy is a well-known risk factor

for irritant hand dermatitis (see Chapter 14). A history
of atopic dermatitis seems to be linked to an increased
susceptibility to irritant dermatitis because of a lower
threshold for skin irritation, impaired skin barrier
function, and a slower healing process.33
In summary, the most important ICD risk factors
are the inherent toxicity of the chemical for human
skin and its penetration.34 The most important endogenous factors are an atopic diathesis and skin barrier
function.26
CLINICAL TYPES OF IRRITANT

CONTACT DERMATITIS
ICD has a spectrum of clinical features, which can be
divided into several different categories, depending on
the irritant and its exposure pattern.35 But these manifestations also depend on mechanical, thermal, climatic, and constitutional factors.17 The clinical types of
ICD vary according to the irritant in question: ulceration (e.g., strong acids or alkalis), folliculitis (e.g., oils
and greases), miliaria (e.g., aluminum chloride), hyperpigmentation (e.g., heavy metals), hypopigmentation
(e.g., p-tert-butylphenol),10 alopecia (e.g., borax), urticaria (e.g., foods and plants), and granulomas (e.g.,
silica, talc)36 (see Table 211-1).
At least ten clinical types of ICD have been described.
They are listed in Table 48-3 along with a number of
clinical subtypes of acute and chronic ICD.
AGE. Children younger than 8 years of age are more

susceptible to percutaneous absorption of chemicals
and to irritant reactions.4 Most studies show no compromise in skin barrier permeation with increasing
age. Data on the influence of aging on experimental
skin irritation are conflicting. Visible skin irritation
(erythema) is decreased in older persons while invisible skin irritation (barrier damage) might be increased
in the elderly.26
SKIN SITE. There are significant site differences in

barrier function, making the skin of the face, neck,
scrotum, and dorsal hands more susceptible to ICD.
The palms and soles are comparatively more resistant.32
::
GENDER. The majority of clinical ICD affects the

hands, and women account for a majority of these
patients.23 Rather than a gender-related skin susceptibility, this demographic may reflect the facts that
women have more extensive exposure to irritants and
wet work and are more likely to seek treatment than
men.4,17,24 On the other hand, there are anecdotal
reports that suggest that the menstrual cycle can affect
the sensitivity of women to primary irritants and can
affect their dermatological response.25 No gender difference for ICD has been established experimentally.
Chapter 48
an individuals ability to quench free radicals, to

change the levels of antioxidant enzymes, and the ability to form protective heat shock proteins may all be
under genetic control. These factors also determine the
variability in responsiveness to irritants.21 Additionally, a genetic predisposition to irritant susceptibility
may be specific for each irritant.22
dark skin, early studies30 using erythema as the only

parameter to quantify irritation may have led to an
erroneous interpretation that black skin is more resistant to irritation than white skin. It is also possible that
variations among individuals rather than ethnicity
play a role in the intensity of an irritant response.31
1. Irritant reaction: An irritant reaction clinically
presents as an acute monomorphic reaction that

includes scaling, low-grade erythema, vesicles,
or erosions and is usually localized on the
dorsum of the hands and fingers. It is often seen
in individuals who are exposed to wet work.
An irritant reaction can resolve or progress to
cumulative irritant dermatitis.10,12
2. Acute ICD: Acute ICD usually results from
a single skin exposure to a strong irritant or
caustic chemical, such as alkalis and acids, or as
a result of a series of brief chemical or physical
contacts. Most cases of acute irritant dermatitis
are a consequence of accidents at work. A
sensation of burning, itching, or stinging may
occur immediately after the exposure to the
irritant. The patient may present with erythema,
501
edema, and vesiculation and with exudation,

bullae formation, and tissue necrosis in more
severe cases. The healing process of acute ICD
occurs as a decrescendo phenomenon, where
the irritant reaction quickly peaks and then
immediately begins to heal upon removal of the
irritant. Complete healing may take 4 weeks,
with a good prognosis.4,12,17
Other forms of acute irritant reaction have
been also described (see Table 48-3), such as
airborne contact dermatitis resulting from
exposure to irritant volatile substances and
Section 7
TABLE 48-3
Types of Irritant Contact Dermatitis (ICD)
::
Irritation
Onset
Irritant reaction
Acute, often multiple

exposures
Acute ICD
Acute, often single exposure
Delayed acute ICD
Delayed (1224 hours or

longer)
Chronic (cumulative) ICD
Slowly developing (weeks to

years)
Subjective (sensory) irritation
Acute
Suberythematous
(nonerythematous) irritation
Slowly developing
Frictional dermatitis
Moderateslow developing
(weeks to months)
Traumatic ICD
Slowly developing after

preceding trauma
Pustular or acneiform ICD
Moderately slowly
developing (weeks to
months)
Asteatotic irritant eczema

(exsiccation eczematid)
Moderateslow developing
Other clinical subtypes of acute and chronic ICD

Interdigital
Slowly developing (days to
weeks)
Frictional melanosis
Slowly developing (months
to years)
Diaper dermatitis
Acute or delayed
Chemical burns
Acute or delayed
Nonimmunologic contact
Acute
urticaria
Airborne
Acute
Scalp irritation
Acute or delayed
Nail irritation
Delayed to slow
Acute or delayed
Tandema
Photoirritationa
Acute
a
502
Personal communication HI Maibach, June, 2005.

Source: Data from Weltfriend S, Maibach HI: Irritant dermatitis: Clinical heterogeneity and contributing factors. In Marzulli and Maibachs
Dermatotoxicology, 7th edition, edited by H Zhai, K-P Wilhelm,
HI Maibach. Boca Raton, CRC Press, 2008, pp. 125-138; Chew A-L,
Maibach HI: Ten genotypes of irritant contact dermatitis. In: Irritant
Dermatitis, edited by A-L Chew, HI Maibach. Germany, SpringerVerlag Berlin Heidelberg, 2006, pp. 6-9.
TABLE 48-4
Airborne Irritants
Volatile Substances
Acids and alkalis
Ammonia
Anhydrous calcium sulfate
Carbonless copy paper
Dichlorvos
Domestic cleaning products
Epoxy resins
Formaldehyde
Industrial solvents
Powders
Metallic oxide powders
Sawdust from toxic trees
Silver fulminate dust
Wool dust (in atopic patients)
Cement
Calcium silicate
Particles, Salts, Foams
Arsenic
Fiberglass
Phenol formaldehyde resins
Sodium sesquicarbonate
Urea-formaldehyde insulating foam, dust foam
Data from Denig NI, Hoke AW, Maibach HI: Irritant contact dermatitis. Clues to causes, clinical characteristics, and control. Postgrad
Med 103:199-200, 207-208, 212-213, 1998; Weltfriend S, Maibach HI:
Irritant dermatitis: Clinical heterogeneity and contributing factors.
In: Marzulli and Maibachs Dermatotoxicology, 7th edition, edited by
H Zhai, K-P Wilhelm, HI Maibach. Boca Raton, CRC Press, 2008, pp.
125-138.
fumes or powders and dusts and particles

(Table 48-4).4,17 Irritant cheilitis may result from
lip licking or use of cosmetics and medication.
Diaper dermatitis and perianal dermatitis
may be the result of prolonged or too frequent
contact with urine or fecal residues.17 Dermatitis
resulting from sodium azide released by airbag
deployment has also been described,37 causing
an alkaline chemical burn; the accompanying
talc powder may also contribute to the
dermatitis.
3. Delayed acute irritancy: The delayed irritant
reaction is acute but without visible signs of
inflammation appearing until 824 hours or
more after exposure. Otherwise, the clinical
appearance and course are similar to those of
an acute ICD.4,12 The delayed presentation may
simulate that of an ACD, sometimes making
differentiation of the two disorders difficult,
even with patch testing. Substances causing
delayed irritancy are listed in Table 48-5.
Delayed acute irritancy in general has a good
prognosis.10,12,17
4. Chronic cumulative ICD: This is the most frequent
type of contact dermatitis encountered in
clinical practice. Also called traumiterative ICD,
cumulative ICD develops as a result of repeated
insults to the skin, where the chemicals involved
TABLE 48-5
Chemicals Causing Delayed Irritant Reactions
are often multiple and weak and would not in

themselves be strong enough to cause irritant
dermatitis.10,12,17 The most common marginal
irritants include soap, detergents, surfactants,
organic solvents, and oils,2 which may also act
as perpetuating factors once the dermatitis has
become established. Cosmetic cumulative ICD is
not infrequent in women, particularly involving
the eyelids.17
Initially, cumulative contact dermatitis
can appear with itch, pain, and a few
localized patches of dry skin; then erythema,
hyperkeratosis, and fissuring can develop.2,4,12,17
The symptoms do not immediately follow
exposure to the irritant, appearing after days,
months, or years of exposure. With extensive
and frequent exposure to some irritants, the
skin becomes hardened, with better resistance
to future irritant exposures. Hardened skin
appears coarse and lichenified, which may
contribute to resistance. However, even
brief periods away from exposure lower the
resistance, and with reexposure, patients
are once again at risk for irritation. Chronic
cumulative ICD can be confused with
ACD because of the delayed and variable
presentation, and appropriate diagnostic
patch testing is indicated to exclude ACD. The
prognosis of cumulative ICD is variable.4,12
::
Data from Denig NI, Hoke AW, Maibach HI: Irritant contact dermatitis.
Clues to causes, clinical characteristics, and control. Postgrad Med
aspects of irritant contact dermatitis. In: Contact Dermatitis, 4th edition, edited by PJ Frosh, T Menn, J-P Lepoittevin. Germany, SpringerVerlag Berlin Heidelberg, 2006, pp. 255-294; Weltfriend S, Maibach HI:
Irritant dermatitis: Clinical heterogeneity and contributing factors. In:
Marzulli and Maibachs Dermatotoxicology, 7th edition, edited by H
Zhai, K-P Wilhelm, HI Maibach. Boca Raton, CRC Press, 2008,
pp. 125-138.
Patients complain of itching, tingling,

stinging, burning, or smarting sensation
within minutes of contact with an irritant,
but without visible cutaneous changes.12,35
Subjective irritancy usually occurs on the
face, head, and neck. Cosmetics, sunscreens,
and woolen garments are commonly
implicated.3,4,35 Other common sensory
irritants include lactic acid (a model for
this phenomenon), propylene glycol, and
aluminum salts. Stimulation of cutaneous
type C nociceptors has been implicated in
this form of irritancy,12 although recently
changes in cutaneous vasculature have been
implicated. Some sensory irritation may be
nonimmunologic contact urticaria. Screening
raw ingredients or final formulations with
the guinea pig ear swelling test or the human
forehead assay may allow one to minimize
subclinical contact urticaria.38
6. Suberythematous (nonerythematous) irritation: This
is a state in which the irritation is not visually
apparent, but is histologically visible. Common
symptoms include burning, itching, or stinging.
Suberythematous irritation has been linked
with the use of consumer products containing
significant amounts of surfactant.4,12
7. Frictional dermatitis: Mechanical irritation can
result from repeated microtrauma and friction.
Nipple dermatitis in patients with ill-fitting
bras, and dermatitis from prosthetic limbs,
mechanical injury from thorns and spines
in plants, adhesive tape, or from handling
coarse paper, glass, and rock wool fiber are
only some.10,17 This type of contact irritation
usually leads to dry, hyperkeratotic abraded
skin, making it more vulnerable to the effects of
irritants.4
8. Traumatic reactions: Traumatic reactions can
develop after acute skin trauma as burns or
lacerations and most commonly occurs on the
hands and persists for about 6 weeks or longer.
The healing process in this type of dermatitis
is prolonged, and erythema, scaling, papules,
or vesicles can appear. The clinical course can
resemble that of nummular dermatitis.4,12
9. Pustular or acneiform reactions: Pustular or
acneiform reactions are usually seen after
occupational exposures to oils, tars, heavy
metals, and halogens but also after the use
of some cosmetics. The pustular lesions are
sterile and transient and may develop several
days after exposure. This type of dermatitis is
seen especially among atopic and seborrheic
patients.4,9,12
10. Asteatotic irritant eczema (exsiccation eczematid):
Exsiccation eczematid usually occurs in elderly
patients who frequently shower without
applying moisturizers to their skin. Intense
itching, dry skin, and ichthyosiform scaling are
clinical features that characterize this irritant
reaction.12
Chapter 48
Acrylates (some)
Butanediol diacrylate
Hexanediol diacrylate
Tetraethylene glycol diacrylate
Anthralin (Dithranol)
Benzalkonium chloride
Benzoyl peroxide
Bis(2-chloroethyl)sulfide
Calcipotriol
Dichlor(2-chlorovinyl)arsine
Diclofenac
Epichlorhydrine
Ethylene oxide
Fluorohydrogenic acid
Nonanoic acid
Octyl gallate
Podophyllin
Propylene glycol
Sodium lauryl sulfate
Tretinoin
5. Subjective (symptomatic, sensory) irritancy:
503
COMMON IRRITANTS
Section 7
::
(Table 48-6)
Water is a hypotonic element that acts as a cytotoxic
agent on eroded skin.17 Hard water has been found to
be more irritating than soft water.39 Skin cleansers
cause irritation depending on the chemistry of their
constituents. They remove surface lipid film, denature
proteins, and damage the cell membrane. Soaps, detergents, and waterless cleansers are the most common
irritants. Preservatives, especially quaternary ammonium compounds, have an irritant effect.17 Lffler and
Kampf40 investigated the biological response of regular
human skin to alcohol-based disinfectants and detergents and demonstrated that the degree of skin irritation is significantly lower after application of alcohol
in comparison to detergents.
Foods, such as citrus peels, garlic, flour, and spices,
can act as irritants.17 Capsaicin produces hand irritation after handling hot peppers and is also present in
some personal defense sprays used by police or by
civilians.1 Pineapple juice contains bromelain, an irritating proteolytic enzyme.41
Other potential irritants include animal products
from seafood and meat, from caterpillars, carpet beetles, and moths, from insect secretions42; cosmetics,
especially when applied to the eyelids; alkalis, present
in soap, bleaches, detergents, oven cleansers, and toilet
bowl cleaners;1 topical medicaments, such as gentian
violet, tar, potassium permanganate, mercury, hexachlorophene, etc.17 The majority of skin reactions due
to transdermal drug delivery systems would be a form
of ICD, this may be minimized by rotation of the application site, careful removal of the patch, and appropriate use of moisturizers and topical corticosteroids.43
Fiberglass dermatitis can develop from wearing clothes
that have been washed together with fiberglass-contaminated work clothes or with fiberglass curtains.44
Other tear gases, [e.g., 2-chlorobenzylidene malononitrile, known as CS (pepper spray) and, rarely, 1-chloro-
TABLE 48-6
Causes of Irritant Contact Dermatitis

Animal products
Cosmetics
Degreasing agents
Detergents
Dusts/friction
Foods
Low humidity
Metal working fluids
Tear gases
Topical medicaments
Solvents
Water/wet work
504
Data from Contact dermatitis and drug eruptions. In: Andrews Diseases of the Skin. Clinical Dermatology, 10th edition, edited by WJ
James, TG Berger, DM Elston. Philadelphia, Elsevier, 2006, pp. 91-94;
Wilkinson SM, Beck MH: Contact dermatitis: Irritant. In: Rooks Textbook of Dermatology, 7th edition, edited by T Burns, S Breathnach,
N Cox, C Griffths. Oxford, Blackwell Publishers, 2004, pp. 19.1-19.30.
acetophenone, known as CN (Mace)] are present in a

variety of self-defense or riot-control sprays1 and cause
lacrimation, sternutation (sneezing), and, occasionally,
cutaneous irritation and sensitization.
DIAGNOSIS
(Box 48-1)
ICD is often diagnosed by excluding other causes for
the dermatitis, including ACD.2 A detailed inquiry,
including occupational, recreational (hobbies), and
past medical histories, and a meticulous clinical examination are important for making the correct diagnosis.
History of exposure to friction, wet work, soaps, and
detergents or exposure to organic or alkaline solvents;
and/or an environmental relative humidity of less
than 35% are key factors that support a diagnosis of
irritancy.45 When an allergic component is considered,
diagnostic patch testing should be performed.33 A
biopsy often cannot differentiate allergic, irritant, or
atopic dermatitis, but may be helpful in excluding psoriasis, in the case of palmar involvement. Measuring
transepidermal water loss (TEWL) can indicate barrier
impairment but cannot distinguish between ACD and
ICD. Rietschel11 has proposed criteria with subjective
and objective features, each with major and minor
findings for the diagnosis of ICD. The more features
identified, the stronger the case for ICD (Table 48-7).
PREDICTIVE TESTS, GENETICS AND

BIOENGINEERING METHODS
In their review of premarket predictive tests for irritants, Basketter and Kimber46 conclude that except
where appropriate human tests, such as the 4-hour prophetic patch test, can be conducted; skin irritation tests,
especially in animals, are of limited value in the characterization of the potential effects associated with actual
exposure of humans to irritants. In the clinical setting
there is likely to be exposure to multiple irritants.
In attempts to predict individual susceptibility to
irritants, a number of tests have been studied, including alkali resistance with sodium hydroxide, ammonium hydroxide, dimethyl sulfoxide, threshold
response to various irritants (SLS, nonanoic acid, benzalkonium chloride, kerosene, croton oil, and anthralin), lactic acid stinging, minimal erythema dose with
UVB radiation, and measurement of TEWL. In their
review, Frosch and John34 conclude that none is so simple and reliable that it can be used on a large scale. A
number of these procedures have been used experimentally, usually with individual chemicals, with the
results having limited applicability, but they may be of
some value in predicting thresholds of irritation. Of
the bioengineering methods used, TEWL measurement is the most frequently used procedure to quantify
impaired functions of the stratum corneum. Clinically
invisible subtle damage, such as by detergents, can be
reliably detected by an increase in TEWL.

of Irritant Contact Dermatitis
(Major Types)
Data from Denig NI, Hoke AW, Maibach HI: Irritant contact dermatitis. Clues to causes, clinical characteristics, and control. Postgrad
Med 103:199-200, 207-208, 212-213, 1998; Rietschel RL: Clues
to an accurate diagnosis of contact dermatitis. Dermatol Ther
17:224-230, 2004.
A TNF- gene polymorphism offers a novel

approach to detect susceptibility to ICD. In humans, a
G to A transition polymorphism has been identified at
position P308 within the promoter region of the TNF-
gene. An analysis of different genotypes revealed a
correlation between the A allele and a low threshold to
irritants.47
According to Astner and colleagues,48 reflectancemode confocal microscopy facilitates the differentiation of acute ACD from ICD. Stratum corneum
disruption, epidermal necrosis, and hyperprolifera-
Minor
Subjective
Onset of symptoms within
minutes to hours of exposure
Pain, burning, stinging, or
discomfort exceeding itching
early in the clinical course
Onset of dermatitis within

2 weeks of exposure
Many people in the
environment affected
similarly
Objective
Macular erythema,
hyperkeratosis, or fissuring
predominating over
vesiculation
Glazed, parched, or scalded
appearance of the epidermis
Healing process begins
promptly on withdrawal of
exposure to the offending
agent
Patch testing is negative
Sharp circumspection of the

dermatitis
Evidence of gravitational
influence, such as dripping
effect
Lack of tendency of the
dermatitis to spread
Morphologic changes
suggesting small
concentration differences or
contact time produce large
differences in skin damage
Adapted from Rietschel RL: Clues to an accurate diagnosis of contact

dermatitis. Dermatol Ther 17:224-230, 2004.
Always Rule Out

Localized
Bowen disease
Disseminated
Major
::
Consider
Localized
Corticosteroid acne
Dermatophytosis
Factitial dermatitis
Herpes simplex
Herpes zoster
Rosacea
Disseminated
Dermatophytosis
Drug eruption
Nummular eczema
Psoriasis
Parapsoriasis
Polymorphous light eruption
TABLE 48-7
Diagnostic Criteria of Irritant Contact Dermatitis
Chapter 48
Most Likely
Localized
Atopic eczema
Asteatosis
Stasis dermatitis
Disseminated
Atopic eczema
Asteatosis
Autoeczematization
Tinea corporis
tion were found to be the hallmarks of ICD, whereas

ACD was more typically presented with vesicle formation.
A recent study49 found the use of polarized light as
an enhanced visual scoring method to increase the
ability to detect low (subclinical) levels of irritation,
indicating this noninvasive method has the potential
to increase the sensitivity of all clinical dermatological
studies.
PATCH TESTING
Patch testing is often essential to distinguish ACD from
ICD or to diagnose concomitant ICD and ACD. Negative patch tests may favor a diagnosis of ICD by exclusion of ACD. A diagnosis of ACD may be missed with
false-negative patch test results (see Chapters 13 and
211).11,33 Conversely, patch testing with obvious irritants, or nonstandard chemicals or mixtures can lead to
false-positive patch test results. Irritant patch test reactions may present as erythema with or without papules
and often remain confined to the test site and are
sharply demarcated. These irritant reactions also show
a decrescendo pattern, in which a decreasing severity is
seen, although this is not always a reliable indicator.3,33
Irritant patch test reactions do not equate with ICD but
only reflect the irritating patch test concentration or
procedure. It is important to perform comprehensive
patch testing with the appropriate substances and concentrations to prevent incorrect conclusions.11
505
Section 7
::
506
TREATMENT
Identification and elimination of the irritants and protection from further exposure are important in the management of ICD.4 Once dermatitis develops, topical
treatment is helpful. The role of topical corticosteroids in
the management of ICD is controversial, but they may be
helpful because of their anti-inflammatory effect.4,50
However, prolonged use of topical corticosteroids may
lead to epidermal atrophy and increased susceptibility to
irritants. Emollients or occlusive dressings may improve
barrier repair in dry, lichenified skin.4,17 Traditional petrolatum-based emollients are accessible, inexpensive,
and have been shown to be as effective as emollient containing skin-related lipids.51 Other barrier creams are
of limited value.52 Topical calcineurin inhibitors (e.g.,
pimecrolimus) may be used as an alternative to lowpotency topical corticosteroids in chronic ICD.53,54
In severe or chronic cases, phototherapy (psoralens
with UVA or UVB) or systemic drugs, such as azathioprine and cyclosporine, may be effective.17,50 Bacterial
superinfection can be treated with topical or systemic
antibiotics.17 In sensory irritation, strontium salts act
by selectively blocking the activation of cutaneous
type C nociceptors.12
PREVENTION
ICD is a risk factor for the development of ACD
because the impaired skin barrier may facilitate the
potential for the induction and elicitation of ACD.
Thus, the prevention of irritant dermatitis reduces the
risk of ACD.10,55
Although long established behavior patterns may be
difficult to change,55 once an irritant has been identified as the causal factor, patients should be educated
about irritant avoidance, including everyday practices
that may cause or contribute to the ICD.
The use of personal protective equipment, especially
in high-risk jobs, is very important. Protective gloves
should be worn for any wet work. However, patients
should avoid wearing waterproof gloves for long periods of time to help reduce sweating. If prolonged
wearing is required, gloves should have a fabric lining
or alternatively, thin cotton gloves can be worn inside
waterproof gloves.3 Bock et al56 evaluated the impact of
semipermeable glove membranes (GoreTex and Sympatex) on skin barrier repair following SLS-induced
irritation and demonstrated an improved barrier
recovery and reduced inflammation compared to
either occlusive membranes (vinyl) or an uncovered
control. These results suggest a unique benefit by semipermeable protective gloves for preventing occupational skin disease by minimizing glove-induced
irritation and by enhancing barrier recovery in cases of
preexisting minor irritant dermatitis. In another study,
the use of gel-filled anti-impaction gloves such as those
used for hand-arm vibration exposure, has been shown
to aid in the return-to-work process for those patients
with occupational frictional hand dermatitis but not
with hyperkeratotic hand dermatitis.57
If used correctly, protective gloves can reduce or

eliminate exposure of the hands to hazardous substances, but if not selected and used properly, gloves
can actually cause or worsen ICD of the hands by
increasing exposure to hazardous chemicals. Hence,
the correct use of gloves is at least as important
as selection of gloves made of the appropriate
material.58
Less irritating substances, such as emollients and
soap substitutes, should be used rather than soap
when washing. Moisturizers are thought to increase
hydration or prevent TEWL, thereby maintaining skin
barrier function and reducing the risk of ICD. Care
should be taken for several months after the dermatitis
has healed, as the skin remains vulnerable to flares of
dermatitis for a prolonged period.3,33,35
PROGNOSIS
The prognosis for acute ICD is good if the causative
irritant can be identified and eliminated. The prognosis for cumulative or chronic irritant dermatitis is
guarded and may be worse than that of ACD.59 An
atopic background, lack of knowledge about the disease, and/or a delayed diagnosis and treatment are
factors that lead to a worse prognosis.17 Persistent postoccupational dermatitis has been reported in 11% of
individuals.60
KEY REFERENCES
11. Rietschel RL: Clues to an accurate diagnosis of contact
dermatitis. Dermatol Ther 17:224-230, 2004
15. de Jongh CM et al: Loss-of-function polymorphisms in the
filaggrin gene are associated with an increased susceptibility to chronic irritant contact dermatitis: A case-control
study. Br J Dermatol 159:621-627, 2008
23. Lammintausta KH. Gender. In: Irritant Dermatitis, edited
by AL Chew, HI Maibach. Germany, Springer-Verlag Berlin Heidelberg, 2006, pp. 173-176
34. Frosch PJ, Jhon SM: Clinical aspects of irritant contact
dermatitis. In: Contact Dermatitis, 4th edition, edited by
PJ Frosh, T Menn, J-P Lepoittevin. Germany, SpringerVerlag Berlin Heidelberg, 2006, pp. 255-294
36. Weltfriend S, Maibach HI: Irritant dermatitis: Clinical
heterogeneity and contributing factors. In: Marzulli and
Maibachs Dermatotoxicology, 7th edition, edited by H Zhai,
K-P Wilhelm, HI Maibach. Boca Raton, CRC Press, 2008,
pp. 125-138
40. Lffler H, Kampf G: Hand disinfection: How irritant are
alcohols? J Hosp Infect 70:44-48, 2008
43. Ale I, Lachapelle JM, Maibach HI: Skin tolerability associated with transdermal drug delivery systems: An overview. Adv Ther 26:920-935, 2009
54. Mensing CO, Mensing CH, Mensing H: Treatment with
pimecrolimus cream 1% clears irritant dermatitis of the
periocular region, face and neck. Int J Dermatol 47:960-964,
2008
58. Kwon S, Campbell LS, Zirwas MJ: Role of protective
gloves in the causation and treatment of occupational irritant contact dermatitis. J Am Acad Dermatol 55:891-896,
2006
Chapter 49 :: The Ichthyoses

:: Philip Fleckman & John J. DiGiovanna
ICHTHYOSES AT A GLANCE
A heterogeneous group of skin diseases
characterized by generalized scaling, and
often areas of thickened skin.
Scales may vary in size, color, and body site.
Pathology is usually nonspecific with the

exception of epidermolytic hyperkeratosis,
neutral lipid storage disease, Refsum
disease, and acquired ichthyosis associated
with sarcoidosis.
The ichthyoses are a heterogeneous group of skin diseases characterized by generalized scaling. Scaling
reflects altered differentiation of the epidermis. In this
chapter, the terms epidermal differentiation, keratinization, and cornification will be used synonymously.
The name ichthyosis is derived from the Greek ichthys,
meaning fish, and refers to the similarity in appearance of the skin to fish scale. Both inherited and
acquired forms are found. Early reports of ichthyosis
in the Indian and Chinese literature date back to several hundred years bc, and the condition was discussed by Willan in 1808.1
Ichthyosis can present at birth or develop later in
life. It can occur as a disease limited to the skin or in
association with abnormalities of other organ systems.
A number of well-defined types of ichthyosis with
characteristic features can be reliably diagnosed. However, because of the great clinical heterogeneity and the
profound effect of the environment on scaling, a specific diagnosis can be challenging in certain patients
and families.
Siemens introduced genetic concepts into the ichthyoses.2 Wells and Kerr classified the ichthyoses on a
genetic basis3 and separated X-linked recessive ichthyosis from ichthyosis vulgaris (IV).4 Gassman developed the concept of retention versus hyperproliferation
hyperkeratosis5. Van Scott, Frost, and Weinstein subse-
The Ichthyoses
May be associated with systemic findings,

such as failure to thrive, increased
susceptibility to infection, atopic dermatitis,
neurosensory deafness, neurologic and other
disease.
::
May be accompanied by erythema,

abnormalities in other parts of skin and
adnexal structures.
Chapter 49
Most types are inherited, and these usually

present at birth. However, some forms are
acquired.
quently proposed a classification of the ichthyoses

based on differences in rates of epidermal turnover,
characterizing them as either disorders of epidermal
hyperproliferation or disorders of prolonged retention
of the stratum corneum.6 Subsequently, Williams and
Elias proposed a classification that lists the disorders of
cornification in which clinical, genetic, or biochemical
data suggest a distinct disease.7 Traupe reviewed the
ichthyoses and suggested classification on a clinical
level.5
Genetic approaches to understanding the ichthyoses
have revealed the gene defects underlying many of
these genodermatoses.8 A new classification is evolving based on the underlying molecular and genetic
bases of these disorders. Knowing which gene is
mutated directs us to the underlying pathophysiologic
process. Understanding and describing these disorders on the basis of common molecular processes leads
to more rational approaches to understanding their
pathophysiology and treatment. A listing of the more
common and the better understood hereditary ichthyoses according to pattern of inheritance and clinical
features is shown in Tables 49-1 to 49-3. Grouping
these disorders according to underlying gene defect
(Table 49-4) facilitates understanding of the clinical
phenotypes in terms of underlying mechanism. However, further work is necessary to clearly understand
how the gene mutations and resultant protein disruptions result in clinical disease, and furthermore, how
therapeutic interventions can be creatively developed.
Online Mendelian Inheritance in Man, OMIM,10
(trademark Johns Hopkins University), a catalog of
human genes and genetic disorders, is a useful reference with links to additional resources.
CLINICAL PRESENTATION
A specific diagnosis in an individual or family with
ichthyosis can help to predict prognosis, is important
for genetic counseling, and may direct treatment. Several features are useful in distinguishing different
forms of ichthyosis. These include the age of onset,
presence of collodion membrane at birth, quality of
scale, presence/absence of erythroderma, abnormalities in other parts of the skin (e.g., palms and soles,
ectropion, eclabium) and adnexal structures (e.g., alopecia, hair follicle, or shaft abnormality), and involvement of other organ systems. In different types of
ichthyosis, the appearance of the surface of the skin
may vary. Visible scaling may be seen in some patients,
with flakes of stratum corneum varying in size from
fine to coarse. There may also be thickening of the skin
with or without visible scale. The term hyperkeratosis
has been used clinically to describe thickened skin,
with or without scale, that reflects thickening of the
stratum corneum. A family pedigree may clarify the
pattern of inheritance. However, many autosomal
507
Section 7
::
508
TABLE 49-1
Features of Selected Ichthyoses, Dominant

AAutosomal Dominant/Semidominant
Autosomal Semidominant
Diagnosis
Onset
Ichthyosis vulgaris
OMIM #146700
Infancy/
childhood
Characteristic Clinical Associated

Features
Features
Fine or centrally tackeddown scale with superficial
fissuring. Relative flexural
sparing; worse on lower
extremities. Hyperlinear
palms/soles.
Keratosis pilaris; atopy
Skin
Histopathology
Gene
Protein
Function
FLG
Absence of filaggrin
Uncertain
Hyperkeratosis; reduced
or absent granular layer
KRT1, KRT10; in Vrner

type (confined to
palms/soles) KRT 9
Keratin 1 or 10; in
Vrner type, keratin 9
Structural protein
abnormality
leading to keratin
intermediate filament
dysfunction
epidermal fragility
Hyperkeratosis;
vacuolated
degeneration of the
epidermal granular
(and often deeper)
layer; large, irregular
keratohyalin granules
KRT2
Keratin 2, which
is expressed in
superficial epidermis
As above for EHK
Similar to epidermolytic
hyperkeratosis, but
confined to the upper
spinous and granular
layer
KRT1mutation in
variable region
Keratin 1
As above for EHK
Upper epidermal
keratinocytes
have perinuclear
vacuolization/
perinuclear shells of
tonofilaments
Autosomal Dominant
EHK (bullous CIE)
OMIM #113800
Birth
Ichthyosis bullosa of
Siemens
OMIM #146800
Birth
Ichthyosis hystrix of
Curth and Macklin
OMIM #146590
Birth
Heterogeneous. May
have verrucous, firm,
hyperkeratotic (hystrix)
spines, often linearly
arrayed in flexural
creases; blisters; may
have erythroderma
and/or palmar/plantar
keratoderma
Redness and blistering
at birth. Later develop
hyperkeratosis,
accentuated over flexures.
Mauserung (molting):
collarette-like lesion where
uppermost epidermis has
been lost.
Resembles EHK,
varies from palmar/
plantar keratoderma
to generalized. Thick
porcupine-like spines. No
blistering.
Frequent skin
infections;
characteristic
pungent odor
Annular epidermolytic
erythema
OMIM #607602
Birth/infancy
Annular
plaques
develop later
Severe, intermittent scaling

with blisters or pustules.
Evolves to widespread,
migratory, annular plaques.
Erythrokeratodermia
variabilis
OMIM #133200
Generalized type
Birth
Generalized hyperkeratosis
and figurate, migratory red
patches
Red patches move

over minutes to
hours, may be
triggered by changes
in temperature
Localized type
Variable
Localized hyperkeratotic
plaques with figurate,
migratory red patches.
Hyperkeratotic
plaques may be
induced by trauma.
Considerable
intrafamilial variability
Progressive symmetric
erythrokeratodermia
OMIM #602036
Shortly after
birth
Erythematous, scaly
plaques, symmetrically
distributed over
extremities, buttocks,
and face; stabilize in early
childhood. Trunk tends to
be spared.
Keratitisichthyosis
deafness (KID)
syndrome
Recessive has been
reported OMIM
#148210
Birth/infancy
Progressive corneal
opacification; either mild
generalized hyperkeratosis
or discrete erythematous
plaques, which may be
symmetric; neurosensory
deafness.
Follicular
hyperkeratosis,
scarring alopecia,
dystrophic nails,
susceptibility to
infection
KRT1, KRT10
Keratin 1 or 10
As above for EHK
As above for EHK
GJB3 or GJB4
Connexin 31 or 30.3;
connexins form gap
junction channels
between cells
Abnormal intercellular
communication
Hyperkeratosis,
acanthosis,
papillomatosis, capillary
dilatation; epidermis
may have church spire
appearance
LOR or GJB4
Connexin 30.3
Cornified envelope
precursor
Nonspecific
GJB2, GJB6
Connexin 26, 30;

connexins form gap
junction channels
between cells
Abnormal intercellular
communication
Nonspecific
CIE = congenital ichthyosiform erythroderma; EHK = epidermolytic hyperkeratosis; OMIM = Online Mendelian Inheritance in Man.
Note: These are the predominant modes of inheritance.
Chapter 49
::
The Ichthyoses
509
Section 7
::
510
TABLE 49-2
Features of Selected Ichthyoses, X-linked

Diagnosis
Onset
X-linked recessive
ichthyosis
OMIM #308100
Birth/infancy
Chondrodysplasia
punctata
X-linked recessive (CDPX)
OMIM #302950
Characteristic
Clinical Features
Associated Features
Gene
Protein
Function
Skin Histopathology
Fine to large scales;

comma-shaped corneal
opacities on posterior
capsule
Cryptorchidism; female
carriers may have corneal
opacities and delay of
onset or progression
of labor in affected
pregnancies
STS
Steroid sulfatase
Lipid metabolism
abnormal cholesterol
metabolism with
accumulation of
cholesterol sulfate
Hyperkeratosis, may
have hypergranulosis;
nonspecific
Birth
May begin as
erythroderma, linear or
whorled atrophic areas or
hyperkeratosis, alopecia,
skeletal abnormalities,
short stature
Cataracts, deafness
ARSE
Arylsufatase E
Lipid metabolism
ill defined: failure of
hydrolysis of sulfate ester
bonds
X-linked dominant
chondrodysplasia punctata
(ConradiHnermann
Happle syndrome) (CDPX2)
OMIM #302960
Birth
CIE at birth, clears and

is replaced by linear
hyperkeratosis, follicular
atrophoderma and
pigmentary abnormalities,
stippled calcifications on
radiographs
Occurs almost exclusively

in females; hair shaft
abnormalities, short
stature, cataracts
EBP
Emopamil
binding protein
(EBP)also
known as 3hydroxysteroid8,7-isomerase
Lipid metabolism
abnormal cholesterol
biosynthesis
CHILD syndrome
X-linked dominant
OMIM #308050
Birth
Congenital hemidysplasia,
ichthyosiform
erythroderma, limb defects
Almost exclusively in
females
NSDHL;
EBP
reported
NSDHL (3 hydroxysteroid
dehydrogenase);
EBP reported
Lipid metabolism
postsqualene cholesterol
biosynthesis
CHILD = congenital hemidysplasia with ichthyosiform erythroderma and limb defects; CIE = congenital ichthyosiform erythroderma; EBP = emopamil binding protein; NSDHL = NAD(P)H steroid dehydrogenase-like
protein; OMIM = Online Mendelian Inheritance in Man.
TABLE 49-3
Features of Selected Ichthyoses, Autosomal Recessive

Diagnosis
ARCI (See Table 49-5)
ARCI/LI
Onset
Characteristic
Clinical Features
Associated Features
Gene
Protein
Function
Skin Histopathology
Birth; often
collodion
presentation
Large, plate-like, brown

scale over most of the
body; accentuated
on lower extremities.
Ectropion; eclabium;
alopecia. Palmar/ plantar
involvement varies.
Fine, white scale;
generalized erythroderma.
Palmar/plantar
involvement varies.
Varies between lamellar
and CIE.
Heat intolerance
See Table 49-5
See Table 49-5
See Table 49-5
Hyperkeratosis, acanthosis,
may show parakeratosis.
Nonspecific.
Harlequin ichthyosis
OMIM #242500
Birth
Markedly thickened skin

with geometric, deep
fissures. Survivors develop
severe CIE phenotype.
Restricted respiration,
feeding; neonatal sepsis;
often leads to neonatal
death. Failure to thrive.
ABCA12
ATP-binding cassette,
subfamily A, member
12
Lipid
metabolism
Membrane
transport,
abnormality of
lipid metabolism
Massively thickened,
orthokeratotic stratum
corneum; variable
acanthosis; granular layer
variably decreased
Ichthyosis prematurity
syndrome
OMIM #608649
Birth
Premature delivery of
infants with erythrodermic,
edematous, caseous
scaling skin resembling
excessive vernix caseosa,
evolves into dry, scaly skin
with follicular accentuation
with signs of atopy
Respiratory distress,
and transient peripheral
eosinophilia. The
respiratory signs resolve.
FATP4 (SLC27)
Fatty acid transport

protein 4
Lipid
metabolism
fatty acid
transport
Trilamellar membrane
inclusions are seen in
the stratum corneum by
electron microscopy.
Netherton syndrome
OMIM #256500
Birth
Ichthyosis linearis
circumflexa or similar to
congenital ichthyosiform
erythroderma;
trichorrhexis invaginata
Atopy; high serum

levels of IgE; may have
aminoaciduria; failure to
thrive
SPINK5
LEKTI (a serine
protease inhibitor)
Protein
metabolism
may result in
premature
desmosomal
and profilaggrin
degradation
in stratum
corneum.
Nonspecific
ARCI/CIE
ARCI/overlap
(continued)
Chapter 49
::
The Ichthyoses
511
Section 7
::
512
TABLE 49-3
Features of Selected Ichthyoses, Autosomal Recessive (Continued)

Diagnosis
Onset
OMIM #270200
Ichthyosis
apparent at
birth
Refsum disease
OMIM #266500
Characteristic
Clinical Features
Associated Features
Gene
Protein
Function
Skin Histopathology
Generalized fine to
coarse hyperkeratosis;
spastic diplegia; mental
retardation; retinal
glistening white dots
Short stature, seizures
FALDH
(ALDH10,
ALDH3A2)
Fatty aldehyde
dehydrogenase
Lipid
metabolism
Fatty aldehyde
metabolism
Nonspecific
Ichthyosis
develops in
adulthood
Progressive neurologic
dysfunction; skeletal,
cardiac, and renal
abnormalities
Retinitis pigmentosa,
elevated plasma phytanic
acid
Most PAHX;
PEX 7 also
reported (see
RCPD below)
Phytanoyl-CoA
hydroxylase (PhyH)
Peroxisome
abnormality
Deficiency of
phytanic acid
catabolism;
results in
phytanic acid
accumulation.
Lipid-containing vacuoles
in basal keratinocytes
Trichothiodystrophy (Tay
syndrome; PIBI(D)S, IBI(D)S,
BI(D)S) OMIM #278730
OMIM #601675
OMIM #234050
Some have
ichthyosis,
which may
be apparent
at birth; may
have collodion
presentation
Brittle hair,
Photosensitivity, Short
stature, Ichthyosis,
Intellectual impairment,
microcephaly, recurrent
infections
Abnormally low sulfur

content of hair.
Majority have
defect in
ERCC2 (XPD).
A few have
mutations
in ERCC3
(XPB), GTF2H5
(TTDA), or
TTDN1.
Most XPD. XPB, TTDA,

or TTDN1 in a few
Components
of transcription
factor TFIIH
Tiger tail banding of

shafts under polarizing
microscopy; hair shaft
abnormalities (trichoschisis,
trichorrhexis nodosa-like
fraying; ribboning)
ChanarinDorfman
syndrome (neutral lipid
storage disease)
OMIM #275630
Birth; may
have collodion
membrane
Generalized scaling,
resembles CIE; variable
extracutaneous
involvement: cataracts,
decreased hearing,
psychomotor delay.
Severe pruritus;
neurologic abnormalities;
hepatic abnormalities;
lipid droplets in circulating
leukocytes
CGI-58
Unknown
Lipid
metabolism
Activates
adiposetriglyceride
lipase for lipolysis
of tryglycerides
Lipid droplets in dermal

and epidermal cells, and
acrosyringia of eccrine
ducts
Neonatal ichthyosis
sclerosing cholangitis
syndrome #6073718
Birth
Neonatal cholestatic
jaundice, mild ichthyosis
with fine, white scales.
Scarring alopecia of the

scalp and eyebrows,
enamel dysplasia
CLDN1
Claudin 1
Abnormal tight
junction
Intracytoplasmic vacuoles
in keratinocytes that do not
stain with oil red O
Multiple sulfatase
deficiency OMIM #272200
SUMF1
C-formylglycine
generating enzyme
Generates
catalytic residue
in active site
of eukaryotic
sulfatases
Nonspecific
Generalized peeling in
superficial, thin flakes
Unknown
Unknown
Unknown
Limited to over hands and

feet
Presents as CIE; evolves to
migratory, scaling patches
TGM5
Transglutaminase 5
Unknown
Unknown
Protein crosslinking
Unknown
Intracellular split within

corneocytes in stratum
corneum
Nonspecific
Birth
Ichthyosis resembling
X-linked recessive
Birth
Neurological
deterioration; skeletal
abnormalities; facial
dysmorphism
Peeling Skin Syndrome

Type A (noninflammatory)
OMIM #270300
Type Aacral variant
OMIM #609796
Type B (inflammatory)
Pruritus, elevated IgE,

aminoaciduria, short
stature
Intercellular split between

stratum corneum and
granular layer; between
keratinocytes
ARCI = autosomal recessive congenital ichthyosis; ATP = adenosine triphosphate; CIE = congenital ichthyosiform erythroderma; CoA = coenzyme A; LEKTI = lympho-epithelial Kazal-type related inhibitor; LI = lamellar
ichthyosis; OMIM = Online Mendelian Inheritance in Man.
Chapter 49
::
The Ichthyoses
513
TABLE 49-4
Ichthyoses Organized by Pathophysiology

Disorder
Section 7
Structural Proteins
Ichthyosis vulgaris
Cytoskeleton
Annular epidermolytic ichthyosis
Epidermolytic hyperkeratosis (EHK)
Ichthyosis bullosa of Siemens
Ichthyosis hystrix of Curth and Macklin
Pachyonychia congenitaa
Palmar/plantar keratodermaa
Palmar/plantar keratoderma with EHK
Cornified Envelope Formation
ARCI/LI
Mutilating keratoderma with ichthyosisa
(Vohwinkle syndrome without deafness)
Progressive symmetric erythrokeratodermia
::
Intercellular Junctions
Naxos disease
NISCH syndrome
PPK, wooly hair, cardiomyopathya
(CarvajalHuerta syndrome)
Striate PPK 1a
Striate PPK 2a
Lipid Metabolism
ARCI
CEDNIK
Maturation and secretion
ChanarinDorfman syndrome
CHILD syndrome
Conradi HnermannHapple syndrome
Ichthyosis prematurity syndrome
Refsum syndrome
X-linked recessive ichthyosis
Intercellular Communication
Erythrokeratodermia variabilis
KID (keratitis, ichthyosis, deafness)
Progressive symmetric erythrokeratodermia
PPK with deafnessa
Vohwinkel syndrome (classic)
Protein Metabolism
KLICK
MEDNIK
Netherton syndrome
PapillonLefevre syndromea
Calcium Homeostasisb
Darier disease
HaileyHailey disease
Other
Cellular Respiration
PPK with deafnessa
Neurotransmitter
Mal de Meledaa
Nucleotide Excision Repair/Transcription
Trichothiodystrophyc
a
Discussed in Chapter 50.

c
b
514
Protein/Function Abnormality
Filaggrin
Keratins
Transglutaminase 1
Loricrin
Plakoglobin
Claudin 1
Desmoplakin
Desmoglein 1
Desmoplakin
Hepoxilin pathway
Lamellar granule maturation and secretion
Function unknown
Steroid dehydrogenase
Sterol isomerase
Sterol isomerase
Fatty acid transport
Phytanic acid catabolism
Fatty aldehyde and fatty alcohol metabolism
Steroid sulfatase
Gap junction proteins: Connexins
Proteosome
Protein trafficking by intracellular vesicles
Protease inhibitor
Protease
Ca++ dependent ATPase
Mitochondrial serine tRNA

Function unknown
Transcription
::
The Ichthyoses
The fully differentiated end product of the epidermis is

the stratum corneum, which is composed of terminally
differentiated keratinocytes, corneocytes (bricks),
surrounded by an intercellular matrix (mortar) (see
Chapter 47). The corneocyte bricks are proteinenriched, and the intercellular mortar is composed of
hydrophobic, lipid-enriched membrane bilayers.7 The
keratin-laden corneocytes are thought to be primarily
responsible for the resilience and water retention properties of the stratum corneum, while the matrix forms
most of the permeability barrier to water loss. The normal stratum corneum undergoes desquamation in an
organized and invisible manner, with individual corneocytes separating from each other and shedding as
single cells. Ichthyotic skin has an abnormal quality
and quantity of scale, the barrier function of the stratum corneum is compromised, and there may be alterations in the kinetics of epidermal cell proliferation
(see Chapter 46). The stratum corneum can be viewed
as a compartment, with thickening of the stratum corneum being the result of cells entering the compartment at an increased rate, or leaving (corneocyte
desquamation) too slowly, or both.
The process of epidermal differentiation is complex
and not completely understood. Defects in many different aspects and steps of this process can lead to a similar end result: abnormal stratum corneum and scale. In
some of these disorders, the underlying gene defect has
been identified. For example, mutations in the genes
that encode the suprabasal epidermal keratins, keratins
1 and 10, cause epidermolytic hyperkeratosis.11 Mutations in the gene encoding transglutaminase-1, an
enzyme that catalyzes the cross-linking of proteins and
attachment of ceramides during the formation of corneocytes, are found in up to 55% of patients with autosomal recessive congenital ichthyosis.1215 The observation
that key components of this process cause ichthyosiform disorders highlights the importance and complexity of normal keratinocyte differentiation.
Steroid sulfatase controls the hydrolysis of cholesterol sulfate in corneocytes and is thought to be important in the regulation of corneocyte desquamation.
Deficiency of steroid sulfatase causes X-linked reces-
sive ichthyosis.16,17 The observation that several drugs

that lower serum cholesterol (e.g., nicotinic acid, triparanol) can induce ichthyotic skin changes indicates the
importance of lipid homeostasis in normal keratinization.7 Further evidence is the identification of mutations in the genes encoding cholesterol biosynthetic
enzymes as a cause of X-linked dominant chondrodysplasia punctata and CHILD (congenital hemidysplasia
with ichthyosiform erythroderma and limb defects)
syndrome, and genes encoding other aspects of lipid
biosynthesis in the autosomal recessive congenital ichthyoses.18 The identification of mutations in SPINK5
(serine protease inhibitor, Kazal type 5), encoding a serine protease inhibitor, in Netherton syndrome confirms a role for proteolysis and protease inhibitors in
normal epidermal differentiation.19 The discoveries of
connexin abnormalities as causes for erythrokeratodermia variabilis, KID (keratitis, ichthyosis, and deafness) syndrome, and other disorders involving
ectodermal tissues highlight the role of intercellular
communication for properly functioning skin.20,21
Mutations in the FLG gene result in reduced or absent
filaggrin and decreased moisture binding in the stratum corneum of patients with IV.22 Mutations in FLG
may also result in more severe clinical phenotype in
other skin disorders.23,24
These examples highlight the complexity of the process of forming a normally functioning stratum corneum and demonstrate that diverse abnormalities can
result in similar clinical phenotypes of thickened stratum corneum and scaling. How do diverse processes
result in similar phenotype? The answers are unclear,
although studies suggest that defects in the barrier
may result in inflammation and hyperproliferation.25
Furthermore, our evolving understanding of these
mechanisms continues to clarify the multisystem, clinical phenotypes observed in several ichthyosiform disorders.
Chapter 49
dominant diseases [e.g., epidermolytic hyperkeratosis

(EHK)] have a high frequency of spontaneous mutation, and the lack of a positive family history does not
rule out autosomal dominant inheritance. Alternatively, the presence of parental consanguinity may suggest autosomal recessive inheritance. Light microscopic
features are usually diagnostic in epidermolytic hyperkeratosis and can be helpful in selected ichthyoses
(e.g., Refsum disease, neutral lipid storage disease,
acquired ichthyosis of sarcoidosis and mycosis fungoides), but histopathologic examination may not be useful to distinguish other ichthyoses. In many cases, the
clinical diagnosis may be clarified by genetic analysis,
although mutations are not always demonstrable. The
development of ichthyosis in adulthood may be a
marker of systemic disease.
ICHTHYOSIS VULGARIS
Ichthyosis vulgaris (OMIM #146700), the most common
ichthyosis, is relatively mild. While infants usually
have normal skin, the disease often manifests within
the first year. The scale of IV is usually most prominent
on the extensor surfaces of the extremities, with flexural
sparing (Fig. 49-1). The diaper area tends to be spared.
There may be fine, white scales over large areas. Particularly on the lower extremities, which are often the
most severely involved area, the scales may be centrally
attached, with cracking (superficial fissuring through
the stratum corneum) at the edges. This turning up at
the edges can lead to the skin feeling rough.
A number of other findings are commonly observed
in association with IV.26 Hyperlinear palms are usually
present, and some patients may have palmar/plantar
thickening approaching a keratoderma. Keratosis pilaris is common, even in individuals with mild IV, and
usually involves the outside of the arms, extensor
thighs, and buttocks. Atopy is also frequently observed
and can manifest as hay fever, eczema, or asthma.
These findings can confound an accurate diagnosis,
515
Section 7
::
Figure 49-1 Ichthyosis vulgaris. Full presentation of IV in individuals with mutations in both alleles of the profilaggrin
gene (A, C, E); milder presentation in an individual with a profilaggrin mutation in a single allele (B, D, F). A and B. Fine,
white scale on lower abdomen. CF. Hyperlinear palms. (From Smith FJ et al: Loss-of-function mutations in the gene
encoding filaggrin cause ichthyosis vulgaris. Nat Genet 38:337, 2006, with permission.)
516
because hyperlinear palms and keratosis pilaris may

be seen in atopic individuals who do not have IV.
Rarely, individuals with IV may have hypohidrosis
with heat intolerance. There is great variation in the
severity of clinical manifestations between affected
individuals in the same family. The condition usually
worsens in climates that are dry and cold and improves
in warm, humid environments where the disease may
clear dramatically.
The disease was thought to be autosomal dominant

and in a study of English school children was found to
affect 1 in 250.4 Recently, mutations in the gene encoding profilaggrin have been found to cause IV. Profilaggrin is the precursor protein for multiple copies of
filaggrin, which functions during cornification. The
inheritance pattern has been clarified to be semidominant; individuals who carry one mutated allele have a
mild phenotype, while those with mutations in both
filaggrin molecules and is localized to keratohyalin

granules. Biochemical studies of epidermis from
patients with IV have shown absence of or decrease in
filaggrin and its precursor, profilaggrin.32,33 In the
Anglo-European population, null mutations in the
gene encoding profilaggrin (FLG) are very strong predisposing factors for atopic dermatitis. A strong association is also found with individuals who have
sensitivity to common allergens, allergic rhinitis, early
onset and persistent eczema, and asthma in the presence of atopic dermatitis.27,34
X-LINKED RECESSIVE ICHTHYOSIS
Figure 49-2 Histopathology. A. Ichthyosis vulgaris. Note absent granular layer. B. X-linked recessive ichthyosis. Note
compact hyperkeratosis and accentuated granular layer. (Used with permission from Rob McFarlane, MD). C. Autosomal
recessive congenital ichthyosis (CIE). Thickened stratum corneum composed of compact hyperkeratosis with foci of parakeratosis. D. Epidermolytic hyperkeratosis. The stratum corneum is thickened (hyperkeratosis) and there is prominent
vacuolar degeneration of suprabasalar epidermis most marked at the granular layer.
The Ichthyoses
::
In the 1960s, X-linked recessive ichthyosis (OMIM

#308100) was distinguished clinically from other ichthyoses.4 Shortly thereafter, the syndrome of placental
steroid sulfatase deficiency was described in pregnancies with failure to initiate labor in association with
low maternal urinary estrogens. Because the majority
of maternal urinary estrogens are derived from the
fetal adrenal and are metabolized by the placenta, low
levels can reflect fetal abnormalities or death. However, in this condition low levels do not indicate severe
fetal morbidity. The association between failure to
Chapter 49
profilaggrin alleles (homozygotes or compound heterozygotes for the mutations) (Fig. 49-1) manifest a
severe clinical phenotype. In the Anglo-European population, the prevalence of clinical disease is as high as 1
in 80.22,27,28
It is difficult to distinguish some patients with mild
IV from simple dry skin (xerosis). Evolving understanding of this very common condition is beginning
to clarify how a spectrum of underlying mutations can
cause the diverse clinical severity of dry skin from
xerosis to severe IV. In addition, on the basis of skin
findings alone, males with severe IV may be difficult to
differentiate from those affected with X-linked recessive ichthyosis.26,29 The histopathologic findings of IV
(Fig. 49-2A) may, as the clinical severity, be more pronounced, with hyperkeratosis and absent granular
layer in individuals with two abnormal alleles.
Filaggrin is an epidermal protein involved in the
aggregation of keratin intermediate filaments30 and
retention of moisture in the stratum corneum.31 Keratin filaments form a network, or cell matrix, that gives
structural integrity to the epidermal keratinocytes. As
keratinocytes mature into corneocytes, the keratin filaments collapse and are cross-linked to the cornified cell
envelope. Filaggrin is synthesized as a high-molecular
weight precursor, profilaggrin, that contains multiple
517
Section 7
::
i nitiate or progress labor and ichthyosis in the male offspring was not appreciated until 1978.16,17 Steroid
sulfatase hydrolyzes sulfate esters, which include cholesterol sulfate and sulfated steroid hormones.35 Sulfated fetal adrenal hormones undergo desulfation to
estrogens, which are excreted in maternal urine. The
absence of steroid sulfatase enzyme in the fetal placenta leads to low maternal urinary estrogens, and in
some pregnancies, to a failure of labor to initiate or to
progress normally. In males with X-linked recessive
ichthyosis, steroid sulfatase enzyme activity is
decreased or absent in many tissues, including epidermis, stratum corneum, and leukocytes, and in cultured
fibroblasts.36 In addition, cholesterol sulfate, an enzyme
substrate, accumulates in serum and in scale. Carrier
females have been found to have leukocyte steroid sulfatase levels intermediate between those observed in
normal individuals and those in affected males.
X-linked recessive ichthyosis occurs in approximately
1 in 2,000 to 6,000 males.4,37 Scaling may begin in the
newborn period and is usually most prominent on the
extensor surfaces, although there is significant involvement of the flexural areas. While the extent and degree of
scaling are variable, X-linked ichthyosis can usually be
distinguished from IV on clinical criteria.4,38 The latter
tends to be associated with hyperlinear palms and soles,
keratosis pilaris, and a family history of atopy. X-linked
ichthyosis tends to have more severe involvement with
larger scale, and comma-shaped, corneal opacities may
be present in half of adult patients39,40 (Fig. 49-3). Corneal
518
opacities do not affect vision and may be present in

female carriers.40 Affected males have an increased risk
of cryptorchidism, and independently they are at
increased risk for the development of testicular cancer.41
Histopathologic examination shows compact orthohyperkeratosis, acanthosis, and papillomatosis. The granular layer is usually thickened (Fig. 49-2).
Cholesterol sulfate levels are elevated in the serum,
epidermis, and scale,42 and there is increased mobility
of -lipoproteins (low-density lipoproteins) on electrophoresis, a feature that can suggest the diagnosis. Steroid sulfatase is one of a group of arylsulfatases located
on chromosome Xp22. More than 90% of the mutations
in X-linked ichthyosis are deletions that can often be
detected by fluorescence in situ hybridization (FISH),
available in many clinical laboratories. Confirmation
of the diagnosis can also be made by finding an elevation in serum cholesterol sulfate levels. Unfortunately,
cholesterol sulfate determination in serum and scale
may not be readily available for laboratory confirmation of the clinical diagnosis. In the rare case where
deletions are not detected and a clinical diagnosis is
necessary, arylsulfatase C (steroid sulfatase) enzyme
activity can be measured in cultured fibroblasts. Deletions that include adjacent sulfatases explain the overlap syndromes involving chondrodysplasia punctata
and X-linked ichthyosis.43 The X-linked form of
Kallmann syndrome, in which hypogonadotropic
hypogonadism and anosmia are found, often with
renal abnormalities, obesity, synkinesis (mirror image
Figure 49-3 X-linked recessive ichthyosis. A. The scales are large and dark and most evident on the flexural areas in this
patient. B. The blue arc is a cross-section of the cornea as seen by slit-lamp examination. The opacities appear white.
The Ichthyoses
The term autosomal recessive congenital ichthyosis (ARCI)

is useful to describe a heterogeneous group of disorders that present at birth with generalized involve-
::
AUTOSOMAL RECESSIVE
CONGENITAL ICHTHYOSIS
ment of the skin. Autosomal recessive ichthyosis is rare

and has been estimated to occur in about 1 in 300,000
persons.4
In older literature, nonbullous congenital ichthyosiform
erythroderma (NCIE) [lamellar ichthyosis (LI), with autosomal recessive inheritance] was distinguished from
bullous congenital ichthyosiform erythroderma (BCIE)
(EHK, with autosomal dominant inheritance) based on
clinical appearance (bullae) and pattern of inheritance.6,46 That the term LI was used interchangeably
with NCIE and included a spectrum of phenotypes has
led to some confusion. Williams and Elias distinguished LI from NCIE [usually called congenital ichthyosiform erythroderma (CIE)], a milder erythrodermic
form.47 Some patients with LI can be clearly distinguished from those with CIE on the basis of clinical
features. In LI one sees large, dark, plate-like scales,
and while infants may be red at birth, adults have little
to no erythroderma (Fig. 49-4). In the more severe, classic presentation of LI, tautness of the facial skin leads
to traction on the eyelids and lips, resulting in ectropion and eclabium. Scarring alopecia, most prominent
at the periphery of the scalp, may be partly due to traction at the hairline. In contrast, CIE has generalized
redness and fine, white scales (Fig. 49-5). Patients with
classic CIE have little to no ectropion, eclabium, or alopecia. However, many patients do not fit neatly into
these two clinical descriptions,48 in that they have features of both LI and CIE with a clinical phenotype
intermediate between both disorders. Therefore, it
can be useful to consider these two distinctive presentations as ends of a spectrum, between which lie a
Chapter 49
movements of the extremities), cleft palate, and spastic

paraplegia, can also be seen in association with X-linked
recessive ichthyosis as part of a contiguous gene deletion syndrome.43 Because of this, and because of the
association with testicular carcinoma, patients with
X-linked recessive ichthyosis should be queried about
anosmia and have periodic testicular examination.44
In the epidermis, steroid sulfatase catalyzes the
hydrolysis of cholesterol sulfate. The identification of
steroid sulfatase deficiency in X-linked ichthyosis supports the importance of cholesterol sulfate hydrolysis in
normal desquamation. Topical application of cholesterol sulfate in mice can induce a scaling disorder,
further supporting the role of cholesterol sulfate hydrolysis in corneocyte desquamation.
A family was described with an ichthyosis inherited in
an X-linked pattern but with normal steroid sulfatase
activity and the absence of corneal opacities.45 This demonstrates heterogeneity within X-linked ichthyosis.
Because of its frequent occurrence, steroid sulfatase deficiency accounts for most cases of X-linked ichthyosis, but
a normal steroid sulfatase level in a male with ichthyosis
does not rule out an X-linked pattern of inheritance.
Figure 49-4 Classic lamellar ichthyosis phenotype. A. Ectropion. B and C. Large, brown, plate-like scales. (From Russell LJ
et al: Linkage of autosomal recessive lamellar ichthyosis to chromosome 14q. Am J Hum Genet 55:1146, 1994, with permission.)
519
LAMELLAR ICHTHYOSIS
Section 7
Figure 49-5 Congenital ichthyosiform erythroderma.

Bright, red erythroderma with fine, white scale.
::
radation of clinical phenotypes with variable degrees

g
of erythema and coarseness of scale. Individual features such as collodion membrane (discussed below),
ectropion, and alopecia can occur across the spectrum.
While attempts to refine the categorization of these disorders by biochemical and ultrastructural observations
have failed to yield a consistent and replicable classification scheme,5 identification of the spectrum of specific molecular defects underlying these conditions
will undoubtedly help.49 Identification of mutations
has, so far, found ARCI to be caused by six different
genes (Table 49-5) which are important for the formation of the intercellular lipid layer or the cornified
envelope of keratinocytes.
Most patients with LI or CIE inherit the disease in
an autosomal recessive pattern. Rarely, families have
been described with similar phenotypes, where the
disease is inherited as an autosomal dominant trait.5
This is an important consideration for genetic counseling.
LI is apparent at birth, and the newborn usually presents encased in a collodion membrane. At this time the
skin may be red. Over time, the skin develops large,
plate-like scales, which appear to be arranged in a
mosaic pattern (see Fig. 49-4). In some areas, the scales
are centrally attached with raised borders. The scales
tend to be largest over the lower extremities, where the
large, plate-like scales separated by superficial fissuring can lead to an appearance similar to that of a dry
riverbed. During childhood and into adulthood the
degree of erythema may vary, but usually is minimal or
absent in the severe presentation of classic LI. Involvement of the palms and soles in LI is variable and ranges
from minimal hyperlinearity to severe keratoderma.
The lips and mucous membranes tend to be spared in
LI, but the adnexal structures may be compromised by
the adherent, firm scales. Thick stratum corneum on the
scalp tends to encase hairs, and in conjunction with the
tautness of the skin, may lead to a scarring alopecia,
most marked at the periphery of the scalp. The hyperkeratosis can interfere with normal sweat gland function, resulting in hypohidrosis, but the degree of
impairment varies between patients. Some patients
have severe heat intolerance and must be vigilant to
avoid overheating. Treatment with oral retinoids can
improve or prevent some sequelae of LI. Patients frequently notice an increase in sweating, with improved
heat tolerance. While retinoid therapy can cause blepharitis or even conjunctivitis, it is usually well tolerated
by patients with LI. Moreover, the ability of systemic
retinoid (and in some cases, topical retinoid) therapy to
decrease thick periocular scale can decrease the tendency to develop ectropion. Nevertheless, patients
with severe, classic LI usually require careful eye maintenance. Because of the ectropion (see Fig. 49-4), the lids
TABLE 49-5
Mutated Genes Identified in ARCI

Genea
Protein
Function
TGM1b
Transglutaminase 1
Cornified envelope formation
ABCA12
ATP-binding cassette, subfamily A, member 12
Membrane transport/lipid metabolism
ALOXE3
Arachidonate lipoxygenase 3 (eLOX3)
Hydroperoxide isomerase
ALOX12B
Arachidonate 12-lipoxygenase, R type (12R-LOX)
Lipoxygenase
ICHYN
Ichthyin
Trioxilin A3 receptor?
Hepoxylin pathway?
FLJ39501 (CYP4F22)
Cytochrome P450, family 4, subfamily F, polypeptide 2
LTB4--hydoxylase?
? (12p11.2-q13)
? (19p13.1-13.2)
a
The same gene may have more than one name.

Approximately one-third of individuals with ARCI have detectable TGM1 mutations.
From Fischer J: Autosomal recessive congenital ichthyosis. J Invest Dermatol 129:1319, 2009.
520
In 1902, Brocq described bullous ichthyotic erythroderma and distinguished the blistering type from the
nonblistering type of congenital ichthyotic erythroderma.56 The original description included three unrelated patients whose clinical manifestations varied.
However, this was probably the first description of epidermolytic hyperkeratosis (EHK; OMIM #113800). The
disease is named for the distinctive histopathologic
features of vacuolar degeneration of the epidermis
(i.e., epidermal lysis) and associated hyperkeratosis.
EHK is also known as BCIE, an earlier descriptive
name signifying the blistering, neonatal presentation,
scaling, and redness.
EHK is transmitted as an autosomal dominant trait
with a prevalence of approximately 1 in 200,000 to
300,000 persons. However, there is a high frequency of
spontaneous mutation, and as many as one-half of the
cases have no family history46 and represent new
mutational events. The disease usually presents at
birth with blistering, redness, and peeling (Fig. 49-6).
With time, generalized hyperkeratosis may develop,
which may or may not be associated with erythroderma. EHK skin usually has a characteristic pungent
odor, thought to be related to superinfection by mixed
flora.
In contrast to most other ichthyoses, the histopathologic picture of EHK is almost always distinctive. A
tremendously thickened stratum corneum and vacuolar degeneration of the upper epidermis are seen, leading to the histologic term EHK (see Fig. 49-2D). The
vacuolar degeneration usually involves the upper
epidermis and occasionally all of the suprabasilar
keratinocytes. Granular cells exhibit dense, enlarged,
irregularly shaped masses that appear to be keratohyalin
The Ichthyoses
As with LI, CIE is apparent at birth, and the newborn

usually presents with a taut, shiny, collodion membrane. After shedding of the membrane, the skin of
infants with CIE remains red, usually with a fine,
white, generalized scale (see Fig. 49-5). On the lower
legs, the scale may be larger and darker. In contrast to
LI, the classic presentation of CIE may have little to no
ectropion, eclabium, or alopecia. As in LI, there is a
wide variation in the ability to sweat, and patients
with CIE may have minimal sweating with severe heat
intolerance. Mucous membranes are usually spared.
Palm/sole involvement is variable. Nails may have
ridging, but they are often spared. As with all the ichthyoses, dermatophyte infection of the skin and nails is
common.
EPIDERMOLYTIC HYPERKERATOSIS
::
CONGENITAL ICHTHYOSIFORM
ERYTHRODERMA
Histopathologic examination shows hyperkeratosis,

acanthosis, and often parakeratosis (Fig 49-2C). Studies of epidermal proliferation have shown markedly
increased epidermal cell turnover, in contrast to LI.50
A small subset of patients with CIE have been found
to have mutations in TGM1, and two siblings with a
collodion presentation, CIE, and palmoplantar keratoderma had an autosomal dominant mutation in the
cornified envelope protein, loricrin.54 Further genetic
heterogeneity within ARCI has been demonstrated,
with exclusion of TGM1 as the disease-causing gene in
families with phenotypes within the spectrum of classic LI and CIE and identification of mutations in other
genes. To date, mutations have been identified in five
additional genes in ARCI (Table 49-5). In addition, two
other genetic loci (12p11.2-q13 and 19p13.1-13.2) have
been found to be associated with ARCI; the responsible
genes have not been identified. The enzymes coded for
by these genes (Table 49-5) are hypothesized to function together to convert arachidonic acid to a specific
hepoxilin in a newly described pathway thought to
form a common link in ARCI.18,55This hypothesis
remains to be tested, and how the most common mutation in ARCI, that of TGM1, might relate to lipid abnormalities is unclear.
Chapter 49
may fail to close fully, particularly during sleep; hydration with liquid tears during the day and ophthalmic
lubricants at night can prevent exposure keratitis.
Histopathologic examination typically shows orthokeratotic hyperkeratosis with mild to moderate acanthosis. Rates of epidermal proliferation are normal or
only slightly elevated in patients with LI, in contrast to
those with CIE, which has significantly greater labeling indices.50
Mutations in TGM1, the gene encoding transglutaminase 1, were found in several families with LI, solidifying the role for transglutaminase 1 in the formation
of a normal stratum corneum and its role as a cause of
LI.12,13 The lamellar phenotype is more commonly associated with mutations in TGM1.15,49 The transglutaminases catalyze calcium-dependent cross-linking of
proteins through the formation of -(-glutamyl)lysine
isodipeptide bonds. During the formation of the stratum corneum, transglutaminase catalyzes the crosslinking of cellular proteins, including involucrin,
loricrin, small proline-rich proteins, and others. The
resulting protein complex is deposited on the inner
side of the plasma membrane to form the cornified
envelope. Transglutaminase also attaches ceramides
secreted into the intercellular space by lamellar bodies
to cornified envelope proteins, notably involucrin, and
thereby is important in the formation of both the protein and lipid components of the stratum corneum.14
Bathing suit ichthyosis is an unusual form of LI where
affected individuals develop the scaling typical of LI,
but limited to the bathing suit area.51 The distribution
correlates with warmer areas of skin. Decreased transglutaminase is found in these areas, and unique,
temperature-sensitive mutations in TGM1 have been
identified in affected individuals.52
In a human skin/immunodeficient mouse xenograph model, transfer of a transglutaminase-1 gene into
transglutaminase-1-deficient keratinocytes from LI
patients resulted in normalization of transglutaminase
expression and epidermal architecture in addition to
restoration of cutaneous barrier function.53 Additional
disease-causing loci have been found (see below).
521
Section 7
::
Figure 49-6 Epidermolytic hyperkeratosis. Newborn

showing blistering and erosions.
granules.6 On electron-microscopic examination,
clumping of filaments is observed to begin in the first
suprabasal layer. These aggregated filaments are
clumps of keratin intermediate filaments that contain
the suprabasal keratins 1 and 10.57
There is striking clinical heterogeneity between EHK
families. Six distinctive clinical phenotypes have been
described.58 Several clinical features can be useful to
distinguish between the different subtypes, including
the presence versus absence of severe palmar/plantar
hyperkeratosis and of erythroderma, quality of scale,
extent of involvement, presence of digital contractures,
and gait abnormality (Table 49-6). Three types without
palm/sole hyperkeratosis are called NPS types.
Patients with the NPS-1 clinical phenotype have generalized involvement with thick, brown verrucous hyperkeratosis, most prominent over joints. Palms and soles
are spared. Cobblestone or hystrix (porcupine-like)
spiny papules are characteristic; this severe clinical
resentation is one of the more commonly recognized

p
types of EHK (Fig. 49-7A). NPS-2 is similar, but much
milder, without the hystrix spines and with relative
sparing of the skin between joints (Fig. 49-7B). Generalized exfoliative erythroderma is found in NPS-3 (Fig.
49-7C). Three types with severe palm/sole hyperkeratosis are called PS types. Patients with the PS-1 type
have a smooth palmar/plantar hyperkeratosis with a
sharp border, often delineated by a red halo. Blisters
may be present at the border. There may be limited
involvement of the trunk, usually confined to areas
over joints (Fig. 49-8A). The PS-2 type is characterized
by generalized erythroderma and scaling. Volar
involvement may be severe, with contractures of the
digits and ainhum-like constricting digital bands (Fig.
49-8B). The PS-3 type has generalized skin involvement
with a pebbly hyperkeratosis that is arrayed in a distinctive, cerebriform pattern on the palms and soles
(Fig. 49-8C).
Sporadic EHK due to a postzygotic, spontaneous
mutation during embryogenesis can present in a
mosaic pattern of skin involvement. Areas of hyperkeratosis alternating with normal skin are often distributed in streaks along Blaschko lines (Fig. 49-9A).
These may be limited to a few streaks, or there may
be many, with widespread, patchy involvement. Unilateral localization can also occur. This clinical mosaic
pattern correlates with underlying genetic mosaicism in that keratin mutations characteristic of EHK,
which were found in lesional skin, were absent in
normal skin.59 If the germ line is involved, individuals with mosaic EHK can transmit the mutation,
which leads to generalized EHK in affected offspring
(Fig. 49-9B).60
Within keratinocytes, keratin intermediate filaments
form an elaborate network that confers structural stability to the cells. In the suprabasilar, differentiating
keratinocytes of interfollicular epidermis, this network
is formed by keratins 1 and 10. In EHK, failure of this
network leads to keratinocyte fragility (particularly of
the upper epidermis), easy blistering, altered barrier
TABLE 49-6
Characteristics of Epidermolytic Hyperkeratosisa
522
NPS-1
NPS-2
NPS-3
PS-1
PS-2
PS-3
Palm/sole
hyperkeratosis
Palm/sole surface
Normal
Normal
Hyperlinear, minimal scale
Smooth
Smooth
Cerebriform
Digital contractures
Scale
Hystrix
Brown
Fine, white
Mild
White scale to
peel
Tan
Distribution
Generalized
Generalized
Generalized
Localized
Generalized
Generalized
Erythroderma
Blistering
Localized
Neonatal
Implied mutation
Keratin 10
Keratin 10
Keratin 10
Keratin 1
Keratin 1
Keratin 1
NPS = types without severe palm/sole hyperkeratosis; PS = types with severe palm/sole hyperkeratosis; minus sign = absent; plus sign = present.
Chapter 49
::
The Ichthyoses
Figure 49-7 Clinical phenotypes of epidermolytic hyperkeratosis. NPS (no severe palm/sole hyperkeratosis) types are
shown. A. NPS-1 (NPS-type 1): Generalized involvement with thick, brown verrucous hyperkeratosis. Palms are spared.
Over the dorsal foot, hyperkeratosis is arrayed in a characteristic cobblestone or hystrix (porcupine-like) pattern. B. NPS-2
(NPS-type 2): Brown hyperkeratosis over the trunk, and accentuated over joints. Palms are spared. Compared to the verrucous hyperkeratosis in NPS-1, involvement is much milder. On the lower legs, note the blistering, hypertrichosis, and
relative sparing of the skin between the joints. C. NPS-3 (NPS-type 3): Generalized erythroderma with white scale and
hyperkeratosis.
function,61 abnormal epidermal kinetics (hyperproliferation), and thickened stratum corneum (hyperkeratosis). Keratin 10 is the coexpressed partner of keratin
1, both of which are required to form keratin intermediate filaments in the cells of the suprabasal layers of
the epidermis. Mutations in genes coding for either
keratin 1 or 10 have been identified in a number of
EHK families.57,62 In most cases, palmar/plantar
involvement implies mutations in K1; this may reflect
the redundancy of K9 (a keratin that occurs only in
the suprabasal epidermis of palmar and plantar skin)
and K10 in palmar/plantar epithelium. Mutations in
keratin 9 have been found in families with the type of
EHK limited exclusively to the palms and soles
(Vrner)63 (see Chapter 50).
DISORDERS RESEMBLING
ICHTHYOSIS BULLOSA OF SIEMENS
Ichthyosis bullosa of Siemens (OMIM #146800) is a rare
autosomal dominant genodermatosis that is similar in
clinical appearance to EHK. Patients are born with redness and blistering. The redness subsides over the subsequent weeks to months, while the skin develops
dark gray hyperkeratosis, particularly over flexural
areas. In some areas, there may be a lichenified appearance to the skin. As with EHK, the epidermis is fragile;
523
Section 7
::
Figure 49-8 PS (Severe palm/sole hyperkeratosis) types are shown. A. PS-1 (PS-type 1): Palmar and plantar hyperkeratosis with sharp border delineated by a red halo. Blisters are present at the border. Note the relatively smooth surface.
There is characteristic involvement at the joints but sparing most of the trunk and extremities. B. PS-2 (PS-type 2): Hands
(left) of a 36-year-old patient with severe palmar hyperkeratosis, contractures, and ainhum-like constricting digital bands.
The palmar hyperkeratosis limits spreading of the fingers. Palms (right) of a 15-year-old patient with severe palmar hyperkeratosis and contractures. Flank (lower right) exhibiting generalized erythroderma and scaling. C. PS-3 (PS-type 3):
Hyperkeratosis in a cobblestone pattern on the knees. Four-year-old patient with hyperkeratosis in a distinctive cerebriform pattern on the palms and soles (not shown). (Adapted from DiGiovanna JJ, Bale SJ: Clinical heterogeneity in epidermolytic hyperkeratosis. Arch Dermatol 130:1026, 1994 with permission.)
524
Chapter 49
::
The Ichthyoses
Figure 49-9 Mosaic epidermolytic hyperkeratosis. A. Streaks of hyperkeratosis distributed along Blaschkos lines in a sporadic case due to postzygotic occurrence of new mutation. B. Grandchild of patient shown in Panel A. Generalized involvement (in this case the NPS-2 clinical phenotype) is transmitted to subsequent generations in an autosomal dominant
inheritance pattern.
however, the fragility is more superficial. This can
result in loss of the uppermost epidermis (predominantly stratum corneum), yielding a characteristic,
collarette-like depressed area that has been described
as mauserung (molting). Histologically, the epidermis shows hyperkeratosis and vacuolization similar to
EHK, but it may be confined to the granular layer.
Mutations have been found in the gene encoding keratin 2,64 a differentiation keratin of the suprabasilar epidermis that is expressed in the more superficial
epidermal layers.
ICHTHYOSIS HYSTRIX OF
CURTH AND MACKLIN
Ichthyosis hystrix of Curth and Macklin (OMIM #146590)
is a rare, autosomal dominant disorder that clinically
resembles EHK. Clinical expression varies, even
within families, from palmoplantar keratoderma to
severe generalized involvement. There can be widespread patchy, thick, graybrown hyperkeratosis,
most marked on the extensor arms and legs. Patients
with extensive involvement resemble those with
severe EHK without palmar/plantar involvement,
with verrucous or porcupine-like (hystrix) hyperkeratosis. However, in contrast to EHK, blistering does
not occur. Histologic examination of the epidermis
shows acanthosis, papillomatosis, and severe orthokeratotic hyperkeratosis, with frequent binucleate
cells. Keratinocytes within the granular and upper

spinous layers may have perinuclear vacuolization,
and some have prominent perinuclear shells. On electron microscopy, there are concentric, unbroken shells
of tonofilaments surrounding the nucleus. Study of a
three-generation family with ichthyosis hystrix of
Curth and Macklin identified a mutation in the variable tail domain (V2) of the keratin 1 gene. Structural
analyses of the resulting abnormal keratin showed a
failure of keratin intermediate filament bundling,
retraction of the cytoskeleton from the nucleus, and
failure of localization of loricrin to desmosomal
plaques.65
ANNULAR EPIDERMOLYTIC
ERYTHEMA
Annular epidermolytic erythema (cyclic ichthyosis with
EHK; OMIM #607602) presents at birth or in the first
few months afterward with severe, intermittent scaling and blistering that resolves during puberty.66
Residual, limited thickened plaques of verrucous scale
in linear rows can be seen in flexural and intertriginous
skin. In some cases, explosive bouts of widespread erythema with blisters and pustules are seen.67 Patients
subsequently develop widespread, migratory, polycyclic, and annular scaling plaques. Light and electron
microscopy reveals findings of EHK. Mutations in keratin 1068 and keratin 167 have been found.
525
A unifying designation of keratinopathic ichthyosis for

all ichthyoses with underlying keratin mutations has
been suggested recently.9
ICHTHYOSIS IN THE NEWBORN

COLLODION BABY
Section 7
::
A collodion baby is born encased in a translucent, parchment-like membrane that is taut and may impair respiration and sucking. Involvement may vary from mild
to severe, but this variation has not been well characterized. In addition, the birth is often premature, which
adds to morbidity. During the first 2 weeks of life, the
membrane breaks up and peels off, often leaving fissures, with impairment of the barrier to infection and
water loss. This can lead to an increased risk of infection, difficulties in thermal regulation, and hypernatremic dehydration.69 Newborn care should include
careful monitoring for infection and of temperature,
hydration, and electrolytes, and measures to keep the
peeling membrane soft and lubricated to facilitate flexibility and desquamation. Appropriate pain management and eye care should be employed, when
indicated. These newborns usually benefit from a
humidified incubator where the air is saturated with
water; wet compresses followed by bland lubricants
can be used to further hydrate the membrane and
achieve maximum pliability.70 If during peeling, residual areas of the membrane are allowed to dry and
harden in areas such as the extremities, the taut membrane can constrict and lead to distal swelling. Collodion presentation can develop into a wide spectrum of
ichthyotic phenotypes as the child grows (Box 49-1). It
is the usual presentation of ARCI (see Fig. 49-10) and is
less commonly seen in several other forms of ichthyo-
BOX 49-1 Disorders Associated

with Collodion Membrane
AEC syndrome
Autosomal recessive congenital ichthyosis (LI, CIE,
overlap)
Chondrodysplasia punctata
Gaucher disease
Loricrin keratoderma
Neutral lipid storage disease
Self-healing collodion baby
Trichothiodystrophy
X-linked hypohydrotic ectodermal dysplasia
Other
Note: This box does not distinguish the frequency in which collodion membrane is found in the different disorders listed. In some
cases, severe peeling may be mistaken for collodion membrane.
(From Okulicz JF, Schwartz RA: Hereditary and acquired ichthyosis
vulgaris. Int J Dermatol 42:95, 2003.)
526
Figure 49-10 Collodion baby. The infant is 36 hours old

and is covered with a macerated membrane that shows
fissures; note ectropion and eclabium. The condition may
develop over time into various clinical phenotypes including ARCI and self-healing collodion baby (Table 49-3).
sis, and rarely Gaucher disease (Box 49-1). In addition,
an autosomal recessive, self-healing collodion baby
has been described, where the skin greatly clears
within the first few weeks and transitions into mildly
affected or normal skin.71 Eleven Swedish and four
Danish patients with a self-improving ichthyosis
resulting in xerosis, hyperlinear palms, red cheeks, and
anhidrosis were found to have mutations in ALOX12B,
ALOX3E, or TGM1.72
The newborn affected with one of the more severe, generalized types of EHK usually has erythema, blistering,
widespread erosions, and denuded skin (see Fig. 49-6).
Because there is a high frequency of new mutations, the
disease may be unexpected and the diagnosis may be
unknown. Epidermolysis bullosa or staphylococcal
scalded-skin syndrome may be suspected, and the infant
treated with antibiotics. The newborn may require intensive care with fluid and electrolyte monitoring. Specialized skin care can minimize blistering and enhance
healing of erosions and may include lubrication to
decrease friction and mechanical trauma, protective
padding, and specialized wound dressings. The newborn with extensive erosions is prone to bacterial infection and sepsis, and carefully chosen topical and systemic
antibiotics can minimize the extent of infection.
HARLEQUIN ICHTHYOSIS
A dramatic, severe, and often fatal presentation of ichthyosis is that of harlequin ichthyosis (OMIM #242500)
(Fig. 49-11). The child is often premature and born with
massive, shiny plates of stratum corneum separated by
deep, red fissures that tend to form geometric patterns,
as seen in the patched costumes of the harlequin
clowns from the Italian Commedia dellArte dating
from the sixteenth and seventeenth centuries. There
are poorly developed or absent ears and marked ectropion and eclabium. The first report is from the diary of
Rev. Oliver Hart, of Charleston, South Carolina, who
described these features in 1750.73 These children are at
great risk during the neonatal period and often die
lipid transport. Premature termination mutations

underlie harlequin ichthyosis,7779 while missense
mutations in ABCA12 have been identified in a subset
of individuals with less severe ARCI80 (Table 49-5).
NETHERTON SYNDROME
Figure 49-11 Harlequin ichthyosis. Note rudimentary

ears and the distorted appearance as a result of the thick
plates of stratum corneum. This baby died a few days
after birth.
The Ichthyoses
::
shortly after birth. Abnormal water loss through the

skin and poor temperature regulation lead to risk of
fluid and electrolyte imbalance. The infants are also at
risk for infection beginning in the skin, but at the same
time (because of poor temperature regulation) do not
show the usual signs of infection. Normal respiration
may be restricted by the taut skin. Treatment with systemic retinoids during the newborn period can facilitate desquamation of the membrane.74,75 Advances in
neonatal intensive care, together with facilitating desquamation by judicious use of systemic retinoid therapy have led to improvements in survival and to the
use of the name harlequin baby rather than harlequin fetus. Some babies have suffered from failure to
thrive and require tube feeding. The skin of those who
survive the newborn period usually resembles the skin
of those with a severe phenotype of CIE.74,75
In harlequin ichthyosis, normal lamellar granules
are not found; instead, there are small vesicles that
lack internal structure. There is also no evidence of the
lipid lamellae that form between granular and cornified cells as a result of discharge of lamellar granule
contents into the intercellular space.76 The disorder
results from autosomal recessive inheritance of mutations in ABCA12, which codes for an adenosine triphosphate (ATP)-binding cassette (ABC) transporter
involved in lamellar granule secretion and epidermal
Chapter 49
Netherton syndrome (OMIM #256500) is a rare, autosomal recessive disorder characterized by the concurrence of ichthyosis, a structural hair shaft abnormality,
and atopy.81,82 The usual cutaneous manifestation is
ichthyosis linearis circumflexa, a distinctive condition of
generalized hyperkeratosis and polycyclic and serpiginous erythematous plaques with a characteristic,
migratory, double-edged scale at the margins (Fig.
49-12A). At birth, affected children may present with
generalized erythroderma. Infants and children may
have feeding problems, with poor absorption and failure to thrive.83 With atopic dermatitis, there may be
pruritus, and scratching can lead to lichenification at
the flexures. In some patients, the ichthyosis resembles
LI or CIE.5,81 Histopathologic examination is not specific and may show features of hyperkeratosis, psoriasis, and atopic dermatitis. Most patients have a specific
hair shaft abnormality called trichorrhexis invaginata, in
which the distal hair segment is telescoped into the
proximal one, forming a ball-and-socket-like deformity on microscopic examination (Fig. 49-12B). This is
also known as bamboo hair and is due to abnormal
cornification of the internal root sheath. Hair from
multiple areas should be examined, because only
2050% of hair may be affected; the characteristic
abnormality may be more commonly observed on eyebrow hair.84 Trichorrhexis nodosa and pili torti (see
Chapter 88) may also occur. The hair defects may not
be detectable at birth, and may disappear with age.
Atopy in these patients may manifest as atopic dermatitis asthma, or severe food allergy (particularly to
nuts), and marked elevations of serum immunoglobulin (Ig) E may occur. In some patients, generalized
aminoaciduria, mild developmental delay, and
impaired cellular immunity may also be present.85
Figure 49-12 Netherton syndrome. A. Ichthyosis linearis circumflexa showing typical annular lesions. (Used with permission from James Stroud, A MD.) B. Bamboo hair shaft shows features of trichorrhexis invaginata.
527
Section 7
::
Netherton syndrome has been found to be due to

mutations in SPINK5, a gene encoding LEKTI (lympho-epithelial Kazal-type related inhibitor).19 LEKTI is
a serine protease inhibitor that is predominantly
expressed in epithelial and lymphoid tissues, and may
be important in the downregulation of inflammatory
pathways. This discovery highlights the importance of
the regulation of proteolysis in the overlap between
epithelial barrier function and the hypersensitivity of
atopy. Subsequently, LEKTI polymorphisms were
associated with common atopy and atopic dermatitis.86
Prenatal testing for Netherton syndrome using molecular data has been successfully accomplished.87 Tacrolimus ointment, a topical immunomodulator (see
Chapter 221), is effective in common atopic dermatitis
with minimal systemic absorption. However, Netherton syndrome is complicated by an abnormal skin barrier, allowing increased percutaneous absorption and
associated risk for systemic toxic effects. This should
be considered when using topical agents such as tacrolimus, where monitoring of serum levels may be necessary,88 and topical steroids, where iatrogenic Cushing
syndrome has been reported.89
LESS COMMON ICHTHYOSES

ARC
ARC (OMIM #208085) is a rare autosomal recessive,
multisystem disorder characterized by arthrogryposis,
renal tubular dysfunction, and cholstasis often with
ichthyosis and other abnormalities. Mutations have
been found in the VPS33B gene that encodes a protein
involved in intracellular trafficking pathways.90
CEDNIK
Cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome (OMIM #609528) is an
autosomal recessive neurocutaneous syndrome characterized by severe psychomotor retardation, ichthyosis, and palmoplantar keratoderma thought to result
from abnormal lamellar granule maturation and secretion.91 In CEDNIK syndrome, lamellar granules are
retained within the cornified cell layer resulting in
reduced secretion of lipids and proteases into the
extracellular space. This results in impaired barrier formation and decreased corneocyte disadhesion.
CHANARINDORFMAN SYNDROME
528
ChanarinDorfman syndrome (neutral lipid storage disease; OMIM #275630) is an autosomal recessive disorder characterized by accumulation of triglycerides in
the cytoplasm of leukocytes, muscle, liver, fibroblasts,
and other tissues. However, blood lipid levels are normal. To date, approximately 30 patients have been
reported, mainly from the Mediterranean basin. The
ichthyosis is a generalized fine scaling with variable
erythema, resembling congenital ichthyosiform eryth-
roderma. Presentation is often that of a collodion baby

with ectropion and eclabium. Skin changes may evolve
to orangered with brown scale, and are associated
with pruritus. Extracutaneous involvement, which is
variable and may be mild, includes cataracts, decreased
hearing, hepatosplenomegaly with abnormal liver
enzymes and fatty liver, psychomotor delay, myopathy with elevations in serum muscle enzymes, and
neurologic abnormalities.
Histopathology of an oil red O or Sudan III stain of
frozen sections of the skin shows lipid droplets in dermal cells, in the basal layer (and, to a lesser extent,
suprabasally), as well as in the acrosyringia of the
eccrine ducts. Examination of peripheral blood smears
shows lipid vacuoles within granulocytes, eosinophils,
and monocytes, a feature that may also be present in
carriers.92 Mutations in the CGI-58 gene have been
identified.93 CGI-58 belongs to a large family of proteins, most of which are enzymes, and appears to activate adipose-triglyceride lipase in the initial step in
lipolysis of triglycerides. In the absence of CGI-58, triglycerides accumulate.94
CHILD SYNDROME
The CHILD syndrome (OMIM #308050) is a rare disorder consisting of congenital hemidysplasia, ichthyosiform erythroderma, and limb defects, which is found
almost exclusively in females.95 The disorder is related
to X-linked dominant chondrodysplasia punctata (CDPX2),
which also has skin and skeletal abnormalities, but is
distinguished by a sharp midline demarcation of the
psoriasiform ichthyosis, with minimal linear or segmental contralateral involvement. Involvement of the
right side occurs more frequently than the left. There
may be bands of normal skin on the affected side. A
case with bilateral involvement has been described.
Limb defects occur ipsilateral to the ichthyosis and
range from digital hypoplasia to agenesis of the
extremity. There may be punctate calcification of cartilage. Unilateral hypoplasia can involve the central nervous system and cardiovascular, pulmonary, renal,
endocrine, and genitourinary systems. The inheritance
pattern is thought to be X-linked dominant, with the
condition being lethal in males. Peroxisomal deficiency
has been described, and mutations in either of two peroxisomal genes were found to cause CHILD syndrome.
One patient was found to have a mutation in the gene
encoding EBP (3-hydroxysteroid-8-7-isomerase)
(the gene underlying CDPX2)96 and six patients
(including one boy) were found to have mutations in
NSDHL [NAD(P)H steroid dehydrogenase-like protein] encoding a 3-hydroxysteroid dehydrogenase.97
Each enzyme functions in the postsqualene cholesterol
biosynthetic pathway, catalyzing intermediate steps in
the conversion of lanosterol to cholesterol.98
CHONDRODYSPLASIA PUNCTATA
Chondrodysplasia punctata is a clinically and genetically
diverse group of rare diseases, first described by
X-LINKED DOMINANT CHONDRODYSPLASIA PUNCTATA. Happle and coworkers identified
X-linked dominant chondrodysplasia punctata (CDPX2)

(ConradiHnermannHapple syndrome; OMIM
#302960) as a distinct variant characterized by a mosaic
pattern of skin involvement and occurrence almost
exclusively in females, with loss of the gene function
hypothesized to be lethal to males.99 Affected females
have a normal life expectancy and there may be
increased disease expression in successive generations
(anticipation). Occurrence in a male has been observed
in association with a 47,XYY karyotype. CDPX2 presents at birth as a congenital ichthyosiform erythroderma that clears over months and is replaced by linear
hyperkeratosis, follicular atrophoderma, and pigmentary abnormalities. Happle hypothesized that the linear
involvement is due to mosaic X-chromosome inactivation (lyonization). Hair shaft abnormalities and cicatricial alopecia can also occur. Stippled calcifications are
Figure 49-13 Erythrokeratodermia variabilis. Generalized

type with widespread hyperkeratosis and migratory, figurate, red patches.
The Ichthyoses
(autosomal recessive; OMIM #215100) is also known as

peroxisomal biogenesis disorder complementation
group 11 (CG11). It is a rare, multisystem developmental disorder characterized by dwarfism due to symmetric shortening of the proximal long bones (i.e.,
rhizomelia), specific radiologic abnormalities (i.e., the
presence of stippled calcifications of cartilage, vertebral body clefting), joint contractures, congenital cataracts, ichthyosis, and severe mental retardation. Skin
changes are present in approximately 25% of patients.
Patients have low levels of red cell plasmalogens and
accumulation of phytanic acid, starting with normal
levels at birth and increasing to more than 10 times
normal by age 1 year. RCDP is a disorder of peroxisomes, membrane-bound multifunctional organelles
found in all nucleated cells. Their functions vary
with cell type and include a variety of pathways
(e.g., hydrogen peroxide-based respiration, fatty acid
-oxidation, and lipid and cholesterol synthesis)
involving the synthesis and degradation of various
compounds. Hereditary human peroxisomal disorders
are subdivided into disorders of peroxisome biogenesis, in which the organelle is not formed normally, and
those involving a single peroxisomal enzyme. RCDP is
one of the groups of peroxisome biogenesis disorders,
which are characterized by loss of multiple peroxisomal metabolic functions and have been sorted into at
least 12 different complementation groups. Many have
been found to be due to defects in peroxins, factors
required for the import of proteins into the organelle.
RCDP is caused by mutations in PEX7, a gene that
encodes peroxin 7, a receptor required for targeting a
subset of enzymes to peroxisomes.102 Refsum disease,
another peroxisome disorder, exhibits genetic heterogeneity. In Refsum disease due to mutations in PAHX,
the gene for phytanoyl-CoA hydroxylase (PhyH), there
is deficiency of the single peroxisomal enzyme PhyH.
Refsum disease can also result from mutations in
PEX7; fibroblasts from those patients show deficiency
of several peroxisomal enzymes, similar to fibroblasts
from patients with RCDP. It is remarkable that different mutations in the same gene can result in such a
wide spectrum of clinical disease.
punctata (CDPX; OMIM #302950) can involve skin (linear or whorled atrophic or ichthyosiform hyper
keratosis, follicular atrophoderma; may begin as
erythroderma) (Fig. 49-13), hair (coarse, lusterless, cicatricial alopecia), short stature and skeletal abnormalities, cataracts, and deafness. Curry et al studied a
family who had atypical ichthyosis and elevated cholesterol sulfate in two affected males and identified an
X chromosomal deletion (Xp22) that included the gene
for steroid sulfatase.100 There is a cluster of arylsulfatase genes at this location. Mutations in ARSE, the gene
encoding the enzyme arylsulfatase E, were found in
five patients; however, it is possible that the disorder
may also be caused by mutations in adjacent arylsulfatase genes.103 The similarity to warfarin embryopathy
suggests that warfarin embryopathy may be due to
drug-induced inhibition of the same enzyme.
::
RHIZOMELIC CHONDRODYSPLASIA PUNCTATA. Rhizomelic chondrodysplasia punctata (RCDP)
X-LINKED RECESSIVE CHONDRODYSPLASIA PUNCTATA. X-linked recessive chondrodysplasia
Chapter 49
onradi, that share the features of stippled calcificaC

tion of the epiphyses and skeletal changes. They are
characterized by abnormal deposition of calcium in the
areas of enchondral bone formation during fetal development and early infancy. Several forms also include
ichthyosiform changes. Clinical severity ranges from
severe dwarfism and death during infancy to a selflimited radiographic abnormality in others. An autosomal recessive (rhizomelic) type and both X-linked
dominant99 and recessive forms100 have been described.
The validity of the originally described autosomal
dominant ConradiHnermann type has been questioned, because some reported cases were later shown
to belong to the X-linked dominant type, and occurrences previously considered sporadic have subsequently been recognized as resulting from warfarin
(Coumadin) anticoagulant embryopathy.99,101
529
Section 7
::
530
seen in radiographs of areas of endochondral bone formation during childhood but may no longer be visible
after puberty. Stature may be short, with asymmetric
shortening of the legs. Cataracts occur, usually asymmetrically, in about two-thirds of patients. Histochemical staining for calcium may show calcifications within
the epidermis, especially within hair follicles in young
children, which may not be present in older children.104
Mutations in the gene encoding the emopamil-binding
protein (EBP) cause the ConradiHnermannHapple
Syndrome. EBP was first identified as a binding target
for the drug emopamil, a calcium-channel blocker.
It was later found to be 3-hydroxysteroid-8-7isomerase that catalyses an intermediate step in the
conversion of lanosterol to cholesterol.105 How this
defect causes clinical manifestations is unclear.
CONGENITAL RETICULAR
ICHTHYOSIFORM ERYTHRODERMA
This rare disorder, also known as ichthyosis variegata or
ichthyosis en confetti(s), presents as congenital ichthyosiform erythroderma. Small islands of normal appearing skin begin to appear late in childhood. Band-like
parakeratosis, psoriasiform acanthosis and vacuolated,
binuclear upper epidermal keratinocytes with a filamentous perinuclear shell by electron microscopy and
dermal amyloid deposits are seen.106 Normal areas of
skin have been shown to arise from loss of heterozygosity on chromosome 17q via mitotic recombination
of disease-causing mutations in the gene encoding
keratin 10 (KRT10).107
ERYTHROKERATODERMIAS
The erythrokeratodermias are a clinically and genetically
heterogeneous group of disorders characterized by
hyperkeratosis and localized erythema. Within a broad
spectrum of phenotypes, at least two disorders can be
delineated: (1) erythrokeratodermia variabilis and (2)
progressive symmetric erythrokeratodermia. There are
overlapping clinical features and phenotypic variability within these two designations.108
ERYTHROKERATODERMIA VARIABILIS. Ery

throkeratodermia variabilis (OMIM #133200), described
by Mendes da Costa in 1925, is a rare disorder that usually presents at birth or during the first year of life. Both
autosomal dominant and recessive inheritance have
been described.109 At least two distinct clinical presentations can be distinguished. One type (Fig. 49-14) is characterized by generalized, persistent, redbrown
hyperkeratotic plaques, and accentuated skin markings. A second, localized type has involvement that is
limited in extent and characterized by sharply demarcated, hyperkeratotic plaques; these are symmetrically
arrayed and remain relatively fixed for months to years.
In the localized type, there may be considerable variability between affected family members, and the disorder may not be apparent until later in life. Both types
are characterized by striking, sharply demarcated,
Figure 49-14 KID syndrome. Discrete, symmetric hyperkeratotic plaques are present on the face. There is a scarring alopecia.
migratory red patches, which vary in size from a few to
many centimeters. These geographic, figurate red
patches appear or regress over minutes to hours; some
individuals complain of burning at these sites, while in
others they are asymptomatic. The red patches develop
independently of the hyperkeratosis. Systemic retinoid
treatment clears the hyperkeratotic lesions and may
also clear the figurate red patches. The hyperkeratotic
skin lesions may be triggered by trauma to the skin and
the red patches may be triggered by a change in temperature. Palmoplantar hyperkeratosis may be present
in either type, but hair, nails, and mucous membranes
are unaffected. Histopathologic features are nonspecific
and include hyperkeratosis, acanthosis, papillomatosis,
and capillary dilatation. Epidermis involved with
severe papillomatosis and suprapapillary thinning
may result in a church spire appearance.
Several variants have been described. Erythrokeratodermia en cocardes was described in a family in which
the erythematous component was in a target-like
configuration.110 In a possible clinical variant of
erythrokeratodermia en cocardes, erythema gyratum
repens-like erythema (see Chapter 153) was described
in a large kindred.111 Another family with erythema
annulare centrifugum-like lesions (see Chapter 43) has
also been described.112 A child with atypical erythrokeratodermia with neurosensory deafness, bilateral talipes
(clubfoot) deformity, and neuropathy was described in
which erythematous component changed only slowly
over the year.113 Erythrokeratodermia with ataxia
(Giroux-Barbeau type) is an autosomal dominant disorder that presents during infancy with well-defined,
symmetric hyperkeratotic plaques, and underlying erythema distributed over the extensor surface of the
extremities.114 Skin lesions regress during adulthood
while a progressive spinocerebellar ataxia develops.
Both the localized type of erythrokeratodermia variabilis and erythrokeratodermia with ataxia have been
ICHTHYOSIS PREMATURITY
SYNDROME
Polyhydramnion complicates the second trimester in the
ichthyosis prematurity syndrome (OMIM #608649),
resulting in premature delivery of infants with erythrodermic, edematous, caseous scaling skin resembling
excessive vernix caseosa, respiratory distress, and transient peripheral eosinophilia.127 The respiratory signs,
erythema and skin changes resolve, leaving signs of
atopy and dry, scaly skin with follicular accentuation
more pronounced than is seen in keratosis pilaris. Characteristic trilamellar membrane inclusions are seen in the
stratum corneum by electron microscopy. Mutations in
the fatty acid transport protein 4 gene, FATP4 (SLC27)
have been identified in affected members of one family.128
KERATITIS, ICHTHYOSIS, AND

DEAFNESS SYNDROME
The Ichthyoses
mia (OMIM #602036), first definitively described by

Darier in 1911,118 is characterized by well-demarcated,
erythematous, hyperkeratotic plaques that are symmetrically distributed over the extremities and buttocks, and often the face.119 The trunk tends to be
spared, but palms and soles may be involved. The
plaques appear shortly after birth, progress slowly
during the first few years, and then stabilize in early
childhood. The plaques usually remain stable in location and appearance but may undergo partial regression at puberty. The variable, migratory erythema that
defines erythrokeratodermia variabilis is absent. The
disorder is inherited in an autosomal dominant pattern
but with incomplete penetrance and variable expressivity. A mutation in the cornified envelope protein
loricrin was found in one family,120 although the diagnosis (and the distinction from erythrokeratodermia
variabilis) has been disputed.121 Recently, a mutation in
GJB4, which encodes connexin 30.3, was found in
patients from the Netherlands with either progressive
symmetric erythrokeratodermia or erythrokeratodermia variabilis, demonstrating that both clinical presentations can arise from the identical mutation.122
::
PROGRESSIVE SYMMETRIC ERYTHROKERATODERMIA. Progressive symmetric erythrokeratoder-
type, with psoriasiform plaques, have been postulated.125 Mutations in the MBTPS2 gene result in
impaired cholesterol homeostasis and ability to cope
with endoplasmic reticulum stress.126
Chapter 49
mapped to a common region (chromosome 1p34-35).115

Subsequently, mutations in GJB3, the gene encoding
connexin 31, were identified in four families with
erythrokeratodermia variabilis.116 Connexins are a
family of proteins that aggregate to form gap junctions,
which are important channels for intercellular communication. This intercellular signaling system is crucial
for maintaining tissue homeostasis, growth control,
development, and synchronized response of cells to
stimuli. The identification of connexin mutations as the
cause of erythrokeratodermia variabilis implicates this
pathway in epidermal differentiation and in the mechanism of skin response to external factors. Different
mutations in the same connexin 31 gene (GJB3) have
been found in other patients with deafness and also in
some with peripheral neuropathy. Mutations in the
related connexin 30.3 (GJB4) have been found in other
families with erythrokeratodermia variabilis117; in the
variants with erythema gyratum repens-like erythema
that have been studied, connexin 30.3 mutations
appear to be found exclusively.109
KID syndrome (OMIM #148210) is a rare disorder

characterized by keratitis (with progressive corneal opacification), ichthyosis, and deafness (neurosensory).
Involvement of multiple ectodermal tissues qualifies KID
syndrome as an ectodermal dysplasia. Most cases are
compatible with autosomal dominant inheritance. However, occurrence in an inbred sibship suggests the existence of an autosomal recessive form. The disease is
characterized by discrete erythematous plaques, and
there may be mild, generalized hyperkeratosis. The
distinctive plaques may have a discrete border and a verrucous appearance with crusting and may be conspicuously figurate and symmetric on the face (Fig. 49-15).
ICHTHYOSIS FOLLICULARIS,
ALOPECIA, AND PHOTOPHOBIA
SYNDROME
Noninflammatory follicular hyperkeratosis, total nonscarring alopecia, photophobia, and characteristic
facies are seen in the IFAP syndrome (OMIM #308205).
Less constant features include recurrent respiratory
infections, nail abnormalities, angular cheilitis, keratotic plaques on the extensor surface of the extremities,
inguinal hernia, cryptorchidism, short stature, seizures, and psychomotor developmental delay.123,124
Inheritance is thought to be X-linked recessive,
although an autosomal dominant form and a third
Figure 49-15 Chondrodysplasia punctata. Newborn

child. Generalized erythroderma with scales forming a
whorled pattern.
531
Section 7
::
Furrowing about the mouth results in characteristic

facies. There may be prominent follicular hyperkeratosis,
which can result in a scarring alopecia of the scalp.
Leather-like palmar/plantar keratoderma is almost
always seen.129 Several authors have suggested that
because the plaques do not scale, this disorder is more
accurately designated an erythrokeratodermia rather
than an ichthyosis.5,129 Descriptions of nail changes vary
from absent, delayed appearance after birth, atrophic, or
brittle to thickened, with loss of or rough cuticles, subungual hyperkeratosis, and leukonychia. The teeth may
be small. Auditory evoked potential studies allow detection of the hearing deficit in infancy. Keratitis may
develop. Affected individuals can have an increased susceptibility to bacterial, fungal, or viral infections. Squamous cell carcinoma of the skin and tongue has also been
reported. In contrast to many other ichthyotic conditions,
treatment of these patients with oral retinoids has been
reported to be of little benefit and possibly to exacerbate
the corneal neovascularization.
Dominant mutations in GJB2, the gene encoding
connexin 26, have been detected in sporadic cases and
one family with KID syndrome. Functional studies of
cells expressing mutated connexin 26 demonstrated
failure of a fluorescent tracer to pass through gap junction channels to neighboring cells, consistent with disruption of intercellular communication.21 Different
mutations in the same gene (GJB2) encoding connexin
26 have also been found in a family with a mutilating
palmoplantar keratoderma (Vohwinkles disease) and
deafness (without ichthyosis)130 (discussed in Chapter
50), and a mutation in GJB6, the gene for connexin 30,
has been demonstrated in one child with KID syndrome.131 The identification of mutations in the genes
encoding a variety of connexin proteins has highlighted the role of connexin-mediated intercellular
communication through gap junctions in the development and maintenance of ectodermal tissues. Connexins 26, 30, and 31 are expressed in the stratified
epithelia of the cochlea and epidermis, and abnormalities in these proteins can cause sensorineural hearing
impairment and/or skin disorders.20
KERATOSIS LINEARIS WITH

ICHTHYOSIS CONGENITA AND
SCLEROSIS KERATODERMA
Keratosis linearis with ichthyosis congenital and sclerosing keratoderma (KLICK) syndrome (OMIM
#601952) is a rare ichthyosis with palmoplantar keratoderma, constricting bands and flexural deformities of
the fingers, and linear keratotic papules at the flexures.
Mutations in the proteasome maturation protein gene
(POMP) suggest a role for the proteasome in the process of cornification.132
MEDNIK
532
Mental retardation, enteropathy, deafness, peripheral

neuropathy, ichthyosis, and keratodermia (MEDNIK)
syndrome is an autosomal recessive disorder described
in a Quebec population with a founder mutation in the

AP1S1 gene that encodes a protein involved in protein
trafficking by intracellular vesicles.133
MULTIPLE SULFATASE DEFICIENCY

Multiple sulfatase deficiency (OMIM #272200) is a rare
autosomal recessive disorder that is characterized by a
deficiency of several sulfatases, which results in the
accumulation of sulfatides, glycosaminoglycans,
sphingolipids, and steroid sulfates in tissues and body
fluids.134 The activity of both lysosomal (arylsulfatases
A and B) and microsomal (arylsulfatase C/steroid sulfatase of X-linked ichthyosis) arylsulfatases is impaired.
The disorder is a composite of the clinical features of
both metachromatic leukodystrophy and of a mucopolysaccharidosis. Clinical features include neurologic
deterioration, skeletal abnormalities, facial dysmorphism, and ichthyosis resembling that seen in X-linked
steroid sulfatase deficiency. This disorder has been
proposed to be due to a defect, common to all sulfatases, in posttranslational protein modification that is
required for generating a catalytically active enzyme.135
The gene coding for sulfatase modifying factor
1 (SUMF1), which generates a unique amino acid
derivative, C-formylglycine, necessary for catalytic
activity of all sulfatases, is mutated in individuals with
multiple sulfatase deficiency.136,137
NEONATAL ICHTHYOSIS WITH

SCLEROSING CHOLANGITIS
Neonatal cholestatic jaundice and mild ichthyosis with
fine, white scales are the presenting signs in the NISCH
syndrome (OMIM #607626). Hypotrichosis with scarring alopecia affecting the scalp and eyebrows, enamel
dysplasia and intracytoplasmic vacuoles within keratinocytes that do not stain with oil red O are also seen.138
In addition to different staining properties, the syndrome differs from ChanarinDorfman syndrome in
the absence of ocular or muscle findings and of fatty
liver. Mutations in CLDN1 the gene coding for claudin-1 have been identified.139
PEELING SKIN SYNDROME

The peeling skin syndrome (OMIM #270300) is an autosomal recessive disorder characterized by lifelong
peeling of the stratum corneum. It may be associated
with pruritus, short stature, and easily removed anagen hairs. Low plasma tryptophan levels and aminoaciduria have also been reported.140 Traupe suggested
that there are two types of peeling skin syndrome.5
Type A, which is noninflammatory and asymptomatic,
is characterized by generalized peeling in thin superficial flakes of differing size and shape. On electron
microscopy, the intracellular separation occurs in the
stratum corneum, within the corneocytes and not
between adjacent cells. Intercellular electron-dense
globular deposits representing abnormal lipids have
The Ichthyoses
Refsum disease (heredopathia atactica polyneuritiformis; OMIM #266500) is a rare, progressive, degenerative disorder of lipid metabolism resulting from the
failure to break down dietary phytanic acid and its
subsequent accumulation in tissues. This autosomal
recessive condition affects mostly the Scandinavians
and populations originating from Northern Europe.
Clinical manifestations include retinitis pigmentosa,
peripheral neuropathy, cerebellar ataxia, cranial nerve
dysfunction (neural deafness, anosmia), miosis, electrocardiographic abnormalities, cardiomyopathy, renal
tubular dysfunction, and skeletal abnormalities
(epiphyseal dysplasia). Ichthyosis, which is variable,
generally develops in adulthood after the neurologic
and ophthalmologic manifestations. Often there are
small white scales over the trunk and extremities
resembling IV. Routine hematoxylin and eosin histologic examination shows variably sized vacuoles in the
epidermal basal and suprabasal cells, which correspond to lipid accumulation seen with lipid stains of
frozen sections.146
Phytanic acid (a 20-carbon, branched-chain fatty
acid) is derived from a variety of dietary sources
including dairy products, ruminant fats, and chlorophyll-containing foods, although chlorophyll-bound
phytol cannot be absorbed in man. Phytanic acid and
other chlorophyll metabolites bind the retinoid X
receptor (RXR), as does its natural ligand, 9-cis-retinoic
acid, and they may be physiologically active in coordinating cellular metabolism through RXR-dependent
::
REFSUM DISEASE
signaling pathways147; however, the role of RXR in the

pathogenesis of Refsum disease is unclear. The disease
is caused by a deficiency of PhyH, a peroxisomal protein that catalyzes the -oxidation of phytanic acid.
This is the first step in the breakdown of phytanic acid,
and PhyH deficiency leads to the accumulation of phytanic acid in the serum and tissues, where it substitutes
for the fatty acids normally present. While mutations
in PAHX, the gene encoding PhyH are responsible for
most cases of Refsum disease,148 there is genetic heterogeneity.149 Some affected patients have mutations in
the PEX7 gene, which is the same gene mutated in
RCDP (see above). Refsum disease is distinguished
from infantile Refsum disease, a fulminant generalized
peroxisomal biogenesis disorder in which young children present with severe neurologic abnormalities,
mental retardation, hepatomegaly, and dysmorphic
features in addition to the other signs of adult Refsum
disease.150
The diagnosis can be made by detection of elevated
levels of plasma phytanic acid. In children who do not
have elevated plasma levels of phytanic acid, the diagnosis may be made by measuring PhyH activity in cultured fibroblasts.147 Treatment includes dietary
restriction of foods containing phytanic acid and its
precursors, and can include plasmapheresis or lipapheresis. In the clinical setting of a delayed onset of
ichthyosis in association with neurologic impairment,
this disease should be considered since therapy can
arrest progression.
Chapter 49
been observed localized to the stratum corneum.141 An

acral variant (OMIM #609796), in which peeling was
limited to over the hands and feet, has been
described.142,143 Abnormal keratohyalin granules
were seen by electron microscopy. Mutations in the
gene coding for transglutaminase 5, a ubiquitously
expressed transglutaminase with widespread expression in skin, have been identified in two families with
the acral form.143 In contrast, type B presents with congenital ichthyotic erythroderma and evolves into erythematous, scaling, migratory patches. This type is
pruritic and may be associated with elevated levels of
IgE, aminoaciduria, and short stature. The stratum corneum is easily separated mechanically from the lower
epidermis, and histologically the split, which occurs
intercellularly, is seen between the stratum corneum
and the granular layer. On electron microscopy,
electron-dense, irregularly vacuolated bodies have
been observed in the granular layer, but observations
have been variable.144 Although the type B is clinically
similar to Netherton syndrome, mutations in SPINK5
have not been identified and the protein product of
SPINK5 is overexpressed. Human tissue kallikreins
and elevated stratum corneum protease activity have
been demonstrated; this is thought to result in excessive desquamation and loss of barrier function.145 A
variant, clinically similar to the inflammatory type B
but with associated hair shaft abnormalities, has been
described.144
RUD SYNDROME
Rud syndrome (OMIM #308200) is a poorly characterized disorder, probably of recessive inheritance, that
includes epilepsy, mental retardation, infantilism, congenital ichthyosis, and retinitis pigmentosa. Steroid
sulfatase deficiency has been reported in some patients.
Traupe critically reviewed the literature and suggested
that the clinical constellation usually labeled Rud syndrome is associated with steroid sulfatase deficiency
(X-linked recessive ichthyosis) and likely reflects a heterogeneous group of disorders; because both the neurologic involvement and the ichthyosis are ill defined,
the term Rud syndrome should be abandoned.5
SJGRENLARSSON SYNDROME
In 1957, Sjgren and Larsson reported on 13 families
from north Sweden with a syndrome of congenital ichthyosis, spastic paralysis, and mental retardation.
SjgrenLarsson syndrome (SLS; OMIM #270200) is a
rare, autosomal recessive disorder that presents at
birth with an ichthyosis that may range from fine scaling to generalized hyperkeratosis. Erythema may be
present at birth but tends to gradually clear by 1 year
of age. Collodion-like membranes are rarely seen. The
ichthyosis manifests as fine scale, large scale, or a
thickening of the stratum corneum without scale and
may be pruritic. Thickened areas may be yellow to
brown in color and have a lichenified appearance with
533
Section 7
Figure 49-16 Trichothiodystrophy hair shows tiger-tail banding (A) under polarization, which is not observed with
normal hair (B).
::
accentuated skin markings. The most involved areas

are the sides and back of the neck, lower abdomen, and
flexures. Hair, nails, and the ability to sweat are generally normal.151 During the first 2 to 3 years, neurologic
manifestations of spastic diplegia or tetraplegia and
mental retardation develop and can be accompanied
by speech defects and seizures. A characteristic ophthalmologic finding is the presence of glistening white
dots in the macula of the retina; these occur after 1 year
of age and may not be present in all patients. Histologic findings of hyperkeratosis, papillomatosis, acanthosis, and a mildly thickened granular layer are
nonspecific. Electron-microscopic examination of the
skin shows lamellar membranous inclusions in the
granular and cornified cells.
Rizzo et al linked SLS to fatty alcohol:NAD oxidoreductase (FAO) deficiency. FAO is a complex enzyme with
two separate proteins that sequentially catalyze the oxidation of fatty alcohol to fatty aldehyde and subsequently to fatty acid. Further work identified the fatty
aldehyde dehydrogenase (FALDH) activity in cultured
fibroblasts from patients with SLS component as the
affected component of FAO in SLS. FALDH is a microsomal enzyme that catalyzes the oxidation of mediumand long-chain aliphatic aldehydes derived from
metabolism of fatty alcohol, phytanic acid, ether glycerolipids, and leukotriene B4.152 Mutations found in the
FALDH gene (FALDH, ALDH10, recently renamed
ALDH3A2) confirmed the role for this enzyme in the etiology of this disorder and the importance of this pathway for normal desquamation.153 Most mutations are
specific to families, although several common mutations suggest founder effect or favored sites for mutation.154 The identification of decreased fibroblast FAO
activity in a family with atypical cutaneous findings
(lack of ichthyosis or discrete plaques rather than generalized ichthyosis) has expanded the spectrum of clinical
phenotypes associated with abnormal FAO activity.155
TRICHOTHIODYSTROPHY
534
Trichothiodystrophy (TTD) (OMIM #601675) is an autosomal recessive disorder that includes a broad spectrum of clinical phenotypes linked by the characteristic
features of sulfur deficient, brittle hair that exhibits

tiger tail banding when viewed under polarizing
microscopy (Fig. 49-16).156 Hair shaft abnormalities
include trichoschisis, trichorrhexis nodosa-like defects
and ribboning157,158 (see also Chapter 139). Patients
may have photosensitivity, ichthyosis, intellectual
impairment, short stature, microcephaly, characteristic
facial features (protruding ears, micrognathia) recurrent infections, cataracts, dystrophic nails, and other
features.159 The spectrum of clinical involvement is
broad, ranging from only hair to severe multisystem
abnormalities. A survey of 112 cases reported in the literature found ichthyosis (65%) as the most common
skin finding, followed by photosensitivity (42%). The
photosensitivity can range from subtle to severe. Of
the patients with ichthyosis, about one-third presented
with a collodion membrane at birth. Collodion newborns may have an erythroderma which decreases
over weeks with evolution into a generalized ichthyosis, usually without erythema, which varies from fine,
translucent scaling to large, dark yellowbrown hyperkeratosis (Fig. 49-17B).160,161 Some largely resolve and
are left with mild ichthyosis. There may be flexural
sparing and palmoplantar keratoderma. Nail findings
are found in over half of the patients and include dystrophic nails (ridging, splitting) (Fig. 49-17A), hypoplasia, brittle nails, and koilonychia.159 Ectropion
usually does not occur.
A series of mnemonics have been used to describe
the constellation of findings as BIDS (brittle hair, intellectual impairment, decreased fertility, and short stature); patients who also have ichthyosis have been
called IBIDS, and with the addition of photosensitivity,
PIBI(D)S has been used.162 However, these terms do
not account for the other multisystem findings commonly present.
The majority of TTD patients have a defect in XPD
(ERCC2). A few have mutations in XPB (ERCC3) or
TTDA (GTF2H5), genes which are components of the
transcription factor IIH (TFIIH) that regulates both
DNA repair and transcription. Some TTD patients
have mutations in TTDN1.163 Although many TTD
patients have photosensitivity, in contrast to xeroderma pigmentosum, these photosensitive patients
have not been observed to be at high risk for the
The development of ichthyosis in adulthood can be a

manifestation of systemic disease, and has been
described in association with malignancies, drugs,
endocrine and metabolic disease, malnutrition, HIV
and other infections, and autoimmune conditions.164,165
The granular layer is often attenuated in this disorder
and the scale often resembles to that seen in mild IV.
While Hodgkin disease is the most common malignancy reported with acquired ichthyosis, non-Hodgkin lymphomas and a variety of other malignancies
have also been observed.166 Histology may be diagnostic in acquired ichthyosis associated with mycosis fungoides.167 Skin involvement may follow the course of
malignancy and clear with effective cancer treatment.
Acquired ichthyosis is commonly seen in association
with AIDS; ichthyotic or xerotic skin has been observed
in up to 30% of AIDS patients.168 A study of HIV-1-positive intravenous drug users found acquired ichthyosis
occurred only after profound helper T cell depletion,
more frequently with coinfection with human T cell
leukemia/lymphoma virus type II (HTLV-II), and suggested that it may be a marker for concomitant infection with both viruses.169
In acquired ichthyosis occurring in association with
sarcoidosis, skin biopsy can be diagnostic, showing
noncaseating granulomas in the dermis.170 Acquired
ichthyosis may be a marker of autoimmune disease,
occurring with systemic lupus erythematosus, dermatomyositis, mixed connective tissue disease, and eosinophilic fasciitis.171,172 It has been described in bone
The Ichthyoses
ACQUIRED ICHTHYOSIS
marrow transplant recipients, where it may be related

to graft-versus-host disease.173
While occurrence in association with cholesterollowering agents (nicotinic acid, triparanol) highlights
the relationship between cholesterol metabolism
and normal desquamation, acquired ichthyosis has
been observed with a variety of drugs, including
cimetidine, clofazimine, hydroxyurea, cholesterol-lowering agents, and others.174178 Kava is a psychoactive
beverage made from the root of a pepper plant and
used for thousands of years by Pacific Islanders. Heavy
kava drinkers can acquire a reversible ichthyosiform
eruption called kava dermopathy. In Western nations,
kava is sold in health food stores as a relaxant.179
::
evelopment of skin cancer. Nucleotide excision repair

d
is one normal cellular mechanism by which structural
DNA damage (e.g., ultraviolet-induced cyclobutane
pyrimidine dimers) is removed and repaired (see
Chapters 110 and 139). TFIIH is involved in the initiation of transcription and also in nucleotide excision
repair, and consists of a complex of proteins including
the XPD and XPB proteins. In the vicinity of the damage, these two helicase subunits of TFIIH unwind the
DNA in opposite directions.
Chapter 49
Figure 49-17 Trichothiodystrophy. A. The nails are thinned and brittle, with onychoschizia, cracking, and irregular transverse depressions of the dorsal surface. B. Skin involvement in TTD can vary from absent to severe ichthyosis. This patient
has a more severe ichthyotic involvement with dark colored, adherent scale. Note involvement of the antecubital fossae.
PITYRIASIS ROTUNDA
Sharply demarcated, round or oval scaly patches with
hypo- or hyperpigmentation are seen in pityriasis rotunda.
Although this uncommon disorder is usually acquired,
occasional familial cases have been described.180
RETICULATED PAPILLOMATOSIS OF
GOUGEROT AND CARTEAUD
Confluent and reticulated papillomatosis of Gougerot and
Carteaud is an uncommon but distinctive acquired ichthyosiform dermatosis seen in young adults and characterized by persistent brown, scaly macules, papules,
patches, and plaques. Lesions tend to be localized predominantly on the neck, upper trunk (intermammary
and interscapular regions), and axillae where they
tend to be confluent and become reticulated towards
the periphery (Fig. 49-18). The lesions bear a clinical
resemblance to tinea versicolor, a skin infection with
Pityrosporum species. A variety of treatment approaches
have been reported, including topical (keratolytics,
derivatives of vitamin A and D, antimicrobials) and
systemic (antibiotics, retinoids) agents. Minocycline
has been suggested as a first-line treatment; successful
retreatment of recurrences supports the concept that
this condition is an abnormal response to an infection
or inflammation.181,182
535
Section 7
::
536
Figure 49-18 Confluent and reticulated papillomatosis of Gougerot and Carteaud. A. Dark, scaly papules and plaques on
the trunk, which become reticulated towards the periphery. B. Close-up view of the distinctive, scaly, reticulated papules
and plaques. (Courtesy of Andrew Montemarano, DO, and Stephen Krivda, MD.)
TREATMENT
Current therapies for the inherited ichthyoses are
symptomatic and focus on hydration, lubrication, and
keratolysis.183,184 Ichthyotic skin, even if thickened, has
a decreased barrier function and increased transepidermal water loss. Because pliability of the stratum
corneum is a function of its water content, hydration
can soften the surface of the skin. In moist, humid climates, most ichthyoses improve, and mild ichthyoses
(e.g., IV) may undergo extensive clearing. Moistening
the skin with, for example, long baths can hydrate it.
Well-hydrated areas of hyperkeratosis can more easily
be thinned with mild abrasives (sponges, buff puffs,
pumice stones, etc.). Addition of bath oils or application of lubricants before drying can prolong the hydration and softening. Depending on the ichthyosis and
environmental conditions, individual patients may
prefer specific lubricating agents, which can take the
form of lotions, creams, oils, ointments, or petrolatum.
In dry climates and winter months, humidifiers can be
used to create a more hospitable environment.
Keratolytic agents are used to enhance corneocyte
desquamation and thereby remove scale and thin
hyperkeratotic stratum corneum. There are many commercially available keratolytic creams and lotions containing urea, salicylic acid, or -hydroxy acids (e.g.,
lactic acid, glycolic acid). Urea may function by its
capacity to bind water. Propylene glycol (4060% in
water), with or without occlusion, can also be effective
in scale removal. Occlusion can effectively increase
skin hydration and facilitate desquamation; it can also

enhance the effect of keratolytic agents. Special care
should be taken when using extensive areas of occlusion with keratolytic agents and in individuals who
may be heat intolerant. Topical retinoid or vitamin D
preparations may also be effective but can be irritating
in some patients. The markedly impaired barrier function in ichthyosis should be considered when using
topical preparations over large areas of body surface.
For example, widespread use of topical salicylic acid
preparations can lead to significant absorption, intoxication (e.g., nausea, tinnitus, dyspnea, hallucinations),
and even death.185 Children are at greater risk because
they have a greater body surface area per unit weight
than adults, a situation that effectively heightens the
possibility of developing systemic toxicity from topicals. Although the use of topical retinoids in most of
the ichthyoses appears to be safe,186 the abnormal skin
barrier should be considered when treating concomitant dermatoses in ichthyosis patients. Topical 0.1%
tacrolimus ointment or 1% pimecrolimus cream is
effective in atopic dermatitis with minimal systemic
absorption. However, the atopic dermatitis of Netherton syndrome is complicated by a defective ichthyotic
skin barrier. The defective barrier is associated with
increased percutaneous absorption and risk for systemic toxic effects. This should be considered when
using topical agents such as tacrolimus, pimecrolimus,
or topical steroids, where increased systemic absorption has been observed and monitoring of serum levels
may be necessary.88,89
The Ichthyoses
Molecular diagnosis is preferred when possible. Alternative methods, including fetoscopy and fetal skin
biopsy, are limited to later times in pregnancy, harbor a
::
PRENATAL DIAGNOSIS
risk of fetal mortality, and are rarely performed.189

When it is possible to do prenatal diagnosis by molecular analysis of a fetal sample, it is optimally performed
early in pregnancy. This can be done with chorionic
villous sampling in the first trimester (1012 weeks
after last menstrual period) or by amniocentesis in the
second trimester190 in disorders where the underlying
genetic defect is known and the specific mutation in
the family has been identified. Prenatal diagnosis by
mutational analysis has been accomplished in a number of the ichthyoses. If a specific mutation has not
been identified, in some circumstances where there is
an appropriate family structure, prenatal diagnosis can
be done using linkage analysis. Prenatal diagnosis of
X-linked recessive ichthyosis by FISH analysis191 and
of TTD by defective DNA repair capacity192 has been
reported. In SLS, the diagnosis can be made by assay of
enzyme activity in cultured amniocytes, even if the
mutation in the ALDH10 gene is undefined. Preimplantation genetic diagnosis is a reasonable alternative, and has been accomplished for many inherited
disorders, including LI and EHK (S. Bale, personal
communication). The procedure requires that the couple undergo in vitro fertilization to obtain embryos.
The embryos are then screened by molecular methods
to detect the mutation that is segregating in the family.
Only those embryos that screen negative for the mutation are selected and then can be used for implantation
in the uterus to achieve pregnancy. Noninvasive methods of molecular diagnosis (evaluation of fetal DNA
circulating in the mothers blood) offer the potential
for the future.188 For autosomal recessive disorders
where the mutation is known (e.g., LI and SLS), carrier
detection may be performed for at-risk relatives.
The Foundation for Ichthyosis and Related Skin
Types provides support and information for affected
individuals, family members, friends, and health care
providers. (FIRST, Tel: 800-545-3286; http://www.first
skinfoundation.org/; e-mail: info@ firstskinfoundation.
org.)
GeneTests (http://www.genetests.org/) provides
disease reviews, genetic testing resources, and educational materials.
Online Mendelian Inheritance in Man, OMIM,
(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=
OMIM) (trademark Johns Hopkins University), a catalog of human genes and genetic disorders, is a useful
reference with links to additional resources.
The National Registry for Ichthyosis and Related Disorders is a resource for investigators to improve diagnosis and treatment of these disorders (University of
Washington, Dermatology, Box 356524, 1959 NE Pacific
St., Seattle, WA 98195-6524 Tel: 1-800-595-1265; http://
www.skinregistry.org/; e-mail: info@skinregistry.org).
Chapter 49
Another risk to children is that in several types of

ichthyosis nutritional requirements may be high, and
inadequate nutrition can lead to failure to thrive. This
was thought to be related to the large turnover of scale;
however, recent studies suggest energy loss from
impaired barrier function is the cause.187 Some patients
with ichthyosis (particularly LI and CIE) have
decreased sweating with heat intolerance. It is important for the parents of a newborn with ichthyosis to be
aware of the possibility of decreased sweating and to
be attentive for signs of heat intolerance, such as flushing and lethargy, particularly during hot weather and,
as the child grows, during exercise. Avoiding hot environments, carrying spray bottles with water to moisten
the skin and cool it through evaporation, and cooling
vests can minimize heat stress.
Systemic retinoid therapy with isotretinoin or acitretin (see Chapter 228) can induce dramatic improvement in many ichthyoses and is particularly useful in
LI, CIE, and erythrokeratodermia variabilis. The decision to initiate systemic retinoid therapy should be
weighed carefully, because once the drug is started,
continued benefit usually requires chronic therapy.
Treatment of the harlequin newborn with systemic
retinoid therapy during the newborn period can be
lifesaving due to enhanced desquamation of a constricting membrane. Retinoic acid metabolism blocking agents, which increase endogenous retinoid levels,
offer a possible alternative.188
Fungal infections are common, both of skin and nails,
and are often undiagnosed because of the generalized
scaling. A high index of suspicion can help diagnose tinea
corporis, capitis, or versicolor where the only symptom
may be localized pruritus and the only sign a difference
in the character of scale or a localized area of alopecia.
The management of EHK varies with the clinical type.
Areas of thick, hard hyperkeratosis, which are not pliable
and have a hard rough surface, are prone to mechanical
trauma. In patients with the hystrix type of porcupinelike hyperkeratosis, the rough surface causes high traction with objects moving across the skin surface, which
tend to catch on the hyperkeratotic horn and peel it off.
Topical agents such as lubricants and keratolytics can
reduce the thickened, rough areas and help to minimize
blistering and erosion. In contrast, patients with erythroderma and peeling, who do not have the thick areas of
hyperkeratotic spines, have less need for keratolytics but
still need lubricants. Acute exacerbations may occur from
skin infections. Bacterial infection of the skin is common,
often leads to enhanced blistering, and may require frequent therapy with topical and oral antibiotics. In patients
with extensive involvement, systemic retinoid therapy
can be dramatically effective in decreasing the hyperkeratosis and the frequency of infections. Because these drugs
can enhance blistering in EHK patients, they should be
administered carefully and started at low doses.
KEY REFERENCES
5. Traupe H: The Ichthyoses: A Guide to Clinical Diagnosis, Genetic
Counseling, and Therapy. Berlin, Springer-Verlag, 1989
537
Section 7
::
9. Oji V et al: Revised nomenclature and classification of

inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Soreze 2009. J Am Acad Dermatol 2010
18. Lefevre C et al: Mutations in a new cytochrome P450 gene
in lamellar ichthyosis type 3. Hum Mol Genet 15:767, 2006
21. Richard G et al: Missense mutations in GJB2 encoding
connexin-26 cause the ectodermal dysplasia keratitisichthyosis-deafness syndrome. Am J Hum Genet 70:1341,
2002
22. Smith FJ et al: Loss-of-function mutations in the gene
encoding filaggrin cause ichthyosis vulgaris. Nat Genet
38:337, 2006
33. Sandilands A et al: Filaggrin in the frontline: Role in skin
barrier function and disease. J Cell Sci 122:1285, 2009
48. Bernhardt M, Baden HP: Report of a family with an
unusual expression of recessive ichthyosis. Review of 42
cases. Arch Dermatol 122:428, 1986
49. Fischer J: Autosomal recessive congenital ichthyosis. J
69. Ozturk A et al: A retrospective study on 16 collodion
babies. Turk J Pediatr 39:55, 1997
72. Vahlquist A et al: Genotypic and clinical spectrum of selfimproving collodion ichthyosis: ALOX12B, ALOXE3,
and TGM1 mutations in Scandinavian patients. J Invest
Dermatol 130:438, 2010
79. Thomas AC et al: ABCA12 is the major harlequin ichthyosis gene. J Invest Dermatol 2006
87. Sprecher E et al: The spectrum of pathogenic mutations
in SPINK5 in 19 families with Netherton syndrome:
Chapter 50 :: Inherited Palmoplantar Keratodermas

:: Mozheh Zamiri,
Maurice A. M. van Steensel, &
Colin S. Munro
INHERITED PALMOPLANTAR KERATODERMAS AT A GLANCE18
Palmoplantar keratoderma (PPK) is chronic
and pathological thickening, predominantly
due to hyperkeratosis, of the hairless skin of
palms and soles.
PPK may be acquired in inflammatory skin
diseases such as eczema, psoriasis, and
lichen planus, and has been reported as a
paraneoplastic phenomenon.
Genetically determined PPKs are a
heterogeneous group of individually
rare disorders inherited by a variety of
mechanisms or occurring sporadically.
PPK may form part of ectodermal syndromes
or be associated with other systemic
anomalies. Important associations of specific
PPKs include cardiomyopathy, impaired
hearing, neuropathy and neurodevelopmental
defects, and esophageal cancer.
538
Implications for mutation detection and first case of prenatal diagnosis. J Invest Dermatol 117:179, 2001
98. Herman GE: Disorders of cholesterol biosynthesis: Prototypic metabolic malformation syndromes. Hum Mol
Genet 12(Spec No. 1):R75-R88, 2003
116. Richard G et al: Mutations in the human connexin gene
GJB3 cause erythrokeratodermia variabilis [see comments]. Nat Genet 20:366, 1998
122. van Steensel MA et al: The missense mutation G12D
in connexin30.3 can cause both erythrokeratodermia
variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia of Gottron. Am J Med Genet A
149A:657, 2009
154. Rizzo WB, Carney G: Sjogren-Larsson syndrome: Diversity of mutations and polymorphisms in the fatty aldehyde dehydrogenase gene (ALDH3A2). Hum Mutat 26:1,
2005
159. Faghri S et al: Trichothiodystrophy: A systematic review
of 112 published cases characterises a wide spectrum of
clinical manifestations. J Med Genet 45:609, 2008
165. Patel N et al: Acquired ichthyosis. J Am Acad Dermatol
55:647, 2006
184. DiGiovanna JJ, Robinson-Bostom L: Ichthyosis: Etiology,
diagnosis, and management. Am J Clin Dermatol 4:81,
2003
187. Moskowitz DG et al: Pathophysiologic basis for growth
failure in children with ichthyosis: An evaluation of
cutaneous ultrastructure, epidermal permeability barrier
function, and energy expenditure. J Pediatr 145:82, 2004
The mechanisms of inherited PPK include altered

differentiation arising from defects in synthesis,
distribution or function of structural components
such as intermediate filaments, desmosomes and
gap junction proteins, or altered inflammatory
responses.
The severity of palmoplantar hyperkeratosis
varies from inconvenience to major functional
and social disability. Plantar pain in focal
keratoderma is one of the most debilitating
features, with hyperhidrosis and secondary
dermatophyte infection contributing to
symptoms.
Treatment is unsatisfactory, as it relies largely on
physical treatments and appropriate foot care, but
oral retinoids are of value in some cases.
EPIDEMIOLOGY
Inherited palmoplantar keratodermas are individually rare; the prevalence of epidermolytic keratoderma in Northern Ireland was 4.4 per 100,000.9
Autosomal recessive keratodermas may occur with
locally high prevalence in sequestered populations or
communities amongst whom consanguineous union
is common.
Chapter 50
::
Inherited Palmoplantar Keratodermas
Palmoplantar skin is structurally specialized,10 with

absence of hair and increased epidermal thickness and
rugosity, features necessary to cope with increased friction and mechanical stress. Dermatoglyphics together
with eccrine sweat also enhance grip. Localized palmoplantar hypertrophy (callus) is a physiological
response to sustained friction, for example, from illfitting footwear or manual work. In the inherited PPKs,
excessive epidermal thickening is the result of a broad
range of pathogenic pathways.
Many keratodermas are associated with defects of
keratinocyte structure. The major structural component of keratinocytes is the 10-nm (intermediate) filament cytoskeleton. Keratins are a family of rod-like
proteins, expressed in pairs in a tissue and differentiation specific manner, which initially dimerize then
assemble to form multimeric intermediate filaments.7
Defects in individual keratins affect skin in a distribution corresponding to the expression pattern of the
particular keratin.3 Keratin 9 (K9) is specific to palmoplantar skin, although its likely partner in these sites,
keratin 1, is also expressed in hair-bearing skin. Other
keratins constitutively or facultatively expressed in
palmoplantar skin include K6, K16 (also found in
mucosa, hair follicles, and nail bed), and K17 (hair follicles and nail bed11). There are multiple K6 isoforms,12,13 and defects in K6a, K6b, and K6c as well as
all the other keratins named above can result in keratoderma. The majority of pathogenic mutations in keratins occur in the highly conserved boundary peptides
of the -helical rod domain regions, which are thought
vital for end-to-end overlap interactions during the
elongation phase of filament assembly.3 Typically, keratin defects result in a disrupted intermediate filament
cytoskeleton. The intermediate filament network is
attached to desmosomes, intercellular junctions which
in turn form paired plaques with the corresponding
structures in adjacent keratinocytes. Defects in desmosomal proteins such as desmoglein 1, desmoplakin 1,
plakoglobin, and plakophilin 1 also cause PPK.6 Structural weakness due to keratin and desmosome defects
has the potential to cause epidermolysis or acantholysis of keratinocytes, of which hyperkeratosis may be an
indirect consequence, but nonmechanical mechanisms
are also probable. Keratins, for example, are also
involved in the regulation of proliferation, apoptosis,
and skin pigmentation.14,15 Moreover, cell stress as a
nonspecific response to an accumulation of misfolded
proteins may contribute to pathogenesis. Mechanically
stressed keratinocytes containing mutant keratins of

the type which cause severe epidermolysis bullosa
simplex show greater resistance to apoptosis than
wild-type keratinocytes; the increased resistance was
dependant on an increase in extracellular signalregulated kinase (ERK) and Akt signaling.16 Keratoderma in tyrosinemia type II may be also due to
tonofilament accumulation secondary to excessive
intracellular tyrosine.17
Another large group of PPK syndromes are due to
defects in connexins, the proteins that make up gap
junction communication channels between cells.5 Gap
junctions are assembled in plaques containing multiple connexon units, each of which consists of a pair of
hemichannels with a central channel through which
small molecules (<1 kDa) can pass between the cytoplasm of adjacent cells. Each hemichannel in turn contains six homomeric or heteromeric connexin proteins.
The 21 human connexin proteins, like keratins, are
expressed in a tissue and differentiation specific manner and the phenotype of gap junction diseases in part
reflects their expression pattern. For example, most
mutations in the gene (GJB2) encoding connexin 26
(Cx26) cause impaired hearing because the gene is
expressed in the inner ear where it is necessary for the
circulation of endolymph. Cx26 is also expressed in
skin, and some Cx26 defects also cause a cutaneous
phenotype, such as PPK. PPK is also found in syndromes due to mutations affecting connexin 30 (Cx30,
associated with hidrotic ectodermal dysplasia18,19) and
connexin 43 (Cx43; oculo-dental digital dysplasia20).
However, point mutations in a single connexin can
cause a range of phenotypes depending on the specific
amino acid affected. While some pathogenic mutations
interfere with the formation of functional gap junctions, others exhibit defects in trafficking to the cell
membrane and the connexins instead accumulate
within organelles.21 Recent evidence in erythrokeratoderma variabilis (EKV) suggests that accumulation of
mutant proteins causes the unfolded protein response.22
In the case of connexin mutations associated with palmoplantar keratoderma, this endoplasmic reticulum
stress may be responsible for hyperkeratosis and
inflammation.
Other mechanisms of PPK are extremely varied. In
loricrin keratoderma, a barrier abnormality is associated with a defective CE scaffold that results in
increased extracellular permeability defect.23 The Cterminal peptide of the mutant loricrin includes polybasic nuclear recognition signals which cause the
aberrant protein to accumulate in the nucleus, which is
likely to interfere with terminal differentiation.2426 In
PapillonLefvre syndrome (PLS), in which PPK is
associated with predisposition to pyogenic infection,
the cysteine protease cathepsin C is inactive.27 This
lysosomal enzyme is important in intracellular protein
degradation28 and in the activation of neutrophil serine
proteases.29 Its absence may have consequences for the
regulation of inflammation,30 but the mechanism of
keratoderma may also relate to aberrant desmosomal
cleavage. In Mal de Meleda, a secreted nicotinic
acetylcholine receptor ligand, SLURP-1, is deficient.
The normally expressed protein may act by modulating
539
keratinocyte behavior or inflammatory responses.3133

Keratoderma is a feature of rare neurodevelopmental
syndromes due to defective intracellular vesicle trafficking,34,35 and of keratosis linearis with ichthyosis con-
genita and sclerosing keratoderma (KLICK) syndrome

where there is a defect in proteasome production.36
Known gene defects causing keratoderma are listed
in Table 50-1.
TABLE 50-1
Gene Defects in Syndromes Which Include Palmoplantar Keratoderma
Section 7
::
540
Presentation (Syndrome)
Inheritance
Gene(s)/Locus Protein(s)
Epidermolytic PPK (Vrner)
AD
KRT9
Keratin 9
Transgredient epidermolytic PPK
AD
KRT1
Keratin 1
Diffuse NEPPK (includes UnnaThost)
AD
KRT1
Keratin 1 (V1 domain)
Ichthyosis hystrix
AD
KRT1
Keratin 1
Focal nonepidermolytic PPK
AD
KRT16, KRT6c
Keratin 6c, 16
Pachyonychia congenita type 1
AD
KRT6a, KRT16
Keratin 6a, 16
Pachyonychia congenita type 2
AD
KRT6b, KRT17
Keratin 6b, 17
Ectodermal dysplasia/skin fragility syndrome
AR
PKP1
Plakophilin 1
Striate PPK
AD
DSG1, DSP, KRT1
Desmoglein 1, Desmoplakin 1, Keratin 1
Keratoderma with cardiomyopathy and wooly hair

(CarvajalHuerta and others)
AR/AD
DSP
Desmoplakin 1
Keratoderma with ARVC and wooly hair (Naxos)
AR
JUP
Plakoglobin
Keratoderma with hearing loss (Vohwinkel,

BartPumphrey, and others)
AD
GJB2, GJB6
Connexin 26, 30
Keratitis/Hystrix, ichthyosis, and deafness (KID/HID)
AD
GJB2
Connexin 26
Hidrotic ectodermal dysplasia (Clouston)
AD
GJB6
Connexin 30
Erythrokeratoderma variabilis
AD/AR
GJB3, GJB4
Connexin 31, 30.3
Oculo-dento-digital dysplasia (of the face, eyes,

skeletal system, heart, and dentition)
AD
GJA1
Connexin 43
Mitochondrial keratoderma with hearing loss
Mito
MSST1
Serine transfer RNA
Loricrin keratoderma
AD
LOR
Insertion mutation in Loricrin
Keratoderma and periodontitis (PapillonLefvre

and HaimMunk)
AR
CTSC
Cathepsin C
Mal de Meleda
AR
ARSB
SLURP-1
Tylosis with Oesophageal carcinoma (Howel-Evans)
AD
RHBDF2
Inhibitor of active rhomboid protease

RHBDL2
Odonto-onycho-dermal dysplasia (includes

SchpfSchultzPassarge)
AR
WNT10a
Signaling molecule implicated in

development
Tyrosinemia type 2 (RichnerHanhart)
AR
TYR1
Tyrosinase
KLICK
AR
POMP
Proteasome maturation protein
CEDNIK
AR
SNAP29
SNARE protein involved in vesicle fusion
MEDNIK
AR
AP1S1
Subunit 1A of adaptor protein-1

complex
Mapped Disorders
Sclerotylosis (Huriez)
Diffuse NEPPK (includes UnnaThost)
Punctate PPK
AD
AD
AD
4q23
12q1113
15q22.215q22.31
AD = autosomal dominant; AR = autosomal recessive; ARVC = arrhythmogenic right ventricular cardiomyopathy; CEDNIK = cerebral dysgenesis,
neuropathy, ichthyosis, keratoderma; KLICK = keratosis linearis with ichthyosis congenita and sclerosing keratoderma; MEDNIK = mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, keratoderma; NEPPK = nonepidermolytic PPK; PPK = Palmoplantar keratoderma;
SLURP1 = Secreted LY6/uPAR domain containing protein 1; SNAP29 = Synaptosomal-associated protein 29kD; WNT10A = wingless-type MMTV
integration site family member 10a.
CLINICAL FINDINGS
EPIDERMOLYTIC KERATODERMA. An example of uncomplicated diffuse keratoderma is epidermolytic PPK (EPPK; Vrner syndrome; MIM 144200).
EPPK is probably the commonest PPK,9 and is an autosomal dominant trait due to defects in keratin 9, the
one keratin specific to palmoplantar skin.42 It presents
in childhood as diffuse PPK with a sharp, livid transition to normal skin at the edge of palms and soles
(Fig. 50-2C; see also eFig. 50-2.3 in online edition).
Severe cases may be accompanied by blistering,
In the history, early age of onset is usual. Punctate keratodermas present in adulthood, but new presentations of diffuse PPK at this age are more likely to be
papulosquamous disorders (see Section Differential
Diagnosis). In inherited PPKs, hyperhidrosis is commonly reported. Pain is a particular feature of focal
keratodermas, but in all forms of keratoderma functional, occupational, or social disability should be
recorded. A family history, including consanguinity,
may be helpful but it is unwise to draw firm conclusions about either clinical type or inheritance patterns
without having examined all available members of a
pedigree, even if said to be affected. Family history of
early onset systemic malignancy or skin cancer should
be noted.
The distribution of keratoderma (punctate, focal,
striate, or diffuse) is not an absolute guide. Feet tend to
be more markedly and diffusely involved, so that in
severe cases the underlying pattern may be more
obvious on the hands. The appearance of the
hyperkeratosisfor example, honeycomb patterned,
waxy, or fissuredmay be significant. Sharp, livid
margins or the presence of transgredient hyperkeratosis on dorsa of hands, feet, and digits should be noted.
The possibility of secondary fungal or bacterial infection, and of the development of malignancy, should be
considered. It is important to examine the whole skin
for signs of other skin diseases such as eczema, psoriasis, and lichen planus. In inherited PPK, mild acral
hyperkeratosis may indicate a generalized cutaneous
disorder that is locally severe on palms and sole;
PUNCTATE KERATODERMA. Punctate keratoderma (BuschkeFischerBrauer syndrome; MIM

146800) is usually inherited as an autosomal dominant
trait.37 Unlike most other inherited PPKs, punctate
PPK presents in adult life as multiple keratinizing papules (Fig. 50-2A). It may be an incidental finding,
although plantar lesions can produce significant disability and also cause secondary focal keratoderma.
From the gradual accumulation of discrete individual
lesions it may be inferred that there is a defect in one
inherited allele, and the disease is expressed when the
remaining allele is damaged. An association with
malignancy of kidney, stomach, breast, and colon, has
been reported in a few pedigrees,38,39 but has not been
generally substantiated. In any case, the condition is
probably genetically heterogeneous. The size of the
papules in different families varies from a few millimeters to tiny filiform lesions (music-box spine keratoderma) (see eFigs. 50-2.1 and 50-2.2 in online edition).
Similarly, histology of the lesions may show orthokeratotic or parakeratotic hyperkeratosis. At least two
genetic loci have been suggested40,41 although that at
15q22.215q22.31 is most certain. Other clinically similar conditions include punctate keratoderma of the
palmar creases, and focal acral hyperkeratosis of the
margins of palms and soles, with or without elastoidosis. Papular palmoplantar lesions may be seen in other
genodermatoses, notably Darier disease (see Chapter
51), in which the pitted lesions common in younger
cases become papular with age. Acquired causes of
punctate palmoplantar lesions include dioxin toxicity
and chronic arsenicism.
::
APPROACH TO THE PATIENT WITH

KERATODERMA
KERATODERMAS WITH MAINLY

CUTANEOUS FEATURES
Chapter 50
Clinical findings vary between different genetic forms

of PPK. The hyperkeratosis may present as multiple
papular lesions (punctate PPK), as callosities localized
to points of particular stress (focal/areate, or striate
PPK) or may extend over the whole palm or sole (diffuse PPK). The distinction between focal, striate, and
diffuse forms is not always easy to make, and the
severity of PPK may vary, even within a family. Hyperhidrosis is a common complaint amongst patients
with focal or diffuse keratodermas. Corynebacterial
overgrowth leading to keratolysis and malodor, and
secondary dermatophyte infection, is common. Transgredient keratoderma extends onto the dorsa of the
hands and other cutaneous sites; circumferential keratoderma of digits is associated with the formation of
constricting bands (pseudoainhum, see Chapter 68)
and sometimes autoamputation (cicatrizing or mutilating keratoderma). It may also cause tapering of the
digits (sclerodactyly) with bony atrophy and nail dystrophy. A number of keratoderma syndromes, in particular Huriez and Olmsted syndromes (see below) are
characterized by the frequency of squamous cell carcinoma in affected skin; melanoma has also been
reported in various PPKs.
ssures at the oral commissures and follicular hyperfi

keratosis are also common. Mild ichthyosis seen in
loricrin PPK may be missed if not specifically sought.
Many PPKs involve mucosa, including genital mucosa.
The presence of other ectodermal abnormalities should
be documented, i.e., abnormalities of nails, teeth, hair
and hair follicles, sweat glands, and sweating. Finally,
specific features associated with syndromic keratoderma should be elicited by history and examination.
These include hearing impairment (which may be subtle), neuropathy, and cardiac disease (conduction
defects or cardiomyopathy).
A pathway to aid diagnosis (Fig. 50-1) is provided,
but is neither comprehensive nor absolute. Individual
presentations are discussed in more detail below.
541
One approach to clinical classification

Focal acral
hyperkeratosis
Acrokeratoelastoidosis
of Costa
Scattered discrete
papules, adult
onset
Punctate or
filiform PPKs
Papular lesions
Linear
accentuation
on volar aspect
of digits
::
Knuckle pads,
dorsal keratoses
or circumferential
PPK of digits,
constricting
bands
No other
cutaneous or
ectodermal features
Localised to
palms and soles
542
Woolly hair,
cardiomyopathy
Subungual and
follicular
hyperkeratosis
Periodontitis,
pyoderma
psoriasiform
lesions
PPK and cardiac

disease syndromes
Papillon-Lefvre or
Haim-Munk syndrome
Localised epidermolytic
hyperkeratosis
Other transgredient
PPKs
Waxy PPK,
inflammation
Other transgredient PPKs

Mal de Meleda
Patterned PPK,
Mild ichthyosis
Loricrin PPK
Atrophy
squamous cell ca
Huriez syndrome
Periorifical lesions
Olmsted syndrome
Impaired hearing
PPK &
deafness syndromes
Fissuring,
epidermolysis,
distinct
livid demarcation
Epidermolytic PPK
(Vrner syndrome)
Diffuse;
no epidermolysis
Unna-Thost PPK
Focal;
no epidermolysis
Focal
non-epidermolytic PPK
Oral leukokeratosis
Pachyonychia
congenita type 1
Epidermal cysts,
natal teeth
Pachyonychia
congenita type 2
Leukoplakia
personal /
family history
esophageal Ca
Howel-Evans syndrome
Eyelid cysts,
hypodontia,
hypotrichosis
Schopf-SchulzPassarge syndrome
Peripheral
neuropathy
learning delay
ichthyosis
PPK & neuropathy

syndromes
Photophobia,
keratitis,
learning delay
Tyrosinaemia type II
Diffuse and focal
Focal, subconfluent or
diffuse keratoderma
Striate PPK
No other features
Diffuse acral
hyperkeratosis
Darier-White disease
Striate
Section 7
Palmoplantar
hyperkeratosis
Palmar pits, linear

nail dystrophy,
acantholytic
dyskeratotic
papular rash
Punctate
Lateral aspects of
palms/soles
Figure 50-1 One approach to clinical classification. Diagnoses shown in italics are pragmatic groups rather than genetically defined syndromes (see text). It is unwise to use the pattern of keratoderma (i.e., papular, focal, striate, diffuse) as the
primary means of classification, since this can vary even within families. It is a good principle to look for ectodermal and
syndromic associations in all new cases.
Chapter 50
::
Figure 50-2 Patterns of familial keratoderma. A. Punctate, which usually does not appear until adulthood. The lesions
have been accentuated by immersion in water for a few minutes. B. Striate, often due to desmosomal disorders. C. Diffuse,
in this case with fissuring and the sharp demarcation typical of keratin 9 defects. D. Focal, seen as an isolated finding due
to keratin 6c mutations. In practice the distinction between these patterns may not be clear, especially on plantar skin.
although in adults the epidermal weakness is more
commonly manifested by fissuring. Histology of the
stratum spinosum shows vacuolated keratinocytes
with keratin filament aggregates at electron microscopic level, accompanied by orthohyperkeratosis of
the stratum corneum. Defects in keratin 1, the presumed partner of keratin 9 in palmoplantar skin, also
cause diffuse transgredient keratoderma with epidermolytic hyperkeratosis at other cutaneous sites, but
extrapalmoplantar involvement may be subtle (see
eFig. 50-2.4 in online edition). A specific defect of the
1B domain of keratin 1 causes tubular tonofilament
structures to form in some pedigrees.43 Keratoderma
may also be a feature of epidermolysis bullosa of the
severe DowlingMeara type (MIM 131760; 44) due to
mutations in the basal layer keratins 5 and 14 (see
Chapter 62). The mechanism(s) by which keratin gene
defects may give rise to the palmoplantar hyperkeratosis are discussed above.
NONEPIDERMOLYTIC DIFFUSE PPK. Nonepidermolytic diffuse PPK restricted to palmoplantar skin

is heterogeneous. The term UnnaThost syndrome
(MIM 600962) should probably be discarded, as even
the original Thost family in fact had epidermolytic
PPK.45 In one pedigree a diffuse nonepidermolytic
phenotype was due to a defect in the variable region of
the keratin 1 gene,46 and in another was mapped to a
locus including the type II keratin gene cluster.47
Another locus proximal to the type II keratin gene

cluster has been identified.48
FOCAL PPK. Focal PPK (see Fig. 50-2 and eFig. 50-2.5
in online edition) may complicate punctate PPK on the
feet, or may occur in isolation; in the latter situation it
may be difficult to distinguish from physiological callosities, and indeed the tendency to these may have a
genetic basis.49 Early onset focal keratoderma of whatever cause leads to disability (hereditary painful callosities), and patients may be so severely affected as to
become wheelchair bound. Autosomal dominant pedigrees of focal PPK are commonly associated with nail
dystrophy and mucosal features as part of the pachyonychia spectrum, but even in the absence of nail dystrophy may be due to mutation in keratin 16.50 In the
majority of cases of focal PPK in isolation, genetic
causes have not been identified, but in three pedigrees
it has been ascribed to mutations in keratin 6c.49 Painful
focal PPK is also found in tyrosinemia type II (see
below and Chapter 131).
STRIATE PPK. Striate PPK (SPPK; MIM 148700) is a
distinct variant of focal PPK in which there is prominent linear involvement of the volar surfaces of the
digits (see Fig. 50-2B) and less distinctly of corresponding areas of the soles. Histology of autosomal dominant inherited striate PPK shows subtle widening of
the intercellular spaces (see Fig. 50-5C). 51,52 Most cases
543
Section 7
::
544
are due to defects in gene encoding desmosomal

plaque proteins of which desmoglein 1 (DSG1) is most
commonly implicated, but mutations in desmoplakin 1
are also reported.53,54 Keratoderma due to defects in
these genes is believed to be due to haploinsufficiency,
i.e., reduced amounts of the relevant structural protein
expressed in the desmosomal plaque result in mechanical weakness which manifest at points of greatest
stress. However, as with keratins, demosomal components are implicated in intracellular signaling and
growth regulation. Striate PPK may also be seen with
some mutations in keratin 1,55 and indeed striate accentuation is a nonspecific component of milder diffuse
keratodermas. Most cases of autosomal dominant
SPPK are simple, but defects in desmoplakin also give
rise to syndromes of cardiomyopathy and wooly hair
(see below).
tial digital involvement, cicatrizing bands, and sometimes autoamputation. However, there is also a mild
generalized ichthyosis, and collodion babies or generalized desquamation at birth are reported.57,58 Compared with true VS, due to mutations in Cx26, the edge
of the keratoderma at the wrists is diffuse, and deafness is not a feature. Multiple mutations are reported
of which the most frequent mutation, 730insG, has
been found in families from the United Kingdom,
Japan, Germany, and Italy.24,57,5964 In all cases they are
single nucleotide insertions resulting in a shift of the
reading frame and a termination codon delayed by
22 amino acids. In the elongated carboxyl-terminal
domain many of the glycine residues are replaced by
arginine, drastically altering the properties of the loricrin polypeptide by producing nuclear recognition signals (see above).
LORICRIN KERATODERMA. Loricrin keratoderma (syn. Camisa syndrome; MIM 640117) was
described as a variant of Vohwinkel syndrome (VS).56
It is characterized by a similar honeycomb patterned
and transgredient keratoderma (Fig. 50-3A; see also
eFig. 50-3.1 in online edition), leading to circumferen-
HURIEZ SYNDROME. Huriez syndrome (PPK with

scleroatrophy, sclerotylosis; MIM 181600), an autosomal dominant disorder, is characterized by diffuse PPK
that affects mainly palmar skin (Fig. 50-3C).6570 The
underlying gene defect is unknown but linkage to
chromosome 4q23 has been reported.71 Sclerodactyly,
Figure 50-3 Rare forms of transgredient PPK. A. Patterned keratoderma in a case of loricrin PPK; note circumferential
keratoderma and early constricting bands. B. Confluent papules in Vohwinkel PPK with impaired hearing due to connexin
26 mutations; honeycomb lesions and circumferential PPK with constricting bands also occur in this syndrome. C. Huriez
syndrome (sclerotylosis), which carries a high risk of squamous cell carcinoma. (Used with permission from Dr. Cameron
Kennedy, Bristol Royal Infirmary, United Kingdom.) D. Mal de Meleda due to mutations in ARS component B, with a waxy
hyperkeratosis, sclerodactyly, and constricting bands.
brachydactyly, and cutaneous erythema and/or atrophy are typical, as are various nail changes; hypohidrosis is also reported. A deficiency of Langerhans cells
in affected skin has been identified.72 The condition
predisposes to squamous cell carcinomas of affected
skin, occurring in the third to fourth decade, which are
unusually prone to metastasis.67,68 Causal treatment is
not available, but benefit from oral retinoids is
recorded.67
PACHYONYCHIA CONGENITA. Pachyonychia

congenita (PC) is a spectrum of dominantly inherited
disorders associated with focal PPK. In addition to
painful focal PPK and hypertrophic dystrophy of the
distal nail, there are numerous reported associations88
(see eFig. 50-4.1 in online edition). Two main syndromes are recognised clinically,89 in which various
associated features can cause significant additional
morbidity and disability. PC-1 (JadassohnLewandowsky; MIM 167210) is associated with follicular keratoses, oral leukokeratosis and hoarseness. Severe oral
lesions can resemble mucosal candidiasis90 and laryngeal involvement may produce infantile respiratory
obstruction.91 The rarer PC-2 (JacksonLawler; MIM
167210) is distinguished by multiple pilosebaceous
cysts, teeth present at birth, and hair changes such as
protuberant eyebrows. Extensive and infected flexural,
vulval or scrotal cysts can present as hidradenitis suppurativa.92 PC-1 is typically associated with mutations
in KRT6A or KRT16 and PC-2, with mutations in KRT6B
or KRT17, reflecting the expression patterns of the
disorders with phenotypes resembling Mal de Meleda

are reported,76,77,78,79,80 but appear to be genetically distinct. A very rare autosomal recessive disorder
(KLICK syndrome) has been described in which a
cicatrizing PPK is associated with ichthyosis and a
bizarre striate hyperkeratosis of flexures.81,82 This has
KERATODERMAS WITH ECTODERMAL

DYSTROPHY
::
OTHER TRANSGREDIENT KERATODERMAS. Recessive transgredient and/or mutilating
Chapter 50
MAL DE MELEDA. Mal de Meleda (MIM 248300)

is a rare autosomal recessive disorder originally
described in communities of the Mediterranean littoral. The transgredient (i.e., it extends over the lateral
margin of the palms and proximally over the wrists)
hyperkeratosis has a waxy ivory to yellow appearance
and is typically inflamed or macerated, with a livid
margin.73 Dermatophyte superinfection, to which
many keratodermas are prone, may mimic these
appearances. Knuckle pads, similar waxy lesions on
acral sites, angular cheilitis, and circumferential sclerosing and cicatrizing lesions of the digits are typical
(Fig. 50-3D; see also eFig. 50-3.2B in online edition); not
surprisingly nails are often dystrophic. The typical
Mediterranean disorder is due to mutations in the
ARSB gene encoding SLURP-1, an acetylcholine receptor analog.31,74,75
recently been shown to be due to defects in POMP

which encodes a protein which is a chaperone for proteasome maturation.36 Similarly, pedigrees of autosomal dominant transgredient PPKs have been described.
The term Greither syndrome has been used,2,83,84 but
may not be a single entity.85 Some autosomal dominant transgredient keratodermas within this spectrum are due to mutations in keratin 1 (Fig. 50-4A),86
but other such pedigrees, for example, Sybert syndrome87 appear not to be keratin disorders.
Figure 50-4 The pattern of plantar PPK is often not diagnostic. A. Diffuse fissured PPK due to mutation in keratin 1 but
with only localized epidermolytic hyperkeratosis of elbows, knees and flexures. B. Similar changes in Papillon-Lefvre
syndrome due to mutation in Cathepsin C. (Used with permission from Barts and the London NHS Trust, United Kingdom.)
C. HowelEvans syndrome (PPK with familial esophageal carcinoma) showing subconfluent keratoderma sparing the
instep. D. Similar changes due to an insertion mutation in keratin 1. E. Focal PPK with impaired hearing due to A7445G
mutation in mitochondrial DNA.
545
Section 7
relevant keratins3: for example K16 is a major secondary keratin in orogenital epithelia. Severity varies
within and between families, and incomplete phenotypes such as PPK without nail dystrophy or steatocystoma multiplex without PPK may be caused by
mutations in the same genes. However, detailed analysis of patients with KRT16 mutations suggests that
mutations which predict a more disruptive effect on
K16 protein structure produce a more severe phenotype.93 A recent large study casts doubt on the consistency of the association of clinical syndrome and
mutated keratin94 and it has been proposed instead that
PC be designated according to the affected keratin
PC-6a, PC-6b, etc. and PC-U (unknown).95 Genotypic
classification has the aim of individualising targeted
molecular therapy, already promising in this disorder.8
SCHPFSCHULZPASSARGE SYNDROME.
::
SchpfSchulzPassarge syndrome (SSPS96; MIM

227450) appears to be allelic with onycho-odontodermal dysplasia (OODD; MIM 257980), a spectrum of
autosomal recessive ectodermal dysplasias with a core
phenotype of abnormal nails, oligodontia with abnormal teeth, and hypotrichosis.97 Dental anomalies may
occur in heterozygotes. Features in addition to palmoplantar keratoderma (see eFig. 50-4.2 in online edition)
include erythematous facial lesions and atrophic lingual papillae. In SSPS, patients commonly develop
benign adnexal tumors. Apocrine hydrocystoma, presenting as eyelid cysts is characteristic of SSPS: eccrine
poroma and syringofibroadenoma also occur.98 Squamous and basal cell carcinomas and porocarcinomas
are reported in affected skin. Disorders within the
OODD spectrum are due to mutations in WNT
10a97,99101; the protein encoded by this gene is a member
of a family of secreted signaling molecules which
inhibit degradation of the -catenin complex and hence
allow it to modulate gene expression. WNT signaling is
important in many developmental pathways, and
WNT10a is implicated in dental and hair follicle morphogenesis, and the formation of ectodermal ridges.
OLMSTED SYNDROME. Olmsted syndrome (mutilating palmoplantar keratoderma with periorificial

plaques,102105) is a severe disorder. Congenital diffuse,
sharply demarcated, and progressive keratoderma of
palms and soles causes flexion deformities, constrictions,
autoamputation, and obliteration of digits. Periorificial
keratoses are characteristic but associated symptoms
include a variety of nail dystrophies and hypotrichosis.
The disease usually manifests within the first 6 months
of life and is progressive. A number of patients have
developed squamous cell carcinoma in affected skin.
The genetic basis is unknown. Most cases are sporadic
but it may be autosomal dominant. In children, the disorder must be distinguished from recessive transgredient PPKs including Mal de Meleda and, because of the
periorificial keratoses, acrodermatitis enteropathica.
546
OTHER ECTODERMAL SYNDROMES WITH

KERATODERMA. PPK is found in the Naegeli
FranceschettiJadassohn syndrome (MIM 161000) and
dermatopathia pigmentosa reticularis (MIM 125595),

allelic syndromes due to dominant mutations in the
nonhelical E1/V1 domains of keratin 14.106 Other features include absent dermatoglyphics, reticulate pigmentary anomalies, hypohidrosis, and other subtle
ectodermal defects. PPK also occurs with keratin 5 and
14 defects in the severe DowlingMeara form of epidermolysis bullosa simplex44 in Kindler syndrome,
due to mutations in FERMT1 encoding kindlin-1, a cell
adhesion molecule involved in signaling via the actin
filament network,107 and in ectodermal dysplasia with
skin fragility due to defects in the desmosomal protein
plakophilin 1.54 PPK is found in hidrotic ectodermal
dysplasia (Clouston syndrome, MIM 129500), due to
mutations in GJB6 encoding connexin 30 (Cx30, see
Chapter 142),18 which can mimic PC,108 and in oculodento-digital-dyplasia (ODDD; MIM 164200) due to
mutations in GJA1 encoding Cx43.20 Similarly, PPK
may be part of the presentation of erythrokeratoderma
variabilis (MIM 133200; Chapter 49) which is due to
mutations in GJB3 or GJB4.4
OTHER KERATODERMAS WITH ORAL

OR MUCOSAL FEATURES
HOWELEVANS SYNDROME. HowelEvans
syndrome [Tylosis and (o)esophageal cancer, TOC;
MIM 148500] is an exceptionally rare autosomal dominant disorder; only a few families are known. In the
original report by HowelEvans et al,109 18 of 48 individuals who had PPK developed squamous cell carcinoma of the esophagus at an average age of 43 years.
Palmoplantar hyperkeratosis appeared on average 30
years earlier. The keratoderma is characterized by
thick yellow focal hyperkeratosis most prominent on
the pressure sites (Fig. 50-4C; see also eFig. 50-4.3 in
online edition).110 Pain is not a major feature, and the
palms are only involved in manual workers. Confluent
hyperkeratoses over pressure sites on the feet may lead
to more diffuse involvement. Oral leukoplakia precedes plantar lesions in children. Follicular hyperkeratosis also occurs and the major differential distinction
to be made is with PC or focal PPK with oral leukokeratosis. In the latter disorders, nail abnormalities are
usually present, although sometimes subtle. The disorder has long been mapped to chromosome 17q25.111
Causative mutations have recently been found in
RHBDF2.112 This inactive member of the rhomboid
family of intramembrane serine proteases may normally inhibit an active rhomboid protease; mutations
may interfere with epidermal growth factor and EphrinB3
signalling.
PAPILLONLEFVRE SYNDROME. PLS (PPK
with periodontitis, MIM 245000) is an autosomal recessive disorder caused by mutations in the CTSC gene
coding for the proteolytic enzyme cathepsin C.27,113 PLS
is characterized by a diffuse palmoplantar erythe
matous and fissured hyperkeratosis (Fig. 50-4B)
with transgredient erythema, and peridontitis.114 If
untreated, deciduous teeth may be lost by the age of
45 years, and subsequently, permanent dentition may
CARVAJALHUERTA SYNDROME. Carvajal

Huerta syndrome (MIM 605676) is the association of
striate keratoderma, wooly hair, and dilated left ventricular cardiomyopathy.128 It is a recessive disorder
due to truncating mutations in the desmoplakin gene
(DSP) which cause the protein to lose its C-terminus.129
Affected family members present with striate PPK,
Many autosomal dominant palmoplantar keratoderma

syndromes with sensorineural hearing loss are caused
by mutations in the gap junction genes GJB2 or GJB6,
encoding the gap junction proteins Cx26 and Cx30,
respectively.4,19,135138 Mutations in GJB2, encoding
Cx26, usually cause nonsyndromic deafness, but a
minority are responsible for most of the PPK-deafness
syndromes. There is a wide range of overlapping phenotypes, and almost every Cx26 mutation associated
with PPK has a clinically distinct phenotype.139,140
Amongst these, VS is most dramatic, with honeycomb
patterned keratoderma, starfish acral keratoses, constricting bands, and autoamputation141143 (Fig. 50-3B;
see also eFig. 50-4.4 in online edition). Even in this syndrome the PPK may be focal, papular, or diffuse. Acral
hyperkeratosis is found in other Cx26 PPKs; in the case
of BartPumphrey syndrome as knuckle pads. Constricting bands around the fingers and autoamputation
occur when there is confluent transgredient PPK. The
genotypephenotype correlation is poorly understood,
but mutations that cause PPK and deafness tend to
cluster in the extracellular domains of Cx26.5,140 Other
mutations in GJB2 give rise to more severe syndromes
in which PPK is part of a generalized oculo-cutaneous
disorder: keratitis ichthosis and deafness (KID; MIM
148210) and hystrix ichthyosis and deafness (HID;
MIM 602540).144,145 These disorders are described in
Chapter 49.
A specific mutation in mitochondrial DNA, A7,445G,
has been reported as causing the combination of hearing loss and a variable keratoderma (Fig. 50-4E) with
matrilineal inheritance in pedigrees from New Zealand, Scotland, Japan, Portugal, and Hungary.146149
This segment of the mitochondrial genome encodes a
serine transfer RNA, MTTS1. Penetrance of both features is incomplete, and the same mutation has been
reported as a familial cause of impaired hearing in the
absence of observed keratoderma.
NAXOS DISEASE. Naxos disease (MIM 601214),

first reported in pedigrees from the eponymous Greek
island, is an autosomal recessive disorder.120 Patients
have a diffuse, grayyellow fissuring but nonepidermolytic keratoderma, wooly hair, and arrhythmogenic
right ventricular cardiomyopathy (ARVC) causing
heart failure and sudden death. The disease is due to
homozygosity for a deletion mutation in the gene for
the desmosomal plaque protein junctional plakoglobin
(JUP), which causes a frameshift and premature termination of the protein.121 More than 90% of homozygous
individuals have electrocardiographic abnormalities
(mostly T wave inversion in V1V3 leads), associated
with arrhythmias, syncope, heart failure, and sudden
death,122125 but heterozygotes show no overall
increased cardiac morbidity or mortality. Another
mutation in JUP caused dominant ARVC without cutaneous features.126 Conversely, in two pedigrees with
keratoderma, skin fragility and wooly hair in the
absence of cardiac disease, homozygosity for novel
recessive mutations in JUP has recently been
reported.127
KERATODERMAS WITH
IMPAIRED HEARING
::
KERATODERMAS WITH
CARDIAC DISEASE
with some extravolar involvement at sites of pressure.

The associated dilated left ventricular cardiomyopathy, developing in teenage years, is characterized by
cardiac enlargement and disrupted cardiac contraction.123 A range of phenotypes with right, left, or biventricular arrthymogenic cardiomyopathy in isolation or
combined with wooly hair and other ectodermal features including keratoderma, are due to dominant or
recessive mutations in desmoplakin.125,130132 Larger
truncations in DSP give rise to lethal acantholytic ectodermal dysplasia.133
Mild PPK with ARVC and wooly hair due to recessive mutation in desmocollin-2 has been reported.134
Chapter 50
also be lost. Redness and thickening of the palms and

soles usually occur in the first years of life, coincidental
with eruption of the deciduous teeth.115 Typically, PLS
patients show scaly erythematous psoriasiform lesions
over knees, elbows, and interphalangeal joints. Transverse ridging of nails, onychogryphosis, sheeted follicular hyperkeratosis and a subtle, generalized white
opalescence of oral mucosa, and dural calcification,
have also been reported. Associated plantar hyperhidrosis can cause malodor. Patients are susceptible to
skin infections (with Staphylococcus aureus) and pyogenic liver abscesses.116 Loss of permanent dentition
will lead to improvement of the periodontitis, but
patients benefit greatly from adequate dental hygiene
and care. HaimMunk syndrome (HMS, MIM 245010)
is allelic with PLS,117 but is a distinct disorder which
appears to have arisen in the Jewish population of
Kochi, Kerala, India. In HMS, the features are more
severe and extensive, and there are additional manifestations of arachnodactyly, acroosteolysis, atrophic
nails, and pes planus. The recently described autosomal dominant hypotrichosisacro-osteolysisonychogryphosispalmoplantar keratodermaperiodontitis
(HOPP) syndrome combines periodontitis, acro-osteolysis, and psoriasiform skin lesions with a unique
focal or reticular keratoderma and progressive scarring alopecia118,119; CTSC mutations have been excluded
in the three reported cases.
KERATODERMAS WITH NEUROPATHY

OR MENTAL RETARDATION
Two autosomal recessive syndromes with the combination of neuropathy and mental retardation have been
547
Section 7
documented genetically. CEDNIK (cerebral dysgenesis,

neuropathy, ichthyosis, and keratoderma; MIM 609528)
is due to a 1-bp deletion in SNAP29, which encodes a
SNARE protein involved in vesicle fusion.34,150 MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma) is due to
a splicing defect in the AP1S1 gene, encoding a subunit
of one of the adaptor protein complexes which regulate
vesicle assembly, protein cargo sorting, and vesicular
trafficking between organelles.35 The similarities
between the disorders may be explained by the fact that
the AP1 complex interacts with the SNAP29 gene product in the transport vesicles. In other reported pedigrees, PPK was combined with spastic paraplegia or
motor and sensory neuropathy,151153 but as yet causative mutations have not been identified.
::
TYROSINEMIA TYPE II. Tyrosinemia type II (Richner

Hanhart syndrome, MIM 276600) is a very rare autosomal recessive disorder154,155 due to deficiency of
tyrosine aminotransferase, leading to accumulation of
tyrosine and phenolic acid metabolites156 (see Chapter
131). Clinical characteristics include painful focal palmoplantar hyperkeratosis, photophobia, and corneal
erosions that may cause scarring or glaucoma.154159
Eye lesions precede the skin phenotype but the latter
may occur in the absence of ocular involvement. Histopathological examination shows eosinophilic inclusions in the basal layer of the epidermis and increased
keratohyaline granules. It is suggested that excess
tyrosine enhances cross-links between aggregated
tonofilaments and stabilizes microtubules.17 The
untreated syndrome causes psychomotor retardation,
but a diet low in phenylalanine and tyrosine will both
ameliorate cutaneous symptoms and prevent further
mental deterioration.
548
Investigation of Keratoderma
Histologically, keratodermas are characterized by definition by increased stratum corneum thickness often
with hypergranulosis but acanthosis, papillomatosis,
and increased stratum lucidum vary. Where vacuolar
degeneration and epidermolysis are present, it suggests keratin 9 defects (Fig. 50-5A), but it may be necessary to biopsy weight-bearing sites to maximize the
chance of finding it. Normal palmoplantar skin contains increased numbers of tonofilaments on electron
microscopy.10 Abnormal aggregated keratin intermediate filaments in EPPK160 and tonotubular structures in
a rare variant form43,161 are identifiable. Overt epidermolysis is not a major feature of PPK due to defects of
other keratins, but prominent eosinophilic cytoplasm
and keratin aggregates can be identified in most
cases of PC (Fig. 50-5B52; Zamiri, unpublished data).
Increased tonofilaments and microtubules are also
reported in tyrosinemia type II.17
In desmosomal disorders, there is increased separation between keratinocytes, although frank acantholysis is unusual with desmoglein mutations (Fig.
50-5C).51,52 Ultrastructurally, desmosomal plaques may
be reduced in number or poorly formed, and keratin
aggregation and compaction has also been noted
with desmoplakin mutations.51,162,163 In loricrin keratoderma, retained nuclei may be seen in the stratum corneum in which the mutant loricrin is detectable.164 In
Mal de Meleda, and in PLS, perivascular inflammation
may be prominent, although this is a nonspecific
finding in other keratodermas. The pathologist should
also look for fungal spores or hyphae.
Punctate keratoderma may be orthokeratotic or
parakeratotic. The latter in two dimensions resembles
Figure 50-5 Histology of keratoderma. A. Vacuolation of spinous layer keratinocytes in epidermolytic PPK due to keratin
9 mutations; inset, tonofilament aggregates (arrows), and cytolysis on electron microscopy. B. Eosinophilic cytoplasm but
without overt epidermolysis and inflammatory infiltrate in pachyonychia congenita due to keratin 17 mutation. C. Subtly
increased cell separation (arrows) in striate PPK due to desmoglein 1 mutation; inset of electron microscopic appearances
shows overtly increased cell separation.
See Box 50-1 and eFig. 50-5.1 in online edition.
MANAGEMENT OF KERATODERMA
Many patients with PPK, particularly those with diffuse
varieties, tolerate the condition without specific treatment. Patient-led self-help groups catering for rare and
orphan disorders offer valuable support, but the rarity
of individual conditions means that specific advice is
difficult to obtain. An important exception is the Pachyonychia Congenita Project (www.pachyonychia.org).
For patients with focal keratoderma, which is often
painful and sometimes disabling, regular paring by a
podiatrist or the patient him/herself helps to control
hyperkeratosis. Topical keratolytic agents such as salicylic acid ointment (5%20%) or benzoic acid compound ointment help to soften the hyperkeratosis
prior to abrasion. Propylene glycol (40%60% in aqueous cream under occlusion at night) can also soften
hyperkeratosis and aid reduction of callosities.
Many patients complain of hyperhidrosis for which
simple measures such as topical aluminum chloride
hexahydrate may be used. Suitable ventilated footwear, insoles, and wicking socks (available from
suppliers of outdoor walking equipment) may offer
some relief. Botulinum toxin has been successfully
used to reduce plantar pain but requires regional anesthesia.165 Malodor due to keratolytic corynebacterial
infection of macerated hyperkeratosis, and fungal
superinfection are also common. Where present,
t opical or systemic antimicrobials produce worthwhile

benefit, but need to be repeated.
Oral retinoids are frequently tried but there are few
systematic studies. Acitretin (10 mg/day or more), etretinate, or isotretinoin may all help, particularly in keratin, loricrin, or connexin disorders; successful use in PLS
and Mal de Meleda is also reported. However, individual dosimetry may need to be adjusted carefully as
excessive shedding of hyperkeratosis can cause palmar
and plantar skin to become tender. In conditions with
painful callosities such as PC, retinoids may reduce the
thickness of the hyperkeratoses but aggravate the pain.
If successful, lifelong treatment is required, with its
associated risks. Oral retinoids have also been used to
rescue impending autoamputation due to circumferential constricting bands.166168 A few reports suggest topical (or systemic) 5-fluorouracil may benefit punctate or
filiform keratoderma.169171 Surgical treatment, including excision and grafting, has been reported,172 most
commonly used to prevent permanent contracture in
Olmsted syndrome.173176 Surgical release of constricting
bands has had poor outcomes and asymptomatic lesions
are probably best left alone.177
For severe disorders where the genetic etiology is
known, prenatal diagnosis is technically possible as a
preventive strategy. Specific gene therapy is an exciting but still distant prospect for disorders of known
etiology. However, a recent study in PC has shown that
inhibition of mutant gene expression by repeated
Onset late in life generally indicates acquired keratoderma, although genetic factors may still be relevant.
Predisposition to callus formation and hyperkeratosis of the heels is common, exacerbated by obesity.
Hypothyroidism should be excluded. The term Haxthausens disease is used for acquired plantar hyperkeratosis in menopausal women.
Hyperkeratotic eczema is distinguished by pruritus,
erythema, the presence of vesiculation, and response
to topical steroid preparations.
In palmoplantar psoriasis, lesions elsewhere and
typical nail changes may help confirm the diagnosis.
Pityriasis rubra pilaris of the palms is distinguished by
characteristic color and associated nail changes.
Reiters syndrome is readily distinguished by its acute
presentation and associated arthropathy.
Keratoderma due to chronic dermatophyte infection
and in crusted (Norwegian) scabies can be diagnosed
by appropriate tests and response to treatment.
Sudden onset of diffuse keratoderma may be paraneoplastic, particularly carcinoma of the bronchus.
Keratoderma has been reported in SLE. Autoantibodies to desmocollin 3 were associated with a diffuse
acquired PPK.178
Punctate keratoderma of late onset should raise the
possibility of arsenical poisoning.
::
Chapter 50
the coronoid lamella of porokeratosis, but nonannular

lesions are not true porokeratoses. Whether these variations are of nosological significance remains to be
determined.
The cysts of PC include epidermoid and vellus hair
cysts as well as true steatocysts, and indeed a single cyst
may vary in its histology in different sections. The periodontal lesions of PLS show pockets of epithelium with
ulceration and a mixed inflammatory cell infiltrate.
It is important to bear in mind the possibility of the
development of squamous cell carcinoma or melanoma within keratoderma, and any changing or suspicious area should be biopsied.
Further investigation will be determined by the clinical syndrome; for example, audiometry, cardiac, or
esophageal studies. In Olmsted syndrome, acrodermatitis enteropathica should be excluded by measuring
serum zinc. Skin scraping for mycology remains the
most useful investigation for many patients with keratoderma.
It is increasingly possible to obtain confirmation of the
gene defect in familial keratodermas, particularly those
involving connexins, by sending DNA to specialist commercial, or academic laboratories, but a reasonably strong
clinical suspicion of the gene responsible is usually
needed. Molecular diagnosis is particularly useful to distinguish focal PPKs with oral lesions, due for example, to
keratin 16 mutations, from HowelEvans syndrome.
549
i njection of a specific small interfering RNA (siRNA)

was effective in reducing hyperkeratosis.8
KEY REFERENCES
1. Irvine AD, McLean WH: Human keratin diseases: The
increasing spectrum of disease and subtlety of the phenotype-genotype correlation. Br J Dermatol 140:815, 1999
2. Itin PH, Fistarol SK: Palmoplantar keratodermas. Clin
Dermatol 23:15, 2005
3. Lane EB, McLean WH: Keratins and skin disorders. J Pathol

204:355, 2004
4. Richard G: Connexin disorders of the skin. Clin Dermatol
23:23, 2005
5. Laird DW: Life cycle of connexins in health and disease.
Biochem J 394:527, 2006
6. Lai-Cheong JE, Arita K, McGrath JA: Genetic diseases of
junctions. J Invest Dermatol 127:2713, 2007
7. Moll R, Divo M, Langbein L: The human keratins: Biology
and pathology. Histochem Cell Biol 129:705, 2008
8. Leachman SA et al: First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther
18:442, 2009
Section 7
::
Chapter 51 :: Acantholytic Disorders of the Skin

:: Susan Burge & Alain Hovnanian
ACANTHOLYTIC DISEASES AT A GLANCE
The acantholytic diseases are a heterogeneous
group of diseases with overlapping clinical
and histological features.
Darier (or DarierWhite) disease (DD) and
HaileyHailey disease (HHD) are autosomal
dominant disorders that are caused by
defective calcium pumpsa sarco/
endoplasmic reticulum pump in DD and a
Golgi apparatus pump in HHD.
Typical DD presents with greasy keratotic
papules in a seborrheic distribution while
HHD is characterized by painful oozing
erosions in flexures and at sites of trauma.
Signs in the nails (DD, HHD), flat-topped
warty papules on dorsa of hands and feet
(DD) and palmar pits (DD, HHD) or palmar
keratotic papules (DD) help to confirm the
diagnosis.
Hypertrophic malodorous flexural disease is
particularly disabling in DD and HHD.
DARIER DISEASE
EPIDEMIOLOGY
550
Darier disease (DD) (OMIM #124200) is an autosomal

dominant disease affecting both sexes and all ethnic
groups. DD was described independently by Darier
and White in 1889 (also known as DarierWhite disease or keratosis follicularis).1 Estimates of prevalence
Grover disease (GD) is a sporadic papular

condition of uncertain etiology that presents most
often in sun-damaged skin. Intractable pruritus is
common.
Histopathological examination of involved
skin in DD, HH, and GD reveals breakdown
of intercellular contacts between suprabasal
keratinocytes (acantholysis) with variable
dyskeratosis.
Acrokeratosis verruciformis of Hopf (AKV) is
autosomal dominant and characterized by signs
that mimic acral DD: flat-topped warty papules
on dorsa of hands and feet and nail dystrophy.
The histology in AKV is not acantholytic, but
some (if not most) cases may be limited variants
of DD.
Treatment options for these diseases include
topical corticosteroids (DD, HHD, GD) and
topical or oral retinoids (DD, GD, AKV).
range from 1 in 30,000 (Northeast England, Scotland,

Slovenia)24 to 1 in 100,000 (Denmark).5 Penetrance is
complete, but spontaneous mutations are frequent.

The gene for DD was mapped by linkage analysis to
chromosome region 12q23-24 in 19936 and ATP2A2
was identified as the defective gene in 1999.7 ATP2A2
::
Acantholytic Disorders of the Skin
proteins by affecting the function of molecular chaperones such as calreticulin and calnexin that prevent protein misfolding and are involved in posttranslational
modification.43 Intracellular signaling through release
of ER Ca2+ regulates trafficking of proteins to the cell
membrane, including those required for the assembly
of desmosomes and adherens junctions.44 The trafficking of desmoplakin to the cell membrane is impaired
in cultured DD keratinocytes.45 Variations in cellular
Ca2+ concentrations are also likely to have an effect on
the expression of Ca2+-dependent genes involved in
keratinocyte differentiation and adhesion.
The epidermis is papillomatous and differentiation
is abnormal, with the expression of hyperproliferative
keratins and premature expression of cornified envelope precursors such as involucrin.34,38,4648 Alterations
in ATP-mediated signaling may contribute to dyskeratosis and hyperproliferation.8,34 Extracellular Ca2+
binds to purinergic ATP receptors that transmit calcium signals into the cytosol. Activation of the G-protein-coupled ATP receptor (P2Y) generates inositol
1,4,5-tris-phosphate (IP3), a calcium-signaling messenger (Fig. 51-1). Binding of IP3 to surface receptors on
the ER and Golgi apparatus triggers release of Ca2+
stores and a rise in cytosolic Ca2+ which activates a further influx of extracellular Ca2+ through plasma membrane Ca2+ channels (store-operated Ca2+ entry),
including transient receptor potential canonical1
(TRPC1). In DD, depleted ER Ca2+ appears to upregulate TRPC1 and enhances influx of Ca2+.8,49
Elevated cytosolic Ca2+ may drive keratinocyte proliferation by activation of Ca2+-dependent messenger
systems that regulate cell division and differentiation.49 Mice with reduced SERCA2 develop papillomas
and SCCs.50 SERCA2 haploinsufficiency in cultured
mouse keratinocytes is linked to upregulation of proliferation but downregulation of differentiation.51 SCC
has been reported rarely in DD, sometimes in association with HPV16.5256
Much of the skin may be able to compensate for the
deficiency in SERCA2 by increasing the expression of
the normal SERCA2 allele or by upregulating other
mechanisms such as the human secretory-pathway
Ca2+/Mn2+ ATPase isoform 1 (SPCA1) in the Golgi (see
section HaileyHailey Disease). However, external
factors such as ultraviolet B (UVB) irradiation or friction, which are known to exacerbate DD, may disrupt
this subtle balance by downregulating ATP2A2 or by
increasing the requirement for SERCA2 until the protein reaches a critical level.8,57 This hypothesis is supported by the observation that UVB irradiation and
proinflammatory cytokines reduce levels of ATP2A2
mRNA in cultured normal keratinocytes and that retinoids and corticosteroids (used in treatment of DD)
prevent this reduction.58 Lithium, another well-known
trigger for DD, reduces epidermal expression of
SERCA2 in rats.59
Chapter 51
encodes sarco/endoplasmic reticulum Ca2+ adenosine

triphosphatase (ATPase) isoform 2 (SERCA2), a calcium pump transporting Ca2+ from the cytosol to the
lumen of the endoplasmic reticulum (ER).811 DD is
caused by mutations inactivating one ATP2A2 allele.
ATP2A2 spans 76 kilobases (kb), is organized in 21
exons, and encodes a 4.4-kb transcript, which is alternatively spliced into three isoforms: (1) SERCA2a, (2)
SERCA2b, and (3) SERCA2c.12,13 SERCA2a is expressed
in the slow-twitch skeletal muscles and cardiac muscle, unaffected in DD.14,15 SERCA2b and SERCA2c are
expressed ubiquitously, but SERCA2b is the major isoform detected in the human epidermis.16 Mutations
specific for SERCA2b are sufficient to cause DD
(despite the presence of functional SERCA2a), confirming the important role of SERCA2b in epidermis.17,18 Most tissues may compensate for deficiencies
in SERCA2 by mechanisms such as SERCA3, which is
not expressed in keratinocytes.16
SERCA2 pumps belong to the P-type Ca2+ ATPase
family. The pumps catalyze the hydrolysis of adenosine triphosphate (ATP) coupled with the translocation
of two Ca2+ ions from the cytosol to the ER lumen,
where Ca2+ is stored at high concentrations. SERCA
pumps comprise three cytoplasmic domains [(1) the
actuator, (2) phosphorylation, and (3) ATP-binding
domains] linked to a transmembrane domain with ten
transmembrane helices that contain the two Ca2+-binding sites. After binding of cytosolic Ca2+ ions and phosphorylation, the pump undergoes conformational
changes and releases Ca2+ into the ER lumen.19
More than 140 pathogenic ATP2A2 mutations have
been reported, including missense mutations (50%),
frameshift mutations (23%), and in-frame deletions or
insertions (8%). No consistent correlation has been
demonstrated between genotype and phenotype, but
missense mutations may be associated with more
severe forms.7,17,18,2033 The considerable phenotypic
variability suggests that other genetic or environmental factors modify the phenotype.
Although the etiology has been explained, the
pathogenesis of DD is less clear. High concentrations
of Ca2+ are required for normal keratinocyte intercellular adhesion and differentiation. Normally, the epidermis displays an increasing epidermal Ca2+ gradient
from the basal to the superficial layers, but in DD this
gradient is disturbed. The level of Ca2+ is reduced in
basal cells from both affected and unaffected skin.34
The earliest ultrastructural change is breakdown of
desmosomes with aggregation of keratin filaments
around the cell nucleus.35 Immunohistological studies
of acantholytic cells reveal internalization of desmosomal components.3638 The dyskeratotic cells in the
epidermis (grains, corps ronds) are formed through
apoptosis, which appears to be triggered by the loss of
adhesion.39 The expression of antiapoptotic proteins in
the Bcl-2 gene family is reduced in DD, possibly as a
secondary phenomenon, but an alteration in Bcl-2 proteins might also contribute to apoptosis.3942
SERCA pumps replenish the ER Ca2+ pool from cytosolic Ca2+, but mutations disrupting critical functional
domains reduce activity of the pump in DD. A reduced
ER Ca2+ pool may impair processing of desmosomal
CLINICAL FINDINGS
HISTORY. (Box 51-1). The first manifestations usually
appear between the ages of 6 and 20 years with a peak
551
Calcium signaling in keratinocytes

Extracellular space
Ca2+
[Ca2+]
0.1M
1
ER
Ca2+
Ca2+
by the emptying of
4
Nucleus
PIP2
PLC
Section 7
IP3
Protein trafficking,
secretion, glysosylation
IP3R
::
[Ca2+]
300M
[Ca2+]
0.1M
Calmodulin
signaling
pathway
Ca2+
Gene expression
DAG
hSPCA1
Ca2+ channel gated

Ca2+ stores
[Ca2+]
500M
SERCA
CaR
Protein folding,
assembly
Cytosol
[Ca2+]
100nM
Na2+
Ca2+
Uniporter
Golgi
Ca2+
Na2+
Mitochondrion
[Ca2+]
0.2M
PMCA pump
NCX
Ca2+
Figure 51-1 A simplified representation of Ca2+ signaling in keratinocytes. 1. Ca2+ binding to its plasma membrane receptor (CaR) activates phospholipase C (PLC). 2. This causes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2)
into inositol 1,4,5-tris-phosphate (IP3) and diacylglycerol (DAG). 3. IP3 binds to its receptor (IP3R) at the surface of the endoplasmic reticulum (ER) and Golgi apparatus, which causes the depletion of intracellular stores and induces an increase
in intracellular Ca2+ levels. 4. This increase triggers the opening of Ca2+ release-activated channels in the plasma membrane, which leads to a sustained increase in Ca2+ intracellular levels. 5. Ca2+ binds to calmodulin; this activates calcineurin
and calmodulin-dependent protein kinases, which regulate gene transcription through phosphorylation/dephosphorylation
of transcription factors. 6. Active Ca2+ transport by the different sarco/endoplasmic reticulum calcium adenosine triphosphatase (ATPase) pumps (SERCA1 to SERCA3) and human secretory pathway Ca2+/Mn2+ATPase (SPCA1) pump is essential
to replenish ER and Golgi Ca2+ stores, respectively. SPCA1 is also required for Mn2+ influx into the Golgi apparatus (not
indicated here). 7. Ca2+ efflux to the extracellular space involves plasma membrane Ca2+ATPases (PMCA) and Na+/Ca2+ exchangers (NCX). 8. Mitochondria take up Ca2+ released from the internal stores during Ca2+ signaling via the Ca2+ uniporter
and return it to the cytosol through an NCX. Thus, Ca2+ homeostasis requires differential Ca2+ concentrations in the cytosol,
the sarco/endoplasmic reticulum, the Golgi apparatus, the mitochondria, and the nucleus of the cell. The largest store of
cellular Ca2+ is located in the ER lumen and in Ca2+-binding proteins. Ca2+ signaling is highly regulated and generated by
influx through Ca2+ receptors, release from internal stores (ER, Golgi apparatus, mitochondrion), and sequestration by Ca2+
pumps (SERCAs, SPCA1) and Ca2+ exchangers. mNCX = mitochondria Na2+/Ca2+ exchanger.
BOX 51-1 Darier Disease: What Should I look for?

A family history
Symptoms such as malodor (many patients are relieved to have an opportunity to discuss this distressing problem)
or pain (may indicate infection with Herpes simplex virus).

Exacerbating factorswhat happens in heat or sun, for example, summer?
History of cold sores. Discuss the risk of eczema
herpeticum and how to recognize.
552
Explore the impact of disease, including mood change. DD is associated with depression including suicidal ideation.
between 11 and 15 years, but DD may develop in

infants or old age.1,60 Symptoms include itch, malodor,
and pain. Heat, sweating, friction, and sunlight (UVB)
exacerbate the signs that may be noticed for the first
time in hot summer months.1,2,61
::
CLINICAL VARIANTS. Variants include painful

erosive DD,79 vesiculobullous DD,80 grossly hyperkeratotic plaques (cornifying DD),8183 nipple hyperkeratosis,84 keratoderma (Fig. 51-9), comedonal DD,33,85,86
freckled Groveroid DD87 and, in pigmented skin,
guttate leukoderma with confetti-like hypopigmented
macules, and/or papules.88,89
Figure 51-3 Darier disease: inflammatory plaques with

fissures and maceration may simulate HaileyHailey
disease. Note that the fingernails are dystrophic.
Chapter 51
CUTANEOUS LESIONS. The discrete, greasy, yellowish-brown keratotic papules (only some are perifollicular) have a predilection for seborrheic areas: central
chest and upper back, scalp (hair growth is not affected),
forehead, neck including supraclavicular fossae, ears,
and skin creases (axillae, groins, and perineum) (Figs.
51-2 and 51-3). Papules tend to coalesce into crusted
plaques (Fig. 51-4). Foul-smelling, hypertrophic disease
in the groin is particularly disabling (Fig. 51-5). In 1889,
White noted the intolerable stench that accompanies
severe disfiguring disease.62 DD may affect schooling,
work, and relationships.1,61,63
Hands and/or nails are affected in >96% of patients
and may show the first signs of disease.1,2 Look for nail
fragility, painful longitudinal splits, or distinctive red
and white longitudinal bands terminating in V-shaped
nicks (Fig. 51-6). Pits or keratotic papules on palms and,
sometimes, soles, help to confirm the diagnosis (Fig.
51-7). Many patients (5070%) have skin-colored, flattopped papules on the dorsa of hands and/or feet like
those of acrokeratosis verruciformis of Hopf (AKV).64
Hemorrhagic macules with jagged margins, possibly
linked to trauma, are the least common acral sign and
may blister (Fig. 51-8). Hemorrhagic DD has been
reported in some kindreds as well as individuals.6568
Oral,1,6971 esophageal,72,73 rectal,74 and cervical75
mucosa may be affected. Corneal abnormalities have
been recorded.7678
Figure 51-4 Malodorous confluent keratotic papules on

the chest with fissuring and hyperkeratosis of nipples in
Darier disease.
Segmental Disease.
Type 1 mosaicism presents

with one or more unilateral bands of keratotic papules
Figure 51-2 Hyperkeratotic pigmented papules on the

trunk of a patient with Darier disease.
Figure 51-5 Hypertrophic flexural Darier disease may

suggest an SCC.
553
Section 7
::
554
Figure 51-8 Hemorrhagic macule and nail dystrophy in

Darier disease.
Figure 51-6 Dystrophic fingernails showing fragility, splitting, and red and white longitudinal bands in Darier disease.
following Blaschkos lines. Hands and/or nails may be
affected on the same side90,91 (Fig. 51-8). This distribution reflects a postzygotic somatic mutation in ATP2A2
early in embryogenesis.9294 Theoretically, patients with
gonadal mosaicism could transmit generalized disease,
but no such cases have been reported. Type 2 mosaicism
is rare and characterized by a severely affected linear
band of DD, superimposed on generalized disease. A
postzygotic mutation causes loss of heterozygosity at
the ATP2A2 locus in the more severely affected skin.95
port the existence of a bipolar disorder susceptibility

gene in the DD region, but ATP2A2 has been excluded as
a common susceptibility gene for bipolar disease.103105
Learning difficulties reported in some patients may be,
at least in part, secondary to social handicap caused by
disfigurement. Bone changes, particularly bone cysts,
have been reported infrequently.106108
LABORATORY TESTS
HISTOPATHOLOGY
Histologic examination shows downgrowths of narrow cords of keratinocytes, suprabasal acantholysis
with suprabasal clefts (lacunae), dyskeratosis (premature and abnormal keratinization), and hyperkeratosis
DD has occasionally been reported in association with

neuropsychiatric disease including seizures, bipolar disorder, and schizophrenia.1,32,9698 Lithium, which may be
prescribed for bipolar disorder, exacerbates disease, possibly by suppressing levels of epidermal SERCA2.59,99101
The lifetime prevalence of major depression (30%), suicide attempts (13%), and suicidal thoughts (31%) appears
higher than in the general population, highlighting the
need for careful assessment.98,102 Reports of cosegregation of DD with bipolar disorder in some families sup-
Figure 51-7 Keratotic papules of the palms in Darier

disease.
Figure 51-9 Keratoderma in Darier disease.
BOX 51-2 Darier Disease:

Differential Diagnosis
SEBORRHEIC
Seborrheic dermatitis (scalp, trunk)
Grover disease (trunk)
Acne (forehead)
Confluent and reticulate papillomatosis (trunk)
Candida infection (inframammary)
EROSIVE
(Box 51-2)
DD may be misdiagnosed as seborrheic dermatitis
or acne, particularly in patients without a family history. Look for signs of DD in the hands or nails. Acneiform facial DD may be confused with familial
dyskeratotic comedones109,110 or comedo-like acantholytic dyskeratosis.111
Erosive, bullous, or hypertrophic flexural disease
simulates HaileyHailey disease (HHD), but HHD
tends to present later and patients do not have keratotic papules or nail fragility.112 Erosive or hypertrophic DD may also resemble pemphigus vulgaris or
vegetans (see Chapter 54), but patients do not have
mucosal ulcers and intracellular immunoglobulin (Ig)
and complement are not detected in the epidermis.
Localized hypertrophic DD may suggest malignancy
(Fig. 51-5). Freckled or papulovesicular forms
may resemble Grover disease (GD),87 but GD is not
familial (see below), or the rare acantholytic variant of
DowlingDegos disease (GalliGalli disease).113,114
Acral papules resemble plane warts or AKV (which
may be a form of DD).64,115,116 Localized papular vulvocrural acantholytic disease may be part of the spectrum of DD or HHD.117120
COMPLICATIONS
Impetiginization and eczematization may complicate
the picture and patients have an increased susceptibility to widespread infection with Herpes simplex (eczema
herpeticum) (Fig. 51-11) or Herpes zoster.121,122 Blockage
of salivary glands has been reported.1,69,80,123 SCC (scalp,
scrotal, vulval, thigh, subungual) has been recorded
COMEDONAL
Acne
Familial dyskeratotic comedones
Comedo-like acantholytic dyskeratosis
ACRAL
Plane warts
Acrokeratosis verruciformis of Hopf
FRECKLED
Grover disease
DowlingDegos diseaseacantholytic variant
Pemphigus vegetans
SCC
::
(Fig. 51-10). Apoptosis results in rounded eosinophilic

dyskeratotic cells in the epidermis (corps ronds)
and flattened parakeratotic cells in the horny layer
(grains).39 The warty papules on the backs of the hands
show the histology of AKV (see below).
VEGETATING FLEXURAL
Chapter 51
Figure 51-10 Histologic preparation of affected skin in

Darier disease showing suprabasal cleft of the epidermis
containing acantholytic cells, rounded eosinophilic dyskeratotic cells in the epidermis (corps ronds), hyperkeratosis,
and flattened parakeratotic cells in the horny layer (grains).

Bullous impetigo
Pemphigus vulgaris
(GalliGalli disease)
GENITAL
Genital warts
Vulval intraepithelial neoplasia
Papular vulvocrural acantholytic disease
infrequently, sometimes linked to the presence of

HPV16.5256
CLINICAL COURSE
DD pursues a chronic relapsing course. Severity is
unpredictable, but in about 30% of patients disease
becomes less severe in old age, while in others DD persists or gradually worsens.1,61
TREATMENT
(see Table 51-1)
The physician should take the time to answer questions, explain that treatments may control but not cure
555
Section 7
Oral acitretin 0.250.5 mg/kg or isotretinoin 0.5 mg/

kg reduces hyperkeratosis and malodor, but will take 3
to 4 months to achieve maximal effect.133 Tailor dose to
the response and monitor for adverse effects (see
Chapter 228). Pregnancy is contraindicated for 2 years
after stopping treatment with acitretin and for 1 month
after stopping isotretinoin. Oral cyclosporine has been
advocated for eczematization134 and in severe vulval
disease,135 but controlled trials are lacking.
Approaches for severe hypertrophic or erosive disease include dermabrasion, laser ablation, and photodynamic therapy, but controlled studies are needed to
evaluate these approaches.79,133,136,137 Botulinum toxin
may control flexural exacerbations by reducing sweating and mammoplasty has been advocated for severe
inframammary disease.138,139
::
ACROKERATOSIS VERRUCIFORMIS
OR ACRAL DARIER DISEASE
AKV is a rare inherited disease described by Hopf in

1931 that may be a variant of DD.64,116

Figure 51-11 Widespread vesicular rash caused by infection with Herpes simplex virus in Darier disease.
DD, and offer genetic counseling if appropriate. It is
important to discuss how to reduce the impact of triggers such as heat and sun, and use emollients containing urea or lactic acid to reduce hyperkeratosis.
Topical antiseptics (washes, bath additives), antibiotics, and antifungals will help to prevent or treat infection. Herpes simplex causes painful flares that require
oral acyclovir.121 Topical corticosteroids in combination with antibiotics reduce inflammation. Limited
disease may respond to a topical retinoid, for example, 0.1% tazorotene124,125 or 0.05% isotretinoin,126 prescribed in combination with a topical corticosteroid to
reduce irritation. Other topical agents such as adapalene,127,128 5-fluorouracil,129131 or tacrolimus132 have
been reported to be effective in small numbers of
cases.
AKV (OMIM #101900) is inherited in an autosomal

dominant fashion.115 Sporadic cases have been
reported. A missense mutation in ATP2A2, the gene
that is affected in DD, was identified in a large British pedigree. The heterozygous Pro602Leu mutation
caused complete loss of Ca2+ transport activity.116
Thus, in some instances, AKV and DD are allelic disorders, a conclusion that is entirely consistent with
the overlapping clinical features. However,
mutations in ATP2A2 were not identified in a Chinese family.140
CLINICAL FINDINGS
AKV usually presents at birth or in early childhood.
The asymptomatic, skin-colored, flat-topped warty
papules are distributed symmetrically on the dorsum
of the hands and feet (Fig. 51-12). Papules may also
develop on knees, elbows, and extensor aspects of legs
TABLE 51-1
Darier Disease: Treatment
556
First Line
Second Line
Third Line (Unproven Efficacy)
Discuss how to avoid triggers (heat,

sweating, friction) and minimize UVBinduced exacerbations.
Emollients containing urea or lactic acid.
Soap substitutes and topical antiseptics.
Moderate or potent topical corticosteroids
with topical antibiotics.
Topical retinoids: isotretinoin (0.05%, 0.1%),
tretinoin, tazarotene gel, adapalene 0.1% gel.
Oral acitretin 0.250.5 mg/kg/day. Takes 3

months to have a maximal effect. Acitretin
should be stopped for 2 years before a
woman attempts to conceive.
Oral isotretinoin 0.5 mg/kg/day.
Less effective than acitretin but may be
indicated in young women.
Isotretinoin should be stopped for 1 month
before a woman attempts to conceive.
Topical 5-fluorouracil.
Oral cyclosporine for eczematization.
Initially 2.5 mg/kg/day.
Laser surgery, electrosurgery, or
dermabrasion.
Photodynamic therapy.
Botulinum toxin to reduce sweating in
recalcitrant flexural disease. Mammaplasty
for severe inframammary disease.
Acral DD may be indistinguishable from AKV, particularly in childhood, when other features of DD may not
be apparent. AKV may resemble plane warts, stucco
keratoses, or seborrheic warts, but the family history,
symmetrical distribution, and nail changes will suggest the diagnosis.
COURSE
AKV persists and may worsen slowly with age.
LABORATORY TESTS
HISTOPATHOLOGY
The classic histopathologic findings are hyperkeratosis, hypergranulosis, and acanthosis with papillomatosis. The spiky elevations of the epidermis are said to
resemble church spires (Fig. 51-13). Epidermis is neither dyskeratotic nor acantholytic.
Figure 51-13 Histopathologic features acrokeratosis

verruciformis showing acanthosis and hyperkeratosis
with church spike elevations of the epidermis, but no
acantholysis or dyskeratosis. (Used with permission from
Dr. Laurence Lamant, Department of Pathology, Purpan
Hospital, Toulouse, France.)
HAILEYHAILEY DISEASE
EPIDEMIOLOGY
HHD (OMIM #169600), also known as familial benign
chronic pemphigus, was described by the Hailey
brothers in 1939. HHD has an incidence of at least 1 in
50,000, but prevalence may be higher as misdiagnosis
is frequent.112

The discovery of the crucial role of SERCA2 in DD
raised the possibility that defects in another calcium
pump could underlie acantholysis in HHD. The defective gene, ATP2C1, was identified in chromosome
region 3q21-24. ATP2C1 encodes an ATP-powered calcium channel pump on the Golgi membrane, the
human secretory-pathway Ca2+/Mn2+ ATPase isoform
1 (SPCA1).143145 SPCA1 belongs to the family of P-type
cation transport ATPases. HHD is dominantly inherited with complete penetrance and is caused by mutations inactivating one ATP2C1 allele.
The gene spans approximately 30 kb on 3q21 and
comprises 28 exons encoding a 4.5-kb transcript. The
predicted protein is approximately 115 kDa. Alternative splicing of ATP2C1 primary transcripts in keratinocytes leads to four splice variants, ATP2C1a to
ATP2C1d, which differ by different splicing of exon 27
and/or 28. ATP2C1d is the largest variant, containing
exons 27 and 28 in their entirety. The structure of SPCA
is similar to that of SERCA (see section Darier Disease), but the SPCA-binding site only transports a
single Ca2+ or Mn2+ ion into the Golgi lumen.19,144,146,147
Around 100 mutations have been reported in HHD
scattered across the ATP2C1 gene.143,144,148161 No correlations have been found between genotype and phenotype; clinical features vary.149 Mutations predict marked
reduction of SPCA1 or cause changes in highly
and forearms.64 As in acral DD, punctate keratoses and

pits may be present on palms and soles, palmar skin
may be thickened, and patients may have subungual
hyperkeratosis, longitudinal striations, splits, and
V-shaped nicks at the free margin of the nail plates. A
linear variant with persistent localized unilateral
lesions has been reported in two unrelated Saudi
patients.141
::
Figure 51-12 Small, flesh-colored papules over the

dorsum of the hand in acrokeratosis verruciformis of Hopf.
None may be needed. Topical retinoids may flatten

lesions. Destruction by cryosurgery, shave, curettage,
or laser surgery can be effective. Oral acitretin has been
helpful.142
Chapter 51
TREATMENT
557
Section 7
::
c onserved domains that are critical for function.143,145,153,162165

Haploinsufficiency appears to be the mechanism for dominant inheritance, but it is not clear how loss of one functional ATP2C1 allele causes acantholysis.
Ultrastructural studies of acantholytic cells reveal
desmosomal breakdown with retraction of keratin filaments from desmosomal plaques to form perinuclear
aggregates.166,167 Desmosomal components, E-cadherin,
and connexins are internalized in acantholytic cells and
the expression of keratins is abnormal in lesional
skin.34,3638,168172 The abnormality in cell adhesion may
be revealed in normal-looking skin in patients with
HHD using suction.173
Immunohistochemical studies suggest that SPCA1 is
localized to the basal layer of normal epidermis.174 Total
[Ca2+] in the epidermal granular layer is reduced and
the normal epidermal Ca2+ gradient attenuated in both
affected and unaffected skin.143,163 Golgi Ca2+ stores are
reduced, Ca2+ signaling is abnormal and the normal
upregulation of transcription of ATP2C1 mRNA by
Ca2+-stimulation is suppressed in HHD keratinocytes.143,145,163,175177 Elevated cytosolic Ca2+ levels could
influence gene expression or alter posttranslational
modification of target proteins. Alternatively, low Ca2+
or Mn2+ concentrations in the Golgi lumen could impair
posttranslational modifications (proteolytic processing,
glycosylation, trafficking, or sorting) of proteins important in epidermal cell-to-cell adhesion.
Cultured keratinocytes from involved skin display
altered patterns of calcium metabolism and reduced proliferative capacity. Increased oxidative stress in HHD
keratinocytes may lead to reduced expression of proteins involved in regulation of the balance between proliferation and differentiation such as Itch and Notch1.161,178
Reorganization of actin is defective, cellular ATP
decreased, and synthesis of involucrin is reduced.161,179181
Mice deficient for SPCA1 develop squamous cell papillomas and carcinomas similar to those seen in SERCA2
deficient mice (see section Darier Disease).176
Although ATP2C1 mRNA is expressed ubiquitously,
HHD is limited to the skin. Keratinocytes may be more
sensitive to levels of SPCA1 than other cells because,
unlike most other cells, the Golgi in keratinocytes lack
SERCA to compensate for deficient SPCA1.147 UVB
irradiation and proinflammatory cytokines reduce
expression of ATP2C1 mRNA in cultured normal keratinocytes, but suppression is inhibited by retinoids,
corticosteroids, cyclosporine, tacrolimus, and vitamin
D3.58 External factors (UVB, sweating, friction) may
reduce the amount of SPCA1 to a critical level leading
to the expression of disease.147
BOX 51-3 HaileyHailey Disease:

What should I look for?
Consider the possibility of HHD in any young adult
with chronic eczema at sites of friction such as the
neckline, axilla, or groins. The diagnosis is often missed.
Look for:
Family history
Exacerbating factors: wearing stiff collars, in heat, or
when exercising
Postinflammatory hyperpigmentation (common)
Longitudinal white bands in nails (uncommon but
very helpful if present)
Signs include crusted weeping erosions, vesicopustules, expanding annular plaques with peripheral
scaly borders and vegetating plaques with fissures
(rhagades). Postinflammatory hyperpigmentation is
frequent (Figs. 51-14 and 51-15). Some patients have
longitudinal white lines on the fingernails and these
can help to confirm the diagnosis112,182,183 (Fig. 51-16).
Disease may be limited to one or two sites, more widespread or rarely generalized with erythroderma,184186
but even mild disease reduces quality of life.63,187 Painful malodorous inguinal or perineal disease is particularly disabling. HHD koebnerizes into inflammatory
dermatoses and has been exacerbated (or diagnosed)
after triggers such as contact dermatitis, removal of
adherent patch tests, UV irradiation, cutaneous
HISTORY AND CLINICAL FINDINGS
558
(Box 51-3)
HHD usually presents between the second and
fourth decades, predominantly at sites of friction
(neck, axillae, inframammary, groin, perineum).112 The
diagnosis is often delayed because HHD simulates
common dermatoses such as eczema, tinea, and impetigo.112 Itch, pain, and malodor are common complaints.
Figure 51-14 Crusted plaques with postinflammatory hyperpigmentation in a patient with HaileyHailey disease.
LABORATORY TESTS
HISTOPATHOLOGY
Involved skin displays widespread partial loss of cohesion (keratinocytes may still be linked together by
adherens junctions206) between suprabasal keratinocytes with an appearance likened to a dilapidated
brick wall (Fig. 51-17). Clusters of loosely coherent
cells float in suprabasal clefts or bullae. Dyskeratosis,

when present, is usually mild, but changes may resemble those in DD.
(Box 51-4)
Eczema or infection (bacterial, fungal, or viral) is the
most common misdiagnosis. Hypertrophic flexural
BOX 51-4 HaileyHailey Disease:

SEGMENTAL DISEASE. In Type 1 mosaicism, a

postzygotic mutation in ATP2C1 manifests as one or
more localized streaks of HHD along Blaschkos
lines.204 Type 2 mosaicism has been confirmed in a
patient with severe linear involvement superimposed
on symmetrical HHD. In the more severely affected
skin, a postzygotic mutation had caused loss of heterozygosity at the ATP2C1 locus.205
::
i nfections, and scabies infestation.173,186,188196 Generally,

HHD does not involve mucosa. Rare instances of conjunctival, oral, esophageal, or vaginal involvement
may have been initiated by trauma or infection.197203
Chapter 51
Figure 51-15 HaileyHailey disease with a hypertrophic

macerated axillary plaque and painful fissures (rhagades).
Figure 51-17 HaileyHailey disease. Extensive partial loss

of intercellular contacts within the epidermis produces the
appearance of a dilapidated brick wall.
ANNULAR OR CRUSTED PLAQUES

Eczema including allergic contact dermatitis
Impetigo
Candida infection
Tinea corporis
Darier disease
VESICOPUSTULES
Eczema
Bullous impetigo
Herpes simplex
Grover disease
Pemphigus vulgaris
Toxic epidermal necrolysis (if widespread)
VEGETATING FLEXURAL
Darier disease
Pemphigus vegetans
SCC
LOCALIZED GENITAL
Figure 51-16 White longitudinal lines on the nail of a

patient with HaileyHailey disease.
Papular vulvocrural acantholytic disease

Genital warts
Darier disease
Vulval intraepithelial neoplasia
559
HHD resembles DD, but acantholysis is more widespread and dyskeratosis less prominent in HHD than
in DD. Eroded or vesiculobullous HHD may simulate
toxic epidermal necrolysis207 or pemphigus vulgaris
(intracellular IgG and complement are not detected in
the epidermis). Genital HHD may simulate viral
warts119,208,209 or vulval intraepithelial neoplasia.210 Papular acantholytic disease limited to the genitalia may
be a separate entity, but the identification of an ATP2C1
mutation in one case suggest that some cases are part
of the spectrum of HHD.117,120,209,211,212
Section 7
::
COMPLICATIONS. Superimposed bacterial or candidal infections are common.213 Herpes simplex causes
painful exacerbations, which may disseminate.214216
Tinea was a cause of treatment failure in one patient.217
Allergic contact dermatitis has been described, but the
frequency of positive patch tests is probably not
increased.218,219 Skin cancers (SCC more often than
BCC) have been reported in association with HHD.
SCC may be linked to the presence of human papillomas virus.220225 Affective disorder cosegregated with
HHD in three families.226228
COURSE
The course is chronic, punctuated by relapses and
remissions, but some patients improve in old age.
TREATMENT
(Table 51-2)
Triggers such as heat, sweating, and friction should
be minimized. Clothing should be soft, loose-fitting,
and cool. Weight loss may be helpful. Patients should
be offered genetic counseling.
Treatment is difficult and no controlled trials have
been performed. Recommendations in the literature
are subject to citation bias and most are based on the
response of one or two cases without any long-term
follow-up.
It is appropriate to culture skin for bacteria and

yeasts, and control infection with antibacterial and/or
antifungal agents. It has been suggested that topical
gentamicin may be particularly effective in patients
harboring a nonsense mutation in ATP2C1, because
aminoglycosides induce read-through of nonsense
mutations in human cells.229 The role of long-term,
low-dose systemic antibiotics is unproven.
Pain may limit application of topical agents, but
potent or ultrapotent topical corticosteroids (aqueous
lotions, foams, creams, or ointments) can be effective.112,230 Cutaneous atrophy after prolonged treatment
with potent corticosteroids increases skin fragility.
Other topical agents that have been recommended
include calcitriol,231,232 tacalcitol,233 and topical 5-fluorouracil.234 Tacrolimus helped some cases,230,235238 but was
ineffective in others.239 Analgesia is crucial and morphine may be needed in severe disease.
Systemic corticosteroids are a short-term option for
widespread disease.240 Other systemic agents that
have been advocated include calcitriol,241 retinoids,242,243 methotrexate,244 cyclosporine,245,246 dapsone,247,248 etanercept,249 and alefacept.250 Surgical
approaches that have been used in recalcitrant disease
include excision with or without grafting,251253 dermabrasion,254256 and laser surgery.256259 Other interventions that have been tried include mammoplasty for
inframammary disease, superficial X-ray therapy
(unhelpful),260 electron beam therapy,261 and photodynamic therapy (very painful with variable outcomes).262,263 Botulinum toxin may help flexural
disease by reducing sweating.256,264,265
GROVER DISEASE
EPIDEMIOLOGY
Grover disease (GD, transient or persistent acantholytic dermatosis) is an acquired condition, first
described in 1970, that is most common in fair skinned
men >age 40 years. The male to female ratio is 3:1.266269
TABLE 51-2
HaileyHailey Disease: Treatment
560
First Line
Second Line
Third Line (Unproven Efficacy)
Minimize friction and sweating

Emollients containing antibacterials
Soap substitutes
Antiseptic bath additives
Moderately potent or potent topical
corticosteroids in combination with
topical or oral antibiotics and/or
antifungal agents to control secondary
infection
Pain relieftopical or oral (some patients
require morphine)
Ultrapotent topical corticosteroid

in combination with topical or oral
antibiotics and/or antifungal agents to
control secondary infection
Prednisolone 2030 mg/day reduced
gradually to control acute exacerbations
Antistaphylococcal antibiotics, e.g., lowdose tetracycline for 6 months or longer

Topical tacrolimus
Topical tacalcitol or calcitriol
Topical 5-fluorouracil
Oral cyclosporine 2.5 mg/kg
Oral retinoidsstart in a low dose to
minimize irritation
Methotrexate 1015 mg/week
Excision, laser surgery, or dermabrasion
Botulinum toxin to reduce sweating in
recalcitrant flexural disease
Mammoplasty for severe inframammary
disease
Chapter 51
CLINICAL FINDINGS
Although GD shares clinical, histologic, and ultrastructural features with DD, ATP2A2 (the defective
gene in DD) does not appear to be involved.270,271 GD
may be triggered by factors that promote sweating,
for example, febrile illnesses or occlusion,272275 but is
also common in the winter in elderly men with dry
skin.269,276278 Other associations include UV or ionizing radiation, inflammatory dermatoses such as
Most often GD presents with an itchy rash on sundamaged skin of the trunk. Itch may be intense and out
of proportion to the signs, which comprise scattered
pinkish or redbrown papules with variable hyperkeratosis, papulovesicles (rarely bullae) or, less often,
eczematous plaques (Figs. 51-18 and 51-19). Neck and/
or proximal limbs can be affected.269,278,284287 GD has
been described in association with widespread
Figure 51-18 Grover disease. Itchy papules on the trunk

resembling folliculitis in a 60-year-old man.
atopic eczema, renal failure, HIV infection, malignancies, organ transplants, and some drugs.268,269,279283
Electron microscopy shows clumping of keratin filaments with loss of desmosomes and immunostaining
reveals that desmosomal components are internalized.36,37
::
Figure 51-19 Grover disease. Discrete papulovesicular

lesions with crusts in a 53-year-old man.
Figure 51-20 A. HaileyHailey-like histological pattern in Grover disease with detached keratinocytes (acantholysis),
focal spongiosis, and epidermal hyperplasia. B. Pemphigus-like pattern in Grover disease with suprabasal acantholytic
cleavage.
561
BOX 51-5 Grover Disease:

Papular eczema or prurigo
Folliculitis
Sun damage with solar lentigines and solar keratoses
Scabies
Insect bites
Miliaria rubra
Darier disease
Pemphigus vulgaris
Precipitating factors, including soap and other topical irritants, should be avoided. Emollients, antipruritics, or wet dressings may be soothing. Sometimes
topical medicaments such as corticosteroids, retinoids, calcipotriol, or tacalcitol relieve irritation.
Oral retinoids, oral corticosteroids, UVB, PUVA, and
methotrexate have been advocated for persistent
disease, but controlled trials are needed to confirm
efficacy. The response to treatment is often disappointing.269,287,294298
Section 7
KEY REFERENCES
::
sun-induced lentigines.271,288 Guttate leukoderma, similar to that seen in DD, has been observed in dark
skin.289 Unilateral GD has been reported, but this may
have been segmental DD.290,291
LABORATORY TESTS
HISTOPATHOLOGY
The histological picture is variable and may suggest
spongiotic dermatitis, DD, HHD, or pemphigus (no Ig
or complement is found in the epidermis). Acantholysis is often subtle and focal.267,278,285 (See Fig. 51-20).
(See Box 51-5)
Other causes of itching such as scabies, insect bites,
and eczema should be excluded. Clinicopathological
correlation, including family history and examination
of nails and mucous membranes, will help to exclude
other causes of acantholysis.
COURSE
GD may clear within a few months (transient acantholytic dermatosis), or the itch may persist with fluctuating intensity for years (persistent acantholytic
dermatosis), especially in the elderly.292,293
562
TREATMENT

9. Hovnanian A: SERCA pumps and human diseases. Subcell Biochem 45:337, 2007
17. Dhitavat J et al: Mutations in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase isoform cause Dariers
disease. J Invest Dermatol 121:486, 2003
34. Leinonen PT et al: Reevaluation of the normal epidermal
calcium gradient, and analysis of calcium levels and ATP
receptors in Hailey-Hailey and Darier epidermis. J Invest
Dermatol 129:1379, 2009
49. Pani B et al: Up-regulation of transient receptor potential canonical 1 (TRPC1) following sarco(endo)plasmic
reticulum Ca2+ ATPase 2 gene silencing promotes cell
survival: A potential role for TRPC1 in Dariers disease.
Mol Biol Cell 17:4446, 2006
112. Burge SM: Hailey-Hailey disease: The clinical features,
response to treatment and prognosis. Br J Dermatol
126:275, 1992
116. Dhitavat J et al: Acrokeratosis verruciformis of Hopf is
caused by mutation in ATP2A2: Evidence that it is allelic
to Dariers disease. J Invest Dermatol 120:229, 2003
133. Cooper SM, Burge SM: Dariers disease: Epidemiology,
pathophysiology, and management. Am J Clin Dermatol
4:97, 2003
145. Missiaen L et al: Calcium in the Golgi apparatus. Cell Calcium 41:405, 2007
161. Cialfi S et al: Complex multipathways alterations and
oxidative stress are associated with Hailey-Hailey disease. Br J Dermatol 162:518, 2010
269. Parsons JM: Transient acantholytic dermatosis (Grovers disease): A global perspective. J Am Acad Dermatol
35:653, 1996
Chapter 52 :: Porokeratosis

:: Grainne M. ORegan & Alan D. Irvine
POROKERATOSIS AT A GLANCE
A chronic progressive disorder of
keratinization, characterized clinically
by hyperkeratotic papules or plaques
surrounded by a thread-like elevated border
that expands centrifugally.
Linear porokeratosis presents at birth or in

childhood with lesions distributed along
Blaschkos lines.
Punctate porokeratosis appears during or
after adolescence as 1- to 2-mm papules on
the palms or soles.
In all variants, a thin column of parakeratotic
cells (cornoid lamella) corresponds to
the hyperkeratotic border and extends
throughout the stratum corneum in
histologic sections.
A genetically heterogeneous disorder;
the majority of forms may be inherited as
autosomal dominant traits.
Malignant epithelial neoplasms are reported
in all subtypes except the punctate variety.
Porokeratosis is a morphologically distinct disorder of

keratinization, characterized clinically by hyperkeratotic papules or plaques surrounded by a thread-like
elevated border that expands centrifugally. Histologically, a thin column of parakeratotic cells extends
throughout the stratum corneum and is seen in all
variants. This distinctive histopathologic feature,
known as the cornoid lamella, corresponds to the raised
hyperkeratotic border evident clinically.
At least six clinical variants of porokeratosis are recognized; however, the clinical distinction between
Porokeratosis is a genetically heterogeneous disorder

with multiple loci identified to date; however, the
pathogenetic mechanisms remain elusive. Loci at chromosome bands 12q23.224.1 and 15q25 (DSAP1 and
DSAP2) have been reported in familial disseminated
superficial actinic porokeratoses; a further locus has
been identified for disseminated superficial porokeratosis (DSP) at 18p11.3.4,5 The locus at DSAP1 corresponds to a candidate gene, SART3 (squamous cell
antigen recognized by T cells 3); this encodes a tumor
rejection antigen thought to be involved in the regulation of messenger RNA splicing. Fine mapping of the
locus at DSAP1 has also revealed mutations in another
potential candidate gene, SSH1 (slingshot 1), and a
variation in the promoter region of ARPC3, which play
a key role in actin dynamics.68 Missense mutations in
SSH1 in this kindred have been shown to result in loss
of heterozygosity in DSAP.9 However, microarray
expression and real time quantative polymerase chain
reaction (PCR) profiles of SART3, SSH1, and ARPC3
have failed to show differential expression patterns.10,11
Porokeratosis punctata palmaris et plantaris maps to a
Porokeratosis
Disseminated superficial actinic

porokeratosis is the most common type, with
multiple papules distributed symmetrically
on sun-exposed areas.
::
The classic form, porokeratosis of Mibelli,

presents in infancy or childhood as
asymptomatic small brown to skin-colored
annular papules with a characteristic raised
border.
these morphological variants may not be justified (Box

52-1). Reports of one type of porokeratosis coexisting
with other forms and different types developing in
multiple members of an affected family suggest more
similarities than disparities, particularly in the disseminated forms.13
Chapter 52
At least six clinical variants of porokeratosis

have been described.
BOX 52-1 Clinical Variants

of Porokeratosis
Porokeratosis of Mibelli
Disseminated superficial
actinic porokeratosis
(DSAP)
Disseminated superficial
porokeratosis (DSP)
Porokeratosis palmaris
et plantaris disseminata
(PPPD)
Punctate porokeratosis
(PP)
Linear porokeratosis (LP)
Syndromic form: CAP
(craniosynostosis, anal
anomalies, and porokeratosis) syndrome
OMIM #175800
OMIM #175900 and
#607728
OMIM #175860
OMIM #603116
OMIM = Online Mendelian Inheritance in Man.
563
Section 7
::
6.9-centimorgan region at chromosome band 12q24.1

24.2, overlapping with the region identified for DSAP1,
suggesting that the two forms may be allelic.12 The centrifugal expansion of lesions is postulated to reflect the
migration of a mutant clone of keratinocytes.13 Supporting this mutant clone theory are findings of abnormal DNA ploidy and chromosomal abnormalities in
lesional keratinocytes.14 The tumor suppressor proteins p53 and pRb are overexpressed in keratinocytes
immediately beneath and adjacent to the cornoid
lamella, although to date p53 mutations have not been
identified, and there is no significant expression of p53
at an mRNA level.1519,11 Cytogenetic abnormalities in
fibroblasts, particularly on chromosome 3, have also
been documented.20,21 Decreased mdm2, abnormal
expression of psi-3, cytokeratins, filaggrin, and involucrin have also been reported.22,23 The increased prevalence of porokeratosis in immunosuppressed patients
suggests that impaired immunity may be permissive
in genetically predisposed individuals.2427 Other
reported triggering factors such as exposure to ultraviolet (UV) light, together with the increased potential
for malignant transformation, highlight the dysplastic
potential of affected keratinocytes. Malignant degeneration has been described in all variants of porokeratosis, with the exception of the punctate variety.2830
CLINICAL FINDINGS
POROKERATOSIS OF MIBELLI
Classic porokeratosis of Mibelli begins during infancy
or childhood as asymptomatic small brown to skin-colored annular papules with a characteristic annular border (Fig. 52-1). The well-demarcated hyperkeratotic
border is usually more than 1 mm in height, with a char-
acteristic longitudinal furrow. The center of the lesion

may be hyperpigmented, hypopigmented, depressed,
atrophic, or anhidrotic. Lesions range in diameter from
millimeters to several centimeters, but giant lesions
measuring up to 20 cm may occur. Such giant porokeratoses are rare and occur predominantly on the lower leg
and foot. Large lesions are associated with a higher
malignant potential.30 Multiple lesions may arise; however, they are usually regionally localized and unilateral. The condition may be familial and inherited as an
autosomal dominant trait. Lesions persist indefinitely.
DISSEMINATED SUPERFICIAL
ACTINIC POROKERATOSIS
Disseminated superficial actinic porokeratosis (DSAP)
is the most common of the porokeratoses. Lesions are
characteristically uniformly small, annular, asymptomatic, or mildly pruritic papules ranging from 2 to 5
mm in diameter, distributed symmetrically on the
extremities. Lesions are more generalized than other
forms of porokeratosis, with typically in excess of 50
lesions located predominantly in sun-exposed sites
(Fig. 52-2A and B). Although widespread, lesions typically spare palms, soles, and mucous membranes.
Compared with porokeratosis of Mibelli, the hyperkeratotic border is characteristically more subtle. As
the lesions progress, the older, central area becomes
atrophic and anhidrotic. DSAP tends to be inherited as
an autosomal dominant disorder, with the earliest
reported age of onset at 7 years, and is usually fully
penetrant by the third or fourth decade of life.5 Initial
reports of induction of lesions by exposure to UV light
and hypersensitivity of DSAP-derived fibroblasts to
X-rays have not been consistently reproduced, and the
pathogenesis of DSAP remains unknown.15,3133
POROKERATOSIS
DSP also shows an autosomal dominant pattern of
inheritance and has its onset in the third or fourth
decade of life. Lesions primarily are morphologically
identical to those of DSAP, occur on the extremities,
and are typically distributed symmetrically, but do not
spare sun-protected areas as in DSAP. As with DSAP, in
excess of 100 lesions may be disseminated, with a predilection for the extensor surfaces of the extremities.
Notably, involvement of the face is rare in both DSAP
and DSP. In both disseminated forms, there is a reported
female predominance, with a femalemale ratio of 3:1.
POROKERATOSES OF
IMMUNOSUPPRESSION
564
Figure 52-1 Porokeratosis of Mibelli is characterized by a

single large lesion with a clearly defined edge. The scaling
is not clearly seen at the border because of the interdigital
location of this lesion.
Disseminated superficial porokeratosis in the context

of immunosuppression is recognized following renal,
hepatic, and cardiac transplantation, electron beam
irradiation,34 immunosuppressive chemotherapy, and
Chapter 52
::
Porokeratosis
Figure 52-2 A. Disseminated superficial actinic porokeratosis with multiple lesions on the forearm in this severely
affected individual. B. The characteristic furrowing (arrows) is clearly demonstrated on the forearm of this patient.
the use of systemic corticosteroids; with hematopoietic
malignancies35; and in the setting of human immunodeficiency virus infection.36 Porokeratosis has also
been reported after bone marrow transplantation in
the absence of ongoing immunosuppressive therapy,
which suggests a more complex association than
immunosuppression alone.37 The distribution and
morphology of DSP of immunosuppression are similar
to those of DSAP, but a history of sun exposure is less
evident.
by the loss of heterozygosity for the DSAP allele and

provides an example of the type 2 segmental manifestations of an autosomal dominant disorder.43,44
POROKERATOSIS PALMARIS ET
PLANTARIS DISSEMINATA
Porokeratosis palmaris et plantaris disseminata (porokeratosis punctata palmaris et plantaris) is a genodermatosis with an autosomal dominant inheritance
LINEAR POROKERATOSIS
Linear porokeratosis is an uncommon variant, traditionally categorized as a separate entity, but is increasingly recognized as mosaic manifestation of one of the
other types of porokeratosis.38 Typically, it presents in
early childhood, although congenital presentations
have been reported.39 Two distinct clinical variants
have been described. The more common presentation
consists of a unilateral lesion confined to an extremity
following Blaschkos lines (Fig. 52-3). In the rare generalized form, multiple lesions affect several extremities
and may involve the trunk. Linear variants have the
highest potential for malignant degeneration of all the
porokeratoses. It has been postulated that this association can be attributed to allelic loss due to a postzygotic
mutation.40 The proband in Mibellis original publication most likely had coexistent linear porokeratosis and
DSAP, with several subsequent reports confirming this
phenomenon.4,38,41,42 These findings may be explained
Figure 52-3 Linear porokeratosis showing the characteristic distribution along Blaschkos lines.
565
lesions appear during adolescence or early adulthood

and are bilateral and distributed symmetrically. Porokeratosis palmaris et plantaris disseminata affects
males twice as often as females.
PUNCTATE POROKERATOSIS
Section 7
Punctate porokeratosis usually appears during adolescence or adulthood and may be seen concomitantly
with other types of porokeratosis. Multiple minute
and discrete punctate, hyperkeratotic lesions surrounded by a thin, raised margin are present on the
palms and soles. Lesions may occur in a linear arrangement, or they may aggregate to form plaques. Punctate porokeratosis must be differentiated clinically
and histologically from punctate keratoderma, also
referred to as punctate porokeratotic keratoderma or
as porokeratosis punctata palmaris et plantaris (see
Chapter 50).
::
CDAGS SYNDROME
Figure 52-4 Porokeratosis palmaris et plantaris disseminata showing multiple superficial lesions on the calf. Note
the similarity to disseminated superficial actinic porokeratosis shown in Fig. 52-2A.
pattern characterized by small, relatively uniform
lesions (Fig. 52-4) that initially appear on the palms
and soles. Subsequently, lesions spread to involve
other parts of the body, including the mucous membranes and nonsun-exposed sites. The palmar and
plantar lesions are generally more hyperkeratotic, and
the characteristic longitudinal furrow along this ridge
may be quite pronounced (Fig. 52-5). Typically, the
CDAGS syndrome (craniosynostosis and clavicular

hypoplasia, delayed closure of the fontanel, anal anomalies, genitourinary malformations, skin eruption),
also referred to as CAP syndrome (craniosynostosis, anal
anomalies, and porokeratosis), is a rare genodermatosis
reported in four ethnically diverse families to date.45,46
The main phenotypic features consist of craniosynostosis and clavicular hypoplasia, anal anomalies, and
porokeratosis. It appears to segregate as an autosomal
recessive trait, with possible linkage to chromosome
band 22q1213. The cutaneous manifestations are
strikingly consistent, with the development of small,
widespread porokeratotic papules from 1 month of
age in affected individuals, predominantly affecting
the face and extremities, with reported photoaggravation of lesions.
HISTOPATHOLOGY
566
Figure 52-5 Sole of the foot in a patient with porokeratosis palmaris et plantaris disseminata. The ridge and furrow
are clearly seen.
Histopathologic patterns are similar in all forms of

porokeratosis, with the characteristic changes evident
at the raised and advancing edge of the lesion. The
stratum corneum is hyperkeratotic, with a thin column
of poorly staining parakeratotic cells, the cornoid
lamella, running through the surrounding normalstaining cells (Fig. 52-6). The underlying keratinocytes
are edematous with spongiosis and shrunken nuclei,
and a striking dermal lymphocytic pattern may be evident. Underlying the cornoid lamella, the granular
layer is either absent or markedly reduced but is of
normal thickness in other areas of the lesion. The epidermis in the central portion of porokeratosis may be
normal, hyperplastic, or atrophic. Although characteristic of porokeratosis, the cornoid lamella is not
pathognomonic and may also be found in other conditions, such as viral warts, some ichthyoses, and nevoid
hyperkeratoses.

of Porokeratosis
LOCALIZED LESIONS
Most Likely
Granuloma annulare
Tinea corporis
Actinic keratosis
Viral warts
TREATMENT
Lesions of porokeratosis are chronic, slowly progressive, and relatively asymptomatic, although intense
pruritus has been reported.47 Intervention is usually
unnecessary, and disease surveillance is standard. If
the lesions are problematic or cosmetically unacceptable, treatment with potent topical steroids, keratolytics, topical retinoids, topical 5-fluorouracil,48 imiquimod
Porokeratosis
The classic lesions of porokeratosis are clinically distinctive, and the diagnosis is usually clinically apparent.
However, atypical lesions may require differentiation
(Box 52-2). Actinic keratoses, for example, may show
cornoid lamellae, but also show cytologic atypia. Verruca vulgaris often shows mounds of parakeratosis that
are sometimes identical to cornoid lamellae, but koilocytosis is usually present. Linear porokeratosis may be
clinically confused with other linear lesions (Box 52-2),
none of which has a cornoid lamella.
Consider
Linear inflammatory verrucous epidermal nevus
Incontinentia pigmenti (stage II)
Linear lichen planus
Ichthyosis linearis circumflexa
::
LINEAR
Chapter 52
Figure 52-6 The cornoid lamella arises from an indentation of the epidermis and extends as a thin column
throughout the stratum corneum. The underlying granular layer is either absent or reduced.
Consider
Elastosis perforans
Lichen planus
Focal dermal hypoplasia (Goltz syndrome)
5%, calcipotriol,49 anthralin,50 cryotherapy,51 carbon

dioxide laser,52 pulsed dye laser,53 or neodymium:
yttrium-aluminumgarnet laser may be considered
(Box 52-3). In order to prevent residual lesions or
recurrence, ablative measures that reach the middermis are required. Techniques such as curettage, excision, and dermabrasion,54 have been used with
variable degrees of success. Oral retinoids have been
shown to give the most reproducible results, although
the disease typically recurs after their discontinuation.
Given the association with malignancy, closer disease
surveillance and a lower threshold for biopsy of suspicious lesions may be warranted in cases of giant porokeratoses, linear lesions, and in immunosuppressed
individuals.
BOX 52-3 Treatment for Porokeratosis

TOPICAL
SURGICAL
First line
Photoprotection
5-Fluorouracil
Cryotherapy
Second line
Calcipotriol
Imiquimod
Topical retinoids
CO2 laser vaporization
Third line
Dermabrasion
Neodymium:yttrium-aluminumgarnet laser
Grenz ray
Surgical excision
SYSTEMIC
Oral retinoids
567
Section 7
::
568
COURSE AND PROGNOSIS

The porokeratoses are generally chronic and progressive, with lesions increasing in size and number with
time. Typically, this process occurs over decades in
porokeratosis of Mibelli, but may be rapid in DSAP,
particularly after sun exposure. In cases of immunocompromise, fluctuations in severity may parallel the
state of immunocompetence, and there are reports of
remission after removal of primary malignancy.27 The
disease is generally considered a benign process; however, malignant degeneration may occur. Malignancy
is thought to arise in 7% to 11% of individuals, although
these figures are likely overestimated. Squamous cell
carcinoma is the most frequently associated tumor and
may be invasive. Bowen disease and basal cell carcinoma have also been reported. Spontaneous resolution
of lesions has been reported, although it is exceptionally rare.55
KEY REFERENCES
1. Lin JH et al: Coexistence of three variants of porokeratosis with multiple squamous cell carcinomas arising from
lesions of giant hyperkeratotic porokeratosis. J Eur Acad
Dermatol Venereol 20:621, 2006
8. Zhang ZH et al: Loss of heterozygosity analysis on chromosome 12q in disseminated superficial actinic porokeratosis. J Invest Dermatol 127(2):482-5, 2007
9. Zhang ZH et al. Gene expression profiling of porokeratosis. J Cutan Pathol 35:1058, 2008
23. Bencini PL et al: Porokeratosis and immunosuppression.
32. Schamroth JM et al: Porokeratosis of Mibelli. Overview and
review of the literature. Acta Derm Venereol 77:207, 1997
37. Happle R: Mibelli revisited: A case of type 2 segmental porokeratosis from 1893. J Am Acad Dermatol 62(1):136-138, 2010
43. Happle R: Somatic recombination may explain linear
porokeratosis associated with disseminated superficial
actinic porokeratosis. Am J Med Genet 39:237, 1991
Disorders of Epidermal and Dermal

Epidermal Adhesion and Vesicular and
Bullous Disorders
Chapter 53 :: E
pidermal and EpidermalDermal
Adhesion

:: Leena Bruckner-Tuderman &
Aimee S. Payne
EPIDERMAL AND EPIDERMALDERMAL ADHESION AT A GLANCE
The adhesive structures in the skin
include desmosomes, focal adhesions,
hemidesmosomes, and basement membranes.
Functional specificity of basement membranes

is provided by additional tissue-specific
glycoproteins.
Desmosomes are primarily responsible for

epidermal adhesion.
In addition to their structural roles, desmosomes,

hemidesmosomes, and the epidermal basement
membrane are biologically active in cellular
signaling.
The major components of desmosomes are

the desmosomal cadherins (desmogleins
and desmocollins), plakins (desmoplakin,
envoplakin, and periplakin), and armadillo
family proteins (plakoglobin and plakophilins).
The hemidesmosomal components comprise
plakin homologs, integrins, and collagenous
transmembrane proteins.
All basement membranes contain collagen IV,
laminins, nidogens, and perlecan.
The cellcell and cellbasement membrane adhesion

in the epidermis provides the skin with its resistance
against environmental influences; epidermal integrity is required for protection of the entire organism
against mechanical, physical, or microbial insults.
The major cellular structures involved are the desmosomes at cellcell junctions in the epidermis and
the hemidesmosomebasement membrane adhesion complexes and related structures at the dermal
epidermal junction. Ultrastructurally, the hemidesmosome closely resembles one-half of the desmosome;
however, at the molecular level, these two structures
are distinct. Both represent specifically organized
assemblies of intracellular and transmembrane molecules. The desmosome anchors cytoskeletal filaments to cellcell junctions, and the hemidesmosome
anchors cytoskeletal filaments of basal epithelial cells
Mutations in the genes encoding the above proteins

cause hereditary skin diseases, ranging from
hypotrichosis and keratoderma to epidermolysis
bullosa and Kindler syndrome.
Protein components of desmosomes,
hemidesmosomes, and epidermal basement
membrane are targeted in autoimmune blistering
diseases of the pemphigus or pemphigoid group
and in epidermolysis bullosa acquisita.
to the basement membrane. Our knowledge of the

desmosomal, hemidesmosomal, and basement membrane molecules has expanded drastically in recent
years due to the great power of both molecular genetics and proteomics. After keratinocyte transmembrane
proteins were initially identified as autoantigens in
pemphigus and pemphigoid, a multitude of molecules have now been characterized at both protein
and gene levels, and their expression, regulation, and
functions have been discerned. The antigenic epitopes
in different autoimmune blistering skin diseases have
been carefully mapped and, to date, mutations in at
least 24 different genes have been shown to underlie
heritable disorders of epidermal or epidermaldermal
adhesion in humans and mice. Morphologic, molecular, and functional aspects of these adhesion structures
are delineated in this chapter.
EPIDERMAL ADHESION
ULTRASTRUCTURE OF DESMOSOMES
Section 8
::
Disorders of Epidermal and DermalEpidermal Adhesion
The desmosome (or macula adherens) is the major cell

adhesion junction of the epidermis, serving to anchor
apposing keratinocyte cell surface membranes to the
intracellular keratin intermediate filament network.
Desmosomes are present in almost all epithelial tissues, including the oropharynx, gut, liver, heart, lung,
bladder, kidney, prostate, thymus, cornea, and central
nervous system, although the desmosomal protein
isoforms and intermediate filament proteins vary by
cell type.1 The primary role of desmosomes in epidermal cell adhesion is evidenced by the histologic findings in epidermal spongiosis, or intercellular edema,
in which adjacent keratinocytes remain attached to
each other only at desmosomal junctions (Fig. 53-1).
These intercellular bridges served as the earliest
description of desmosomes in tissues, their observation made possible with the advent of light microscopy in the nineteenth century.2 The development of
electron microscopy techniques in the mid-twentieth
century allowed for higher resolution micrographs
that revealed the ultrastructure of these intercellular
junctions. Even in the twenty-first century, the desmosome still remains best defined by its electron micrographic appearance, with an electron-dense midline
Figure 53-1 Desmosomes are the primary cell adhesion

junction in the epidermis. Epidermal spongiosis, or intercellular edema due to inflammation, causes separation
of keratinocytes, which remain attached by intercellular
bridges representing desmosomal junctions (arrows).
(Photo used with permission from John Seykora, MD, PhD.)
Electron microscopic image and schematic diagram of desmosome
dg
dm idp
dp
pg
pkp
A
B
dm
570
odp
odp
idp
dsc
dsg
dm
pm
kf
Figure 53-2 Electron microscopic image (A) and simplified schematic diagram (B) of a desmosome (drawing not to scale).
dg = desmoglea; dm = dense midline; dp = desmoplakin; dsc = desmocollin; dsg = desmoglein; idp = inner dense plaque;
kf = keratin filaments; odp = outer dense plaque; pg = plakoglobin; pkp = plakophilins; pm = plasma membrane. (Electron
micrograph used with permission from Kathleen Green and with permission of Elsevier, adopted from Yin T, Green KJ:
Regulation of desmosome assembly and adhesion. Semin Cell Develop Biol 15:665, 2004.)
in the intercellular space halfway between apposing plasma membranes, sandwiched by two pairs of
electron-dense cytoplasmic plaques (Fig. 53-2A).3 The
intercellular space between plasma membranes was
called the desmoglea (from the Greek for desmosomal
glue), because it was presumed to provide the adhesion that kept cells together.4
STRUCTURE AND FUNCTION OF

DESMOSOMAL PROTEINS
CD
SG
SS
SB
PG
DP
PKP3
EP
PP
Dsg1
Dsc1
Dsg4
Dsc1
EP
PP
Dsg1
PKP1
Dsg2
Dsc2
PKP2
Dsg3
Dsc3
Figure 53-3 Expression patterns of desmosomal proteins

in normal human epidermis. SC = stratum corneum, SG =
stratum granulosum, SS = stratum spinosum, SB = stratum
basale.
esmocollin (Dsc) isoforms, each with varying expresd
sion patterns within and among epithelia.1113 Within
normal human epidermis, Dsg1, Dsg4, and Dsc1 are
expressed predominantly in the differentiated cells
of the superficial epidermis, while Dsg2, Dsg3, Dsc2,
and Dsc3 are expressed more strongly in the basal
and/or suprabasal layers14,15 (Fig. 53-3). Among different epithelial tissues, Dsg1 and Dsg3 expression
are largely limited to stratified squamous epithelia in
the skin and oropharynx, as well as thymic epithelial
cells. Dsg3 is also strongly expressed in squamous cell
carcinomas and other head and neck cancers, where
it has been proposed as a potential molecular target
for therapy.16 Dsg2 is the major desmoglein isoform in
most simple and transitional epithelia, as well as cardiac myocytes.17 Dsg4 is prominent in desmosomes of
the hair follicle, testis, and prostate.18,19 The expression
pattern of the human desmocollins is less well characterized. In normal tissues, Dsc1 expression is largely
limited to skin and oral epithelia, while Dsc2 is more
widely expressed in most desmosome-containing epithelia and is the only desmocollin isoform in cardiac
tissue.11 Dsc3, like Dsg3, is most strongly expressed
in the stratified squamous epithelia of the skin and
oropharynx,20 although UniGene data suggest weaker
expression in a variety of other epithelial tissues. Desmocollin switching has been described in colorectal
cancer, with downregulation of Dsc2 and upregulation of Dsc1 and Dsc3.21
The extracellular domains of the desmosomal
cadherins consist of four cadherin repeats plus an
extracellular anchor domain, each separated by a
calcium-binding motif. All cadherins are synthesized
as preproproteins, which include an amino-terminal
signal sequence and propeptide. The propeptide is
thought to prevent intracellular aggregation of newly
synthesized cadherins within the secretory pathway
of the cell. Proprotein convertases in the late Golgi
network cleave the cadherin propeptide, thereby
producing the mature adhesive protein.22 Although
the crystal structure of the desmosomal cadherins
remains unsolved, studies comparing the structure of
desmosomes analyzed by cryo-electron tomography
571
::
Epidermal and EpidermalDermal Adhesion
DESMOSOMAL CADHERINS. Desmogleins

and desmocollins are part of the cadherin superfamily of transmembrane glycoproteins. Members of
this superfamily, which includes the adherens junction protein E-cadherin, mediate calcium-dependent
adhesion in a variety of epithelial tissues. In humans,
there are four desmoglein (Dsg) isoforms and three
SC
Chapter 53
In anchoring the cell surface to the intermediate filament network, desmosomes create a three-dimensional
scaffolding of proteins that extend from the cell surface
all the way to the nuclear envelope. This scaffolding is
critical to stabilize epithelia in the face of shear stress
or external trauma. Early morphologic studies led to
the perception of the desmosome as a static structure, a
spot weld functioning only to maintain intercellular
adhesion.5 Over the last three decades, the individual
proteins comprising the desmosome have been biochemically characterized and cloned, shedding light
on both the dynamic nature of the desmosome structure and the diversity of desmosomal protein function.
Desmosomal proteins fall into three major categories: (1) desmosomal cadherins (desmogleins and desmocollins), (2) armadillo family proteins (plakoglobin
and plakophilins), and (3) plakins (desmoplakin, envoplakin, and periplakin). Additional proteins, such as
Perp, ninein, kazrin, and corneodesmosin, have also
been localized to epidermal desmosomes.69 Immunogold electron microscopy labeling studies have further
refined our understanding of how these molecular
components of desmosomes are ordered within the
desmosome ultrastructure10 (Fig. 53-2B). The desmosomal cadherins are transmembrane proteins whose
extracellular amino-terminal domains interact to form
the trans-adhesive interface between cells, represented
by the electron-dense midline of the desmoglea. Intracellularly, approximately 1020 nm from the plasma
membrane, the outer dense plaque contains the desmosomal cadherin cytoplasmic tails, plakoglobin,
the desmoplakin amino-terminal domain, and plakophilin. Approximately 4050 nm from the plasma
membrane, the desmoplakin carboxyl-terminus interacts with keratin intermediate filaments, producing
the inner dense plaque. The biochemistry, expression
pattern, and diseases of each desmosomal component
are discussed in further detail below. Although the
specific physiologic roles and pathophysiologic mechanisms affecting many of the desmosomal proteins
remain under active investigation, current knowledge
clearly indicates the importance of desmosomes and
their components beyond just cell adhesion.
Expression patterns of desmosomal proteins
Section 8
::
of vitreous sections with the solution structure of the

classical cadherins suggest common mechanisms of
intercellular adhesion, in which a conserved aminoterminal tryptophan residue on one cadherin molecule
interacts with a hydrophobic acceptor pocket in the
first extracellular domain of another cadherin molecule on a neighboring cell to form the trans-adhesive
interface.2326 Additionally, cadherins may participate in
cis interactions with cadherin molecules on the same
cell through their membrane proximal domains, which
may facilitate desmosome assembly. Desmosomal cadherins can engage in both homophilic (i.e., DsgDsg or
DscDsc) as well as heterophilic (i.e., DsgDsc) interactions, although heterophilic interactions are thought to
contribute most to strong intercellular adhesion.2729
The cytoplasmic domains of the desmosomal cadherins are less conserved. Desmocollins have a full length
a and a shorter b splice isoform. The cytoplasmic
domains of desmoglein and desmocollin a isoforms
bind plakoglobin, and some desmoglein and desmocollin isoforms may also directly bind plakophilins30,31
(Fig. 53-2B). Increasing data suggest that desmosomal
cadherins are not just adhesive molecules but may also
actively regulate intracellular signaling, transcription,
and other cellular processes.1 Consistent with this, desmocollin 3-deficiency in mice causes embryonic lethality at day 2.5 before implantation, indicating a central
role for desmocollin 3 in early tissue morphogenesis
independent of its desmosomal adhesive function.32
In dermatology, the desmosomal cadherins are best
known for their role as autoantigens in the immunobullous disease pemphigus (see Chapter 54). The desmoglein 3 gene was originally discovered and cloned
because it was the autoantigen in pemphigus vulgaris33 (Fig. 53-4A). Since then, all of the desmosomal
cadherins have been associated with human autoimmune, infectious, and/or genetic diseases (summarized below and in Table 53-1).
Desmoglein 1 is the target of pathologic proteolytic
cleavage in the infectious disorders bullous impetigo
572
and staphylococcal scalded skin syndrome, as well as

the inherited ichthyosis associated with Netherton syndrome (see Chapter 49).34,35 Cleavage of desmoglein 1 by
staphylococcal exfoliative toxin occurs between extracellular domains 3 and 4.36 Pathogenic autoantibodies to
desmoglein 1 are found in pemphigus foliaceus, mucocutaneous pemphigus vulgaris, and paraneoplastic
pemphigus (see Chapters 54 and 55). Most pathogenic
pemphigus foliaceus autoantibodies bind the first two
extracellular domains of desmoglein 1, overlapping sites
that are critical for desmoglein trans-adhesion.3739 Autosomal dominant mutations causing haploinsufficiency
of desmoglein 1 result in palmoplantar keratoderma
(PPK; see Chapter 50). The PPK is classically striate (Fig.
53-4B), occurring at sites of greatest trauma or friction,
but focal and diffuse forms have also been described.4042
Desmoglein 2 has been implicated in human cardiovascular disease as a cause of autosomal dominant
arrhythmogenic right ventricular cardiomyopathy
(ARVC).43 The lack of skin phenotypes in affected
patients indicates that desmoglein 2 is not required for
epidermal adhesion, likely due to compensatory adhesion from other more highly expressed epidermal desmosomal cadherin isoforms.
Desmoglein 3 is the target of pathogenic autoantibodies in mucosal and mucocutaneous pemphigus vulgaris and paraneoplastic pemphigus (see Chapters 54
and 55.) Most pathogenic autoantibodies in pemphigus vulgaris target the amino-terminal extracellular
(EC12) domains of desmoglein 3.37,44,45 Because desmoglein 3 deficiency in mice phenotypically resembles
autoimmunity to desmoglein 3 in mucosal pemphigus
vulgaris with oral suprabasal erosions, pemphigus
autoantibodies are thought to cause loss of desmosomal cadherin function.46 More recent research has
focused on signaling pathways activated after binding
of pemphigus vulgaris autoantibodies to keratinocytes,
as several biochemical inhibitors have been shown to
prevent blistering in a neonatal mouse passive transfer
model47 (discussed in further detail in Chapter 54).
Figure 53-4 Desmosomal proteins are pathophysiologic targets in human autoimmune and genetic diseases. A. Indirect
immunofluorescence on monkey esophagus with pemphigus serum that contains autoantibodies to desmoglein 3. The
cell surfaceintercellular pattern staining is diagnostic of pemphigus. B. Striate palmoplantar keratoderma is associated
with haploinsufficiency of desmoglein 1 or desmoplakin.
TABLE 53-1
Desmosomal Targets in Human Disease

Desmosome
Component
Desmosomal cadherins
Desmoglein 1a
Desmoglein 2
Desmoglein 3
Desmoglein 4
Desmocollin 1
Pemphigus foliaceus,
pemphigus vulgaris
Striate PPK (AD)

ARVC (AD)
Pemphigus vulgaris,
paraneoplastic pemphigus
Pemphigus foliaceus,b
pemphigus vulgarisb
IgA pemphigus (subcorneal
pustular dermatosis)
Pemphigus vulgaris
Desmoplakin I/II
Other plakinsc
Plakoglobin
ARVC (AR and AD)

Hypotrichosis (AR)
Striate PPK (AD); Carvajal syndrome (AR):
diffuse PPK, wooly hair, left ventricular
cardiomyopathy; lethal acantholytic
epidermolysis bullosa (AR); skin fragility
wooly hair syndrome (AR): PPK, wooly hair,
nail dystrophy
Plakophilin 1
Plakophilin 2
Naxos disease: diffuse PPK, wooly hair,

ARVC (AR)
Skin fragility and ectodermal dysplasia (AR)
ARVC (AD)
Corneodesmosin
Hypotrichosis simplex of the scalp (AD)
Also targeted by exfoliative toxin in bullous impetigo and staphylococcal scalded-skin syndrome and hyperactive serine proteases in Netherton
syndrome.
b
Desmoglein 4 immunoreactivity is due to cross-reactivity with desmoglein 1 in pemphigus sera.
c
Including envoplakin, periplakin, and bullous pemphigoid antigen 1.
AD = autosomal dominant; AR = autosomal recessive; PPK = palmoplantar keratoderma; ARVC = arrhythmogenic right ventricular cardiomyopathy.
Desmoglein 4 mutations have been described in

rare autosomal recessive forms of hypotrichosis and
monilethrix.4851 One patient demonstrated transient
scalp erosions during the first 2 weeks of life. Most
of the mutations in Dsg4 are frameshift or nonsense
mutations that would be predicted to lead to haploinsufficiency, although missense mutations have also
been reported,52 Desmoglein 4 immunoreactivity is
observed in pemphigus vulgaris and pemphigus foliaceus sera,51 but subsequent studies have attributed this
to cross-reactivity from Dsg1 autoantibodies.53
Desmocollin 1 is the target of autoantibodies in the
subcorneal pustular dermatosis of IgA pemphigus (see
Chapter 54.)
Desmocollin 2, like desmoglein 2, is mutated in both
autosomal dominant and recessive forms of ARVC,
with no epidermal phenotype in affected patients.54,55
Desmocollin 3 mutations were found in one Pakistani
kindred with autosomal recessive hypotrichosis.56
Autoantibodies to desmocollin 3 have also been found
in pemphigus vulgaris patients, particularly those
with vegetative lesions.57
PLAKOGLOBIN. Plakoglobin (also known as

-catenin) directly binds the cytoplasmic tails of the
desmogleins and desmocollin a isoforms, as well
as E-cadherin, the major transmembrane protein of

adherens junctions in epidermal keratinocytes.58,59 It
is expressed throughout all layers of the epidermis
and is ubiquitously expressed in all epithelia. Plakoglobin, like plakophilin, is a member of the armadillo
gene family, characterized by a conserved protein
structure with head and tail domains that flank multiple homologous arm repeats.60 Various domains of
plakoglobin modulate its binding to the desmosomal
cadherins.6163 Other domains bind to desmoplakin,
thus linking desmogleins and desmocollins to desmoplakin.64 Plakoglobin can also localize to the nucleus,
where it may modulate gene transcription by TCF/
LEF family members.65,66 Although most depictions
of the desmosome show both plakoglobin and plakophilin binding to desmoplakin, biochemical studies
suggest that these interactions are mutually exclusive.67 Likely, the armadillo family proteins play more
dynamic roles in recruitment of desmosomal proteins
to the plaque, similar to -catenin in adherens junctions.68,69
Plakoglobin mutations result in Naxos disease, an
autosomal recessive syndrome of diffuse PPK, wooly
hair, and arrhythmogenic right ventricular cardiomyopathy, the latter of which may present in late childhood to adolescence.70
Desmocollin 2
Desmocollin 3
Hypotrichosis (AR); Monilethrix (AR)
::
Stratum corneum desmosome

protein
Genetic Target
Chapter 53
Desmosomal plaque proteins
Autoimmune Target
573
Section 8
::
574
DESMOPLAKIN. Desmoplakin exists in two RNA

splice variants, desmoplakin I and II.71,72 It is unknown
whether different isoforms perform different cellular
functions, although human disease mutations suggest
that desmoplakin I is required for normal desmosomal
function.73 Desmoplakin is part of the plakin gene family,74 which includes the hemidesmosomal proteins
bullous pemphigoid antigen 1 and plectin, as well as
envoplakin and periplakin. Similar to other desmosomal components, desmoplakin is a modular protein,
with different modules fulfilling different functions.
The central part of one desmoplakin molecule coils
around the central part of another to form a rod-like
center. The amino-terminal head domain binds to
plakoglobin,64 and the carboxyl-terminal tail binds to
keratin.75 Therefore, desmoplakin provides the major
link between the keratin filaments and the desmosomal
plaque. Desmoplakin also plays a critical role in development independent of its function in desmosomes, as
desmoplakin-null mice die early in embryogenesis at
E6.5, before desmosomes are formed.76
A broad range of desmoplakin mutations have been
associated with human disease, leading to variable
phenotypic combinations of PPK (striate or diffuse),
dilated cardiomyopathy (left or right), wooly hair,
nail abnormalities, and/or skin blisters.52 Haploinsufficiency of desmoplakin leads to autosomal dominant
striate PPK.77 Autosomal recessive mutations in desmoplakin were described in three Ecuadorian families
with Carvajal syndrome, consisting of diffuse PPK,
wooly hair, and arrhythmogenic left ventricular cardiomyopathy.78 A Naxos-like syndrome of PPK, wooly
hair, and ARVC occurs with the p.R1267X nonsense
mutation, which affects only the desmoplakin I splice
isoform, indicating that desmoplakin II is not sufficient
to restore normal desmosomal function in epidermis.73
Lethal acantholytic epidermolysis bullosa (widespread
epidermolysis, generalized alopecia, anonychia, and
neonatal teeth) was attributed to compound heterozygous mutations in desmoplakin that caused loss of the
desmoplakin tail.79 Additionally, desmoplakin autoantibodies are observed in paraneoplastic pemphigus
sera (see Chapter 55).
PLAKOPHILINS. Plakophilins, like plakoglobin,
can localize both to the plasma membrane as well as
the nucleus, although their function outside of desmosomal adhesion is not well characterized. Plakophilins
directly bind to desmoplakin, and may also directly
bind keratins and desmosomal cadherins, which is
thought to aid in clustering and lateral stability of the
desmosomal plaque.30,31,67 Plakophilin 1 also associates
with the eukaryotic translation initiation factor eIF4A1
in the mRNA cap complex, where it functions to regulate translation and cell proliferation.80
Mutations in plakophilin 1 cause ectodermal
dysplasia-skin fragility syndrome, suggesting a role
for plakophilin 1 in epidermal morphogenesis as well
as adhesion.81 Plakophilin 2 mutations are the most
common cause of autosomal dominant ARVC.82 Currently, there are no known human diseases associated
with plakophilin 3.
OTHER DESMOSOMAL PROTEINS. Envoplakin and periplakin are desmosomal plaque proteins
expressed in the superficial layers of the epidermis.
Both proteins incorporate into the corneodesmosomes
of the stratum corneum. Mice deficient in envoplakin,
periplakin, and involucrin do not demonstrate adhesion defects, but instead show impaired desquamation
and epidermal barrier function.83 Envoplakin and periplakin autoantibodies are characteristic of paraneoplastic pemphigus sera (see Chapter 55).
Corneodesmosin is a secreted glycoprotein that incorporates into corneodesmosomes and is also expressed
in the inner root sheath of the hair follicle. Heterozygous mutations in corneodesmosin are associated with
an autosomal dominant hypotrichosis simplex of the
scalp.84 Loss of cohesion in the inner root sheath and
aggregates of proteolytically cleaved corneodesmosin
around the hair follicle are observed in scalp biopsies
of affected patients.
EPIDERMALDERMAL adHESION
STRUCTURAL AND FUNCTIONAL
CHARACTERISTICS OF BASEMENT
MEMBRANES
Basement membranes underlie epithelial and endothelial cells and separate them from each other or from the
adjacent stroma. Another form of basement membrane
surrounds smooth muscle or nerve cells. The physiologic functions of basement membranes are diverse:
in the various organ systems they provide support for
differentiated cells, maintain tissue architecture during remodeling and repair, and, in some cases, acquire
specialized functions, including the ability to serve as
selective permeability barriers (e.g., the glomerular
basement membrane or the bloodbrain barrier) or
acquire strong adhesive properties, like the basement
membrane at the dermalepidermal junction, or that
surrounding smooth muscle cells, which provide the
tissues resistance against shearing forces. All of these
characteristics of basement membranes are also used
during development and differentiation of multicellular organisms (Box 53-1).
Ultrastructurally, basement membranes most often
appear as trilaminar structures, consisting of a central
electron-dense region, known as the lamina densa, adjacent on either side to an apparently less-dense area,
known as the lamina lucida or lamina rara. The lamina
lucida directly abuts the plasma membranes of the
adherent cells. The relative size of each of these regions
varies in different tissues, among the basement membranes of the same tissue at different ages, and as a
consequence of diseases. For example, the trilaminar
glomerular basement membrane in humans varies
from 240 nm to 340 nm in width, whereas the bilaminar
basement membrane of the dermalepidermal junction
measures 50 nm to 90 nm. This ultrastructure demonstrates that basement membranes serve as substrates for
the attachment of cells and fix their polarity. Their continuity throughout the various organ systems stabilizes
Box 53-1 Major Functions of

Basement Membranes
Scaffold for tissue organization and template for
tissue repair.
Selective permeability barriers. The renal basement
The dermalepidermal junction is an example of a

highly complex form of basement membrane,86,87
which underlies the basal cells and extends into the
upper layers of the dermis (Fig. 53-5A). This basement
membrane is continuous along the epidermis and skin
appendages, including sweat glands, hair follicles, and
sebaceous glands. The dermalepidermal junction can
be divided into three distinct zones. The first zone contains the keratin filamenthemidesmosome complex of
the basal cells and extends through the lamina lucida
to the lamina densa. The plasma membranes of the
basal cells in this region contain numerous electrondense plates known as hemidesmosomes. The intracellular architecture and organization of the basal
cells are maintained by keratin intermediate filaments,
ULTRASTRUCTURE OF THE
::
the tissue orientations and provides a template for

orderly repair after traumatic injury. Major disruptions
in the basement membrane result in the formation of
scar tissue and the loss of function in that area.
Different basement membranes contain both common and unique components. All share a basic network structure to which specific macromolecules have
been appended. These molecules are responsible for
the specialized functions of different basement membranes. The basic constituents of these structures are
collagen IV, laminins, nidogens, and proteoglycans
of the perlecan type, which all are highly conserved,
although the isoforms, the number of the polypeptide
subunits, and their individual structures vary among
species.84,85 The nearly ubiquitous distribution of heparan sulfate proteoglycans in all basement membranes
suggests that these serve as selective permeability barriers in multiple locations, including the kidney and
the bloodbrain barrier. Ultrafiltration may be especially important during development and morphogenesis of all tissues.
Basement membranes also provide physical separation between epithelia and their underlying extracel-
Chapter 53
membranes serve for the ultrafiltration of plasma,

and other basement membranes also demonstrate
selective filtration.
Physical barriers between different types of cells
or between cells and their underlying extracellular
matrix.
Firmly link an epithelium to its underlying matrix or
to another cell layer and provide polarity.
Regulate cellular functions.
lular matrices. This barrier is especially important in

the containment of tumors. With the exception of certain cells of the immune system, nonmalignant cells
seldom cross a basement membrane. In contrast, malignant cells bind the basement membrane, regionally
disrupt its structure, and migrate through the rupture.
Laminins and integrins mediate the tumor-cell binding,
and the basement membrane dissolution is catalyzed
at least in part by metalloproteases produced by the
tumor cell. The absence of distinguishable basement
membranes in tumor biopsies is used as an indicator of
malignancy, and there appears to be a high correlation
between metastasis and basement membrane disruption. These observations underline the importance of
the basal lamina as an obstacle to cell migration.
By binding biologically active signaling molecules,
basement membranes regulate a multitude of biologic
events. The constituent proteoglycans can bind growth
factors that can be released from the complexes. Thus,
the basement membranes are potent regulators of cell
adhesion and migration, cytoskeleton and cell form,
cell division, differentiation and polarization, and
apoptosis.85
Figure 53-5 A. Ultrastructure of the human dermalepidermal junction as visualized by transmission electron microscopy after standard fixation and embedding protocols. af = anchoring filament; AF = anchoring fibril; AP = anchoring plaque;
BM = basement membrane; Hd = hemidesmosome; Ld = lamina densa; Ll = lamina lucida. (Bar = 200 nm.) B. Ultrastructure
of the human dermalepidermal junction by transmission electron microscopy following protocols using high-pressure
fixation and embedding techniques. Note the dense character of both the basement membrane and the subjacent papillary dermis. Anchoring filaments, anchoring fibrils, and anchoring plaques are not distinguishable. (Both photos used with
permission from Douglas R. Keene, MD, Shriners Hospital, Portland, Oregon.)
575
Section 8
::
576
7 nm to 10 nm in diameter that course through the basal

cells and insert into the desmosomes and hemidesmosomes. External to the plasma membrane is a 25-nm
to 50-nm-wide lamina lucida that contains anchoring
filaments, 2 nm to 8 nm in diameter, originating in
the plasma membrane and inserting into the lamina
densa. The anchoring filaments can be seen throughout the lamina lucida but they are concentrated in the
regions of the hemidesmosomes. Thus, the anchoring
filaments appear to secure the epithelial cells to the
lamina densa.
The existence of the lamina lucida in vivo has been
questioned.86,88 When the ultrastructure of the basement
membrane is evaluated after high-pressure preservation techniques, the lamina densa appears intimately
associated with the epithelial cell surface. When the
dermalepidermal junction is similarly prepared, no
distinct lamina lucida is seen (see Fig. 53-5B). This suggests that the lamina lucida may result from shrinkage
of the cell surface away from the lamina densa due to
dehydration. The appearance of anchoring filaments
spanning the lamina lucida may then result from the
firm attachment of constituents of the lamina densa at
the hemidesmosome that is subsequently pulled from
the lamina densa by shrinkage. Other components that
are also tightly fixed to the keratinocyte plasma membrane, either at the hemidesmosomes or at other sites
along the membrane, may similarly become displaced
into the shrinkage space. Regardless of its actual occurrence in vivo, the evaluation of the lamina lucida by
standard electron microscopy techniques has allowed
identification of specific structures that would otherwise have been difficult to detect. In addition, the morphologic term lamina lucida remains practical in the scientific communication and continues to be used.
The second zone, the lamina densa, appears as an
electron-dense amorphous structure 20 nm to 50 nm in
width. At high magnification, it has a granularfibrous
appearance.86 The major molecular components of the
lamina densa are collagen IV, nidogens, perlecan, and
laminins, which all can polymerize to networks of
variable thickness.84,86
The subbasal lamina contains microfibrillar structures. Two of these are readily distinguishable. Anchoring fibrils appear as condensed fibrous aggregates 20
nm to 75 nm in diameter.89 At high resolution, they
appear to have a cross-striated banding pattern (see
Fig. 53-5A). The length of the anchoring fibril is difficult to measure because of its random orientation
in relation to the plane of the section. In toad skin,
these structures have lengths of approximately 800
nm. The anchoring fibrils in human skin appear to be
somewhat shorter. The ends of the fibrils appear less
tightly packed, giving a somewhat frayed appearance.
The proximal end inserts into the basal lamina, and
the distal end is integrated into the fibrous network of
the dermis.90 Many of the anchoring fibrils originating
at the lamina densa loop back into the lamina densa in
a horseshoe-like manner; others insert their opposite
ends into amorphous-appearing structures, termed
anchoring plaques.90 These structures are believed to
be independent islands of electron-dense material,
although some controversy exists in the literature.91
Anchoring fibrils are primarily aggregates of collagen

VII.
Fibrillin-containing microfibrils, 10 nm to 12 nm in
diameter, are also localized in the sublamina densa
region. These are elastic-related fibers, because elastic
components of the dermis are formed from microfibrillar and amorphous components.92 The microfibrillar
component in the presence of abundant amorphous
component is known as the elastic fiber. In the papillary
dermis, the microfibrils insert into the basal lamina
perpendicular to the basement membrane and extend
into the dermis, where they gradually merge with the
elastic fibers to form a plexus parallel to the dermal
epidermal junction. These two elastic components
appear to be continuous with the elastic fibers present
deep within the reticular dermis.92
In summary, the ultrastructure of the dermal
epidermal junction strongly suggests that the lamina
densa functions as a structural scaffold for the attachment of the epidermal cells at one surface, secured by
anchoring filaments extending from the lamina densa
to the hemidesmosomes. The latter also serve as insertion points for intracellular keratin filaments that form
scaffolding for the basal cells. On the opposite surface,
the extracellular matrix suprastructures of the dermis
are firmly attached to the lamina densa. The interaction of collagen-containing dermal fibers with the
lamina densa appears to be mediated by the anchoring
fibrils. The elastic system of the dermis inserts directly
into the basal lamina via the microfibrils. Thus, the
dermalepidermal junction provides a continuous
series of attachments between the reticular dermis and
the cytoskeleton of the basal cells. These observations
suggest four major functions for the epidermal basement membrane: (1) a structural foundation for the
secure attachment and polarity of the epidermal basal
cells; (2) a barrier separating the epidermis and the
dermis; (3) firm attachment of the dermis to the epidermis through a continuous system of structural elements; and (4) modification of cellular functions, such
as organization of the cytoskeleton, differentiation, or
rescue from apoptotic signaling via outside-in signaling mechanisms.
BIOCHEMICAL
CHARACTERIZATION OF THE
BASEMENT MEMBRANE
Basement membranes contain collagenous and noncollagenous glycoproteins and proteoglycans. The content
of the collagen-specific amino acids hydroxyproline
and hydroxylysine suggests that collagens account for
40% to 65% of the total basement membrane protein.
All basement membranes contain certain isoforms of
collagen IV, laminin, nidogen, and the heparan sulfate
proteoglycan perlecan (Box 53-2). For example, the
3 chain of collagen IV is localized in the basement
membrane of the kidney and lung, but not in those of
the skin and blood vessels. In contrast, collagens VII
and XVII are associated with the squamous epithelia
of skin but are not found in glomerular and alveolar
Box 53-2Ubiquitous Components

of Basement Membranes

Collagen IV
Laminins
Nidogens
Perlecan
Laminins.
Laminins are very large glycoproteins

(600 to 950 kDa) within the lamina lucida/lamina
densa of all basement membranes.99 Three types of
subunit chains have been designated , , and chains,
and each laminin is a trimeric aggregate of one , ,
and chain. The trimers have semirigid and extended
structures, which appear as an asymmetric cross in
rotary shadowing electron microscopy (see Fig. 53-6C).
The long arm of the cross is approximately 125 nm in
length; the short arms are variable. Each laminin molecule contains globular and rod-like domains that have
been individually implicated in various functions,
such as aggregation with itself and with other components of the lamina densa (Fig. 53-8), cell attachment
and spreading, neurite outgrowth, or cellular differentiation.85,99 The C-terminal laminin-type globular (LG)
domain of the chain, at the foot of the long arm of the
laminin cross, harbors the binding site for integrins.99
To date, 15 laminin isoforms have been identified.
These represent different trimeric combinations of five
distinct chains, three chains, and three chains
known so far. Historically, laminins were named as
laminin-1 to laminin-15, in the order of their discovery,
but this classification had grown quite impractical,
with the need to memorize the numbers. The current,
COLLAGEN IV. Collagen IV is a heterotrimer of

three chains.84,94 Each of these contains three distinct
domains (Fig. 53-6A): (1) the N-terminal cysteine-rich
(7-S) domain, (2) a central triple-helical domain, and
(3) a C-terminal globular domain (NC-l). The trimer
composition is determined by the NC-l domains, and
the chains are linked to each other by covalent interactions through these domains.95 The triple helix of collagen IV is long and contains several discontinuities,
which result in increased flexibility in the collagen IV
helix, but also render it susceptible to proteases.
The suprastructure of collagen IV has been partially
elucidated by rotary shadowing electron microscopy
that indicated that the major interactions among collagen IV molecules occur at their amino- and carboxylterminal domains, and by lateral association of their
triple helices (see Fig. 53-6A).84,95 Covalent interactions
among 7-S regions of different molecules are the basis
for the specialized network characteristic of basement
membranes (see Fig. 53-6B). The individual 7-S regions
overlap in both the parallel and antiparallel directions,
producing a characteristic four-legged spider form.
The NC-l domains at the end of each leg of the spider
interact with the NC-l domain of the adjacent aggregates (see Fig. 53-6B). Association is stabilized by covalent bonds. These end-to-end interactions result in an
extended two-dimensional network that is the basis of
basement membrane organization.
The high flexibility of the basement membrane
network structure makes the possibility of interactions
with other molecules very attractive. An open meshwork of collagen IV with, for example, laminins or perlecan, can be easily visualized (Fig. 53-7).85 The implied
porosity of this structure would then be limited by
the size of the pores in the collagen network and by
structural elements associated with it. This model of
the basement membrane structure allows considerable
mechanical stability while retaining physiologic flexibility. These properties of strength and elasticity would
be expected for a dynamic surface, such as that seen in
::
UBIQUITOUS COMPONENTS OF
BASEMENT MEMBRANES
Chapter 53
basement membranes. In addition, many other

tissue-specific components are found in basement
membranes, including different collagens, laminins,
fibulins, and fibronectin.84,85,92,93 Differences in macromolecular composition are responsible for morphologic and functional variance of basement membranes.
the dermalepidermal junction and surrounding blood

vessels.
Collagen IV molecules in different basement membranes contain genetically distinct but structurally
homologous chains. The 1 and 2 chains are ubiquitous, but the 3, 4, 5, and 6 chains show restricted
distribution among tissues.93 The chain organization
and discriminatory interactions between the NC-1
domains govern network assembly in the basement
membranes.95 The six chains of collagen IV are distributed in three major networks, (1) 12, (2) 345,
and (3) 1256, whose chain composition is
determined by the NC-l domains. Two networks,
namely 12-containing and 345-containing
networks, exist in the glomerular basement membrane. Smooth muscle basement membranes have an
1256-containing network in addition to the
classic 12 network. Within the dermalepidermal
junction, the 12-containing collagen IV network
dominates, but 1256-containing network is
also likely to be present.96
Mutations in the genes encoding the 1 and 2
chains cause pathologies in different organs, ranging from small-vessel disease, which often underlies
ischemic strokes and intracerebral hemorrhages to
the eye and the HANAC (hereditary angiopathy with
nephropathy, aneurysms, and muscle cramps) syndrome.93,97,98 Interestingly, despite the ubiquitous presence of the 1 and 2 chains of collagen IV in basement
membranes, aberrations do not occur in all basement
membranes, suggesting varying tissue-specific roles
for collagen IV. Structural aberrations in the genes
encoding the 3, 4, 5, and 6 chains cause different
forms of Alport syndrome, a genetic disease characterized by nephritis and deafness.93 The 3(IV) chain is
the antigen recognized by the circulating autoantibodies in the Goodpasture syndrome.93
577
Section 8
::
Figure 53-6 Images of basement membrane molecules visualized by rotary shadowing. A. Collagen IV monomer and a
dimer resulting from aggregation of C-terminal NC-1 domains. B. Collagen IV tetramer (spider) demonstrating the 7-S
domain with the four protruding molecules and their large terminal NC-1 domains. C. Laminin 111 molecules. D. Nidogen
molecules. E. Procollagen VII. The NC-1 and NC-2 regions are indicated. F. Laminin 332 molecules. (All micrographs were
provided by Douglas R. Keene, MD, Shriners Hospital, Portland, Oregon.)
578
simplified nomenclature is based on the chain composition and the number of each , , and chain (Table
53-2).100 For example, the classic prototype laminin-1, with chain composition 111, is now called
laminin 111. The major laminin of the epidermal basement membrane, the previous laminin-5, with chain
composition 332, is now called laminin 332.
The 2 chain containing laminins are present primarily within the basement membranes of the muscle
fibers, nerves, neuromuscular junction, and glomerulus. The 3 chain is involved in epithelial adhesion,
and the 4 and 5 chains are found in a variety of tissues including endothelia, epithelia, neuromuscular
junction, and glomerulus.101 Laminin 511 is present in
Laminin molecules
::
Figure 53-7 A. Representation of the networks formed by the ubiquitous components of the basement membranes. Monomeric collagen IV (Col-IV) self-assembles into dimers and tetramers that further aggregate into a complex lattice. Laminins self-polymerize into networks. Perlecan can oligomerize in vitro, and the glycosaminoglycan side chains interact with
the Col-IV framework. Nidogen is thought to bind components of all three networks and also fibulins. Therefore, nidogen
plays a central role as a stabilizer of the lamina densa framework. Individual molecules are not drawn to scale. (Drawing
used with permission from Peter Yurchenco, MD, Robert Wood Johnson Medical School, Piscataway, NJ, USA.) B. Rotary
shadowing image of a quick-freeze, deep-etch replica of Col-IV polymers. The replica shows an extensive, branching, and
anastomosing network with occasional globular structures (arrowhead), which can be visualized as a model for the structure of the lamina densa. (Photo provided by Toshihiko Hayashi, PhD, University of Tokyo, Japan. See also Nakazato K et al:
Gelation of lens capsule type IV collagen solution at a neutral pH. J Biochem 120:889, 1996.)
Chapter 53
Laminin III
2
3
1
5
4
3A
Laminin 3A32
2
3
3B
1
5
4
Laminin 3B32
2
3
1
5
4
Figure 53-8 A schematic representation of laminin molecules. Each laminin is a heterotrimer of an , a , and a
chain. On the left, the classic prototype laminin 111 consisting of 111 chains is shown. The N-terminal short
arm of each chain is free, the long C-termini fold to a
coiled-coil and form the long arm. The distal C-terminus
of the chain contains five globular LG domains, which
harbor the integrin-binding site. Laminin 332 exists in two
forms, 3A32 and 3B32. These represent splice variants of
the chain, the short variant is 3A and the full length
chain 3B. The N-termini of the 3 and 2 chains are proteolytically processed to yield mature laminin 332.
579
TABLE 53-2
Most Common Laminin Isoformsa
Section 8
::
580
Name
Chain Composition
Tissue Distribution
Laminin 111
111
Developing epithelia
Laminin 121
121
Myotendinous junction
Laminin 211
211
Muscle, nerves
Laminin 213
213
Muscle
Laminin 221
221
Neuromuscular junction, glomerulus
Laminin 3A11
311
Stratified epithelia
Laminin 3A21
321
Amnion, maybe other stratified epithelia
Laminin 3A32
332
Stratified epithelia
Laminin 3B32
332
Stratified epithelia, uterus, lung
Laminin 411
411
Endothelia, nerves, smooth muscle, adipose tissue
Laminin 421
421
Endothelia, neuromuscular junction, smooth muscle, glomerulus,

adipose tissue
Laminin 423
423
Retina, central nervous system, kidney, testis
Laminin 511
511
Mature epithelia and endothelia, smooth muscle
Laminin 521
521
Mature epithelia and endothelia, smooth muscle, neuromuscular junction,

glomerulus
Laminin 523
523
Retina, central nervous system, muscle, kidney
See Durbeej M: Laminins. Cell Tissue Res 339:259-268, 2010.
the basement membrane of the epidermis and the hair

follicles, where it is believed to be involved in developmental signaling.99,100 The distribution of the 2 chain
is largely restricted to the neuromuscular junction, but
it is also found in nonmuscle tissues such as the kidney
glomerulus and the capillary basal lamina.99 The 3
chain is involved in epithelial adhesion. Three chain
variants1, 2, and 3are known. The 2 chain is
found only in laminin 332 in the skin. The 3 chain,
a component of laminins 423 and 523, binds nidogens
and is localized in basement membrane zones of adult
and embryonic brain, kidney, skin, muscle, and testis.
It is present in much lower concentrations than the 1
chain, a fact that may indicate highly specialized functions.99 The functions of all laminins are not yet fully
understood, but by interacting with integrins and
other cell surface components laminins control cellular
activities such as adhesion, migration, proliferation,
and polarity in a wide variety of organs.99,100
Several human congenital diseases are caused by
mutations in the laminin chains.99 Since some chains
can be components in several different laminins, the
mutations can affect functions of multiple laminins
in different tissues. For example, mutations in the 2
chain cause congenital muscular dystrophy and a significant decrease in the amount of basement membrane
accumulated surrounding muscle cells.99 The absence
of the basement membrane leads to progressive degeneration of the muscle due to cell death. Therefore, the
prediction is that laminins, and basement membranes
in general, are required to prevent apoptosis by the
cell types they surround.99 Mutations in the 3, 3, or

2 chains underlie junctional epidermolysis bullosa,
and mutations of the 4 chain are associated with cardiomyopathy. Pierson syndrome, a severe congenital
condition affecting mainly the kidney and the eye, is
caused by mutations of the 2 chain.
Nidogens. Two nidogens, nidogen 1 and 2, previously known as entactin, are distinct gene products.
Both are relatively small molecules (see Fig. 53-6D),
which bind laminins at a specific site within the 1 and
the 3 chain,93,102 but also collagen IV, perlecan, and
fibulins. Nidogens are likely to act as connecting elements between the collagen IV and laminin networks
and integrate other basement membrane components
into this specialized extracellular matrix.84 Targeted
ablation of nidogens in mice showed that the loss of
either isoform has no effect on basement membrane
formation and organ development, but lack of both
results in severe defects of the lung and the heart102
that are not compatible with life. Interestingly, despite
the ubiquitous presence of nidogens in basement
membranes, aberrations did not occur in all basement
membranes, suggesting distinct roles for nidogens in
different basement membranes.102
Heparan Sulfate Proteoglycans. Another
class of ubiquitous integral basement membrane constituents are the proteoglycans. Three proteoglycans
are characteristically present in vascular and epithelial basement membranes: (1) perlecan, (2) agrin, and
The dermalepidermal junction of skin is an excellent

example of specific divergence in basement membrane
structure. The structural components of hemidesmosomes, anchoring filaments, and anchoring fibrils in
the basement membrane zone are quite well characterized.8487,107,108 A cartoon depicting the relative locations of the proteins found at the dermalepidermal
HEMIDESMOSOMES
Ultrastructurally, the hemidesmosome closely resembles one-half of the desmosome at cellcell junctions
in the epidermis. However, the components of these
two structures are distinct. The 230-kDa BPAG1 (bullous pemphigoid antigen 1, or BP230) is a coiled-coil
dimeric protein with homology to plakins, which bind
intermediate filaments. BPAG1 is the major component
of the hemidesmosomal inner dense plaque. Ablation
of BPAG1 is associated with epidermolysis bullosa
simplex in mice and humans.72,109 The 180-kDa BPAG2
or BP180, and the major antigen in bullous pemphigoid (Fig. 53-10), is a transmembrane collagen now
known as collagen XVII, where the collagenous domain
is extracellular. In fact, collagen XVII is a prototype
of the novel protein family of collagenous transmembrane proteins, type II transmembrane molecules with
one or more collagenous stretches in the extracellular
domain.110 The intracellular ligands of collagen XVII
are plectin, BPAG1 and 4 integrin, and the extracellular ligands 6 integrin and laminin 332.107,108 The
120-kDa ectodomain of collagen XVII is shed from the
cell surface by proteinases of the ADAM (a disintegrinlike and metalloproteinase-containing) family through
cleavage within the juxtamembranous NC-16 domain
(Fig. 53-11).111 Mutations in collagen XVII cause junctional epidermolysis bullosa (see Chapter 62), indicating that it stabilizes interactions of basal keratinocytes
with the basement membrane.112 Ablation of the mouse
Col17a1 gene resulted in moderate skin blistering, dental anomalies, and graying hair.113,114 Plectin, another
dimeric plakin homolog, is also a component of the
hemidesmosome. However, its tissue distribution is
not limited to hemidesmosome-containing basement
membranes. Mutations of plectin result in epidermolysis bullosa simplex and progressive muscular dystrophy and, in some cases, epidermolysis bullosa simplex
with pyloric atresia,115 indicating a role for plectin in
the stability of cellbasement membrane adhesion in a
variety of tissues.
One key component of the hemidesmosome is the
integrin 64.107 It has a high affinity for laminin 332
and is essential to integration of the hemidesmosome with the underlying basement membrane and
stroma.107,108 Mutations in either the 6 or 4 chains
result in junctional epidermolysis bullosa associated
with pyloric atresia.108,112
A member of the widely expressed cell surface transmembrane proteins of the tetraspanin family, CD151,
is also a component of the hemidesmosome. It forms
complexes with 31 and 64 integrins at the basolateral surface of basal keratinocytes and stabilizes
their functions.116 CD151-null mice have apparently
normal hemidesmosomes, but exhibit some functional
aberrations, for example, poor keratinocyte migration
in explant cultures. A very rare human genetic condition delivered indirect information on the functions
of CD151. In addition to the expression of CD151 in
EPITHELIUM-SPECIFIC BASEMENT
MEMBRANE COMPONENTS
::
Fibulins. Fibulins are a family of six highly conserved, calcium-binding extracellular matrix proteins.
They are located in vessel walls, basement membranes,
and microfibrillar structures and they have overlapping binding sites for a variety of ligands, both basement membrane proteins and components of the
interstitial connective tissues.106 Therefore, fibulins are
believed to function as intermolecular bridges that stabilize the supramolecular organization of extracellular
membrane structures, such as elastic fibers and basement membranes. Genetic defects of the genes encoding fibulin 4 and 5 cause different forms of cutis laxa.
junction is shown in Fig. 53-9. These proteins are listed

in Table 53-3 and discussed in the following sections.
Chapter 53
(3) collagen XVIII.103 They consist of a core protein of

various lengths, and carry primarily heparan sulfate
side chains. The name perlecan is derived from its
rotary shadowing appearance reminiscent of a string
of pearls. Perlecan represents a complex multidomain
proteoglycan with enormous dimensions and a number of posttranslational modifications. Knockout mice
lacking perlecan exhibited abnormalities in many tissues, including basement membranes, and embryonic lethality. The basement membranes deteriorated
in regions under increased mechanical stress, such as
myocardium or skin, resulting in lethal cardiac abnormalities and skin blistering.103 Agrin is a major heparan
sulfate proteoglycan of neuromuscular junctions and
renal tubular basement membranes. Collagen XVIII is
considered to be a hybrid collagenproteoglycan in
various organs.104 In collagen XVIII knockout mice,
basement membranes were broadened in different
organs, accompanied with mesangial expansion and
reduced function of the kidney. The proteoglycans can
interact with several other basement membrane components and are believed to contribute to the overall
architecture of the basement membrane as well as
provide tissue-specific functions. The high sulfate
content makes them highly negatively charged and
hydrophilic, and the charge density is responsible for
providing the selective permeability of the glomerular
basement membrane.
Syndecans are transmembrane heparan sulfate
proteoglycans present on most cell types, including
basal keratinocytes of the epidermis. The extracellular
domains have affinity for laminins and, presumably
through these interactions, they engage in outside-in
signaling and regulate cellular processes ranging from
growth factor signaling, cell adhesion, and cytoskeletal organization, to infection of cells with microorganisms.105
581
Hypothetical relationships of molecules within the dermal-epidermal junction basement membrane
Hemidesmosome
Keratin 5/14
Cell membrane
BPAG1
Plectin
CD 151
Section 8
Lamina lucida
64
integrin
Laminin 332
31
integrin
Collagen
XVII
Laminin 332
Actin
Kindlin
Vinculin
Talin
Laminin 311
Collagen XIII
Nidogen
Perlecan
::
Lamina densa
Dermal fibril
Dermis
Collagen VII
Anchoring fibrils
Figure 53-9 Model of the hypothetical relationships of molecules within the dermalepidermal junction basement membrane. The illustration depicts laminin 332 as the bridge between the transmembrane hemidesmosomal integrin 64
and the collagen VII NC-1 domain. The tight binding of laminin 332 to 64 and to collagen VII provides the primary
resistance to frictional forces. The transmembrane collagen XVII also participates in this stabilization, because its extracellular domain also binds laminin 332. Within the epithelial cell, the transmembrane elements bind the proteins of the
hemidesmosomal dense plaque, bullous pemphigoid antigen (BPAG)1 and plectin, which then associate with the keratins.
Collagen XVII binds BPAG1, integrin 64, and plectin, and integrin 64 binds plectin. The laminin 332311 complex is
shown within the basement membrane between hemidesmosomes, bound by integrin 31, and associated with the
intracellular proteins kindlin-1, talin, and vinculin. This complex presumably maintains basement membrane stability. In
vitro, integrin 31, kindlin-1, talin, and vinculin, and another transmembrane collagen, type XIII, are localized to the focal
contacts, which may function as the link between the basement membrane and the epithelial cortical actin network. In
the lamina densa, collagen IV and perlecan networks are stabilized by nidogen. Anchoring fibrils are secured to the lamina
densa by the NC-1 domain of collagen VII. The fibrils project into the dermis and either terminate in anchoring plaques
or loop back to the lamina densa. The anchoring fibril network entraps dermal fibrils, thus securing the adhesion of the
lamina densa to the papillary dermis. None of the molecules is drawn to scale.
several tissues like the kidney and the skin, its gene
also encodes the MER2 blood group antigen on erythrocytes. Homozygous CD151-null mutations were
identified in three MER2-negative patients, who also
presented with hereditary nephritis, sensorineural deafness, pretibial epidermolysis bullosa, and
-thalassemia minor.117 These symptoms suggest that
CD151 is important for the assembly of the basement
membrane in the kidney, skin, and inner ear and plays
a role in erythropoiesis.
OTHER EPIDERMAL ADHESION

COMPLEXES
582
Focal contact
In addition to the hemidesmosomal components, other

adhesion molecules are known to be present at the basolateral aspect of basal keratinocytes, for example, integ-
rin 31, the receptor for the laminin 332311 complex

in the basement membrane between the hemidesmosomes,118 and another transmembrane collagen, type
XIII.94 Since these proteins are localized to focal contacts in vitro, together with vinculin and talin, they are
predicted to function as the link between the basement
membrane and the epithelial cortical actin network. A
novel intracellular component of this complex, kindlin-1, or fermitin-family-homolog 1, was identified by
the genetic studies. The kindlin-1 gene, FERMT1, is
mutated in the Kindler syndrome,119,120 a disorder with
skin blistering in infancy, progressive poikiloderma,
skin atrophy, pigment anomalies, and, occasionally,
skin cancer. In the epidermis, kindlin-1 is expressed
at the basolateral surface of basal keratinocytes and
has important functions in 1 integrin-mediated outside-in signaling that regulates cellmatrix adhesions,
cell migration, and polarity.121,122 Thus, kindlin-1 is
TABLE 53-3
Hemidesmosomal and Basement Membrane Zone (BMZ) Targets in Skin Disease

Hemidesmosome/BMZ
Component
Cytoskeletal proteins
Keratin 5 and 14
Hemidesmosomal plaque
proteins
Bullous pemphigoid antigen

1/BP230
Plectin
Autoimmune Target
Genetic Target
EBS
BP
EBS
BP, CP
EBS-MD
JEB-PA
Collagen XVII/BP180
BP, CP, LAD, PG
JEB-non-Herlitz
64 integrin
CD151
BP, CP
JEB-PA
Pretibial EB, nephritis, deafness,
-thalassemia minor
Laminin 332
CP
Ectodomain of collagen XVII
LAD, BP
JEB-Herlitz
JEBnon-Herlitz
JEBnon-Herlitz
Collagen VII
EBA
DEB
Anchoring fibril proteins
BP = bullous pemphigoid (see Chapter 56); CP = cicatricial pemphigoid (see Chapter 57); DEB = dystrophic EB (see Chapter 62 for all); EB = epidermolysis bullosa; EBA = EB acquisita (see Chapter 60); EBS = EB simplex; EBSMD = EBS with muscular dystrophy; JEB = junctional EB;
JEBPA = JEB with pyloric atresia; KS = Kindler syndrome; LAD = linear immunoglobulin A dermatosis (see Chapter 58); PG = pemphigoid
gestationis (see Chapter 59).
necessary for the stability of the dermalepidermal

junction and that, in addition to hemidesmosomes,
tethering the actin cytoskeleton to cellmatrix adhesions offers alternative means to anchor basal epithelial cells to the basement membrane.
Hemidesmosomal
transmembrane components
Anchoring filament proteins
KS
::
Kindlin-1
Chapter 53
Other intracellular adhesion

complex proteins
ANCHORING FILAMENTS
Figure 53-10 Indirect immunofluorescence staining of

human skin with a pemphigoid serum that contains autoantibodies to collagen XVII.
The anchoring filaments contain laminin 332 and the

ectodomain of collagen XVII, two ligands that interact
with each other through noncovalent bonds.99,100,108 The
ectodomain of collagen XVII, which protrudes from
the plasma membrane into the lamina lucida, has a
loop structure consistent with its role as an anchoring
filament protein.123 Laminin 332 is a disulfide-bonded
complex of 3, 3, and 2 chains. The two splice variants of the 3 chain, 3A and 3B, associate with the
3 and 2 chains to form laminin 3A32 and 3B32 (see
Fig. 53-8).99,100 Rotary shadowing imaging indicates
that laminin 332 has a rod-like structure terminating in
the globular regions (see Fig. 53-6F), a shape consistent
with its role as an anchoring filament protein. The individual chains are considerably truncated relative to
other laminin chains, and this truncation is reflected in
the loss of the structures equivalent to the short arms
of other laminins. Additionally, the 3 and 2 chains
are proteolytically processed after secretion from the
keratinocyte, further trimming the short arms.99,100 The
583
Collagen XVII and ectodomain shedding
Plasma
membrane
abnormalities of ameloblast differentiation in developing teeth, and perinatal lethality.125 Therefore, the
severity of the laminin 332 null phenotype indirectly
emphasizes its functional importance in bridging the
hemidesmosomes and the anchoring fibrils.
NC-16A
EPITHELIAL LAMINA DENSA

ADAMs
Section 8
::
584
Transmembrane
form 180 kd
Shedding
Soluble
ectodomain
120 kd
Figure 53-11 Schematic representation of collagen XVII

and its ectodomain shedding. Collagen XVII is a hemidesmosomal transmembrane protein with an intracellular
N-terminus. The extracellular C-terminus (ectodomain)
contains several collagenous subdomains (brown) and
intervening noncollagenous sequences (beige). The ectodomain can be shed from the cell surface by proteinases
of the ADAMs (a disintegrin-like and metalloproteinasecontaining) family, themselves transmembrane proteins.
Thus, the 180-kDa full-length molecule yields a shorter
soluble ectodomain of 120 kDa. The 180-kDa full-length
molecule is the classic bullous pemphigoid antigen-2, and
the ectodomain is the 120-kDa linear immunoglobulin A
(IgA) dermatosis antigen. Further degradation of the Cterminus of the ectodomain results in the 97-kDa linear
IgA dermatosis antigen.
C-terminus of the chain, longer than that of the and

chains, comprises five globular LG modules, LG1
through LG5, which interact with cell surface receptors. The 31 and 64 integrins have affinity for the
LG1-3 domains, whereas the LG4-5 tandem has affinity
for syndecans and -dystroglycan on the keratinocyte
surface.99,105 The LG4-5 modules are proteolytically
cleaved in most laminins, a process which may modulate interactions with cell surface receptors.99,100 Laminin 332 forms covalent complexes with laminin 311
(311), binds to the NC-1 domain of collagen VII, the
anchoring fibril protein.124 and to the distal ectodomain
of collagen XVII.123 Genetic evidence demonstrates that
laminin 332 is essential in keratinocyte adhesion, as
null mutations in any of its component 3, 3, or 2
chains result in severe Herlitz junctional epidermolysis bullosa112 (see Chapter 62). Targeted disruption of
the mouse lama3 gene prevented the synthesis of both
laminin 332 and 311 molecules and resulted in abnormal hemidesmosomes, severe junctional blistering,
The basement membrane beneath and between the

hemidesmosomes contains the 12-containing
collagen IV network, probably some 1256containing collagen IV network, as well as nidogen,
perlecan, and 3 and 5-chain containing laminins.93
The laminin 3 chain can associate with the 1 and
1 chains of laminin 311, which has the unique property of forming disulfide-bonded dimers with laminin 332.99,100 The major 3-containing laminin in the
lamina densa between hemidesmosomes is probably
the laminin 332311 complex.99,100,108 As the laminin
3 chain is a ligand for integrin 31 present between
hemidesmosomes, binding of laminin 332311 complex to the intracellular actin cytoskeleton is likely to
be mediated by this integrin. This is consistent with
studies in mice in which targeted ablation of the integrin 3 chain causes loss of the basement membrane
between hemidesmosomes but not beneath them.93,99
The N-termini of laminin 332 bind to collagen VII, the
main component of the anchoring fibrils in the sublamina densa, so that anchoring filaments and fibrils are
directly connected.93 The laminin 332311 complex and
laminin 511 (511) contain a 1 chain and can therefore bind nidogens and the collagen IV network.93,99
Further, nidogen 1 and fibulin 1 and 2 were shown to
be ligands for the laminin 2 chain.93 These interactions
are important for the integration of laminin 332 into
the extracellular matrix before the maturation of the
2 chain, as a substantial portion of N-terminus of the
2 chain is cleaved in human adult skin.108 Yet another
link, which strengthens dermalepidermal cohesion, is
provided by molecular interactions between perlecan
within the lamina densa and fibrillin 1 in the microfibrils.126
ANCHORING FIBRILS
Collagen VII is the major component of the anchoring
fibrils.90,124 The collagen VII molecule is distinguished
from other collagens in that it has a very long triplehelical domain, 450 nm in length. Globular domains
exist at both ends of the triple helix, and the N-terminal
domain NC-1 is very large and trident-like (see Fig.
53-6E). The smaller C-propeptide, NC-2, is believed
to facilitate the formation of the antiparallel, centrosymmetric dimers, before it is removed by the metalloproteinase bone morphogenetic protein 1127 to yield a
mature collagen VII. The dimers are covalently crosslinked through disulfide bonds at the carboxyl terminus, and they aggregate laterally to form the anchoring
fibrils. The fibrils are further stabilized by tissue transglutaminase, which catalyzes the formation of covalent -glutamyl--lysine cross-links.128
KEY REFERENCES
1. Getsios S, Huen AC, Green KJ: Working out the strength
and flexibility of desmosomes. Nat Rev Mol Cell Biol
5:271, 2004
26. Al-Amoudi A et al: The molecular architecture of cadherins in native epidermal desmosomes. Nature 450:832,
2007
45. Payne AS et al: Genetic and functional characterization
of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display. J Clin Invest 115:888, 2005
79. Jonkman MF et al: Loss of desmoplakin tail causes lethal
acantholytic epidermolysis bullosa. Am J Hum Genet
77:653, 2005
85. Yurchenco PD, Amenta PS, Patton BL: Basement membrane assembly, stability and activities observed through
a developmental lens. Matrix Biol 22:521, 2004
90. Keene DR et al: Collagen VII forms an extended network
of anchoring fibrils. J Cell Biol104:611, 1987
93. van Agtmael T, BrucknerTuderman L: Basement membranes and human disease. Cell Tissue Res 339:167, 2010
100. Aumailley M, et al: A simplified laminin nomenclature.
Matrix Biol 24:326, 2005
109. Groves RW et al: A homozygous nonsense mutation
within the dystonin gene coding for the coiled-coil
domain of the epithelial isoform of BPAG1 underlies a
new subtype of autosomal recessive epidermolysis bullosa simplex. J Invest Dermatol E-publication Feb 18, 2010
126. Ramirez F, Dietz HC: Extracellular microfibrils in vertebrate development and disease processes. J Biol Chem
284:14677, 2009
The basement membrane constituents are products of

both epithelial and mesenchymal cells. In vitro modeling of basement membrane formation using different
skin equivalent culture models has demonstrated that
a tight interplay between fibroblasts and keratinocytes
contributes to the dermalepidermal basement membrane. Differentiated fibroblasts adjacent to epithelia
in vivo produce basement membrane components
and assist in basement membrane assembly.138141 Of
the known basement membrane components, only
laminins 332 and 311A are exclusively produced by
the epidermis. Conditional knockout of collagen VII
has demonstrated that both epithelial and mesenchymal cells manufacture collagen VII,142 whereas mainly
mesenchymal cells synthesize collagen IV, nidogen,
perlecan, and the laminin 2 chain.93 Because the mesenchymal products are translocated to the baso-lateral
epithelial surface where they condense, that surface
must provide the localization cues. Integrins 64 and
31 and collagen XVII have been implicated in this
process, suggesting that the laminins coordinate basement membrane polymerization.99 An interesting regulatory step may be added by dermal enzymes (e.g.,
bone morphologic protein 1), which process epithelial
cell products, such as laminin 332 and procollagen VII,
to mature basement membrane molecules.99,127
::
Figure 53-12 Skin fragility and blistering in dystrophic

epidermolysis bullosa. Functional deficiency of collagen
VII as a result of mutations in the COL7A1 gene leads to
trauma-induced separation of the epidermis and the
dermis. The blister roof is below the lamina densa, leading
to scar formation on healing of the blisters.
CELLULAR ORIGIN OF THE DERMAL

EPIDERMAL BASEMENT MEMBRANE
Chapter 53
The NC-1 domain of collagen VII binds to laminin

332 and collagen IV within the lamina densa (see Fig.
53-5A).124 The triple helical domains of an antiparallel collagen VII dimer make the length of the anchoring fibril. It extends perpendicularly from the lamina
densa and either loops back into the lamina densa or
inserts into the anchoring plaques.90,91 The anchoring
plaques are electron-dense structures that contain collagen IV and laminin 332, and perhaps other basement
membrane components, but which are believed to be
independent of the lamina densa itself.90 They are distributed randomly in the papillary dermis below the
lamina densa and are interrelated by additional anchoring fibrils. The anchoring fibril network forms a scaffold that entraps large numbers of dermal fibrils and,
most probably, binds them through covalent cross-links
between collagen VII and collagen I,129 thus securing the
lamina densa to the subjacent dermis.124 In the acquired
form of epidermolysis bullosa, epidermolysis bullosa
acquisita (see Chapter 60), and in bullous systemic
lupus erythematosus (see Chapter 155), autoantibodies
target mainly the NC-1 domain of collagen VII.130
Mutations in COL7A1, the gene encoding collagen
VII, result in dystrophic epidermolysis bullosa (see
Chapter 62). Almost 500 COL7A1 mutations have
been found in both recessive and dominant forms of
dystrophic epidermolysis bullosa (Fig. 53-12), and the
spectrum of biologic and clinical phenotypes is very
broad.131 In mouse models, complete or partial deficiency of collagen VII recapitulated the clinical and
morphologic characteristics of recessive dystrophic
epidermolysis bullosa in humans.132,133 These mice
have been useful for testing of molecular therapy strategies for dystrophic epidermolysis bullosa. Both cell
therapy approaches using fibroblasts134 or bone marrow-derived mesenchymal stem cells135 and protein136
therapy have shown promise in terms of increasing
collagen VII and stabilizing the dermalepidermal
junction. A human clinical trial to treat recessive dystrophic epidermolysis bullosa using bone marrow
transplantation is currently ongoing.137
585
Chapter 54 :: Pemphigus

:: Aimee S. Payne & John R. Stanley
PEMPHIGUS AT A GLANCE
Two major types: pemphigus vulgaris and
pemphigus foliaceus.
Pemphigus vulgaris: erosions on mucous
membranes and skin; flaccid blisters on skin.
Section 8
::
586
Pemphigus foliaceus: crusted, scaly skin

lesions.
Diagnosis depends on histology showing
intraepidermal acantholysis and
immunofluorescence studies documenting
the presence of cell surface autoantibodies,
either bound to patient skin or in the serum.
Pemphigus vulgaris histology: suprabasal
acantholysis.
Pemphigus foliaceus histology: subcorneal
acantholysis.
Direct immunofluorescence shows
immunoglobulin G (IgG) on the keratinocyte
cell surface of the patients skin; indirect
immunofluorescence shows IgG in patient
serum that binds the cell surface of normal
keratinocytes.
Autoantigens are desmogleins,
transmembrane desmosomal adhesion
molecules.
Therapy includes topical and systemic
corticosteroids and immunosuppressive
agents.
The term pemphigus refers to a group of autoimmune

blistering diseases of skin and mucous membranes
that are characterized histologically by intraepidermal
blisters due to acantholysis (i.e., separation of epidermal cells from each other) and immunopathologically
by in vivo bound and circulating immunoglobulin
(Ig) directed against the cell surface of keratinocytes.
The nosology of this group of diseases is outlined in
Box 54-1. Essentially, pemphigus can be divided into
four major types: (1) vulgaris, (2) foliaceus, (3) paraneoplastic (see Chapter 55), and (4) IgA pemphigus (see
Chapter 54). In pemphigus vulgaris (PV), the blister
occurs in the deeper part of the epidermis, just above
the basal layer, and in pemphigus foliaceus (PF), also
called superficial pemphigus, the blister is in the granular layer.
The history of the discovery of pemphigus, and

its various forms, is covered in Walter Levers classic monograph Pemphigus and Pemphigoid.1 Both PV
and PF display a spectrum of disease. Various points
along these spectra have been given unique names,
but because the presentation of these diseases is fluid,
patients disease usually crosses these artificial designations over time. Thus, patients with PV may present with more localized disease, one form of which is
called pemphigus vegetans of Hallopeau. This may become
slightly more extensive and may merge into pemphigus
vegetans of Neumann. Finally, with more severe disease,
full-blown PV may appear. Similarly, patients with PF
may present with more localized disease, represented
by pemphigus erythematosus. However, these patients
often go on to more widespread PF.
The discovery by Ernst Beutner and Robert Jordon in 1964 of circulating antibodies against the cell
surface of keratinocytes in the sera of patients with
PV pioneered our understanding that PV is a tissuespecific autoimmune disease of skin and mucosa.2
Ultimately, their work led the way to the discoveries
of autoantibodies in other autoimmune bullous diseases of the skin.
EPIDEMIOLOGY
INCIDENCE AND PREVALENCE
A few prospective and several retrospective surveys
of patients with pemphigus clearly indicate that the
epidemiology of pemphigus is dependent on both
the area in the world that is studied as well as the
ethnic population in that area.310 PV is more common in Jews and probably in people of Mediterranean descent and from the Middle East. This same
ethnic predominance does not exist for PF. Therefore, in areas where the Jewish, Middle Eastern, and
Mediterranean population predominates, the ratio of
PV to PF cases tends to be higher. For example, in
New York, Los Angeles, and Croatia, the ratio of PV
to PF cases is approximately 5:1; in Iran the ratio is
12:1; whereas in Singapore it is 2:1; and in Finland,
it is only 0.5:1. Similarly, the incidence of pemphigus varies by region. In Jerusalem, the incidence of
PV has been estimated to be 1.6 per 100,000 people
per year and in Iran approximately 10.0 per 100,000
people per year. Elsewhere in Europe, the incidences
are lower, ranging from a high of 0.7 PV cases per
100,000 person years in the United Kingdom to tenfold less, 0.51.0 per million person years, in Finland,
France, Germany, and Switzerland.
The prevalence and incidence of PF are also very
dependent on its location, as best exemplified by the
finding of endemic foci of PF in Brazil, Colombia, and
Tunisia. The first recognition of endemic PF was in
Box 54-1 Differential Diagnosis of Pemphigus

PEMPHIGUS SUBTYPES

Pemphigus vulgaris
Pemphigus vegetans
Pemphigus foliaceus
Pemphigus erythematosus
Endemic pemphigus foliaceus (e.g., fogo selvagem)
Immunoglobulin A (IgA) pemphigus
Subcorneal pustular dermatosis
Intraepidermal neutrophilic dermatosis
syndrome
Blisters from herpes simplex and zoster
Allergic contact dermatitis (e.g., rhus dermatitis)
Epidermolysis bullosa simplex
SUBEPIDERMAL BLISTERING DISEASES

WITH AUTOANTIBODIES
Bullous pemphigoid
Herpes gestationis
Linear IgA disease and chronic bullous disease of
childhood
Bullous lupus erythematosus


WITHOUT AUTOANTIBODIES

razil and is called fogo selvagem, which means wild

B
fire in Portuguese. It is a disease that is clinically,
histologically, and immunopathologically the same
as sporadic PF in any individual patient, but its epidemiology is unique.11,12 Fogo selvagem is endemic in
the rural areas of Brazil, especially along inland riverbeds. The geographic distribution of disease clustering
is similar to that of a black fly, Simulium nigrimanum,
thought by natives to be a vector of this disease. A
study of potential environmental risk factors has also
implicated the bite of this black fly, showing it to be significantly more frequent among those with the disease
compared to an age-, sex-, and occupation-matched
control population with unrelated dermatoses.13 The
prevalence on some well-studied Indian reservations
in rural Brazil can be as high as 3.4%, with the incidence up to 0.84.0 new cases per 1,000 people per
year.12,14 On the reservation in Limao Verde, up to 55%
of unaffected individuals have a low-level IgG1 antibody response against desmoglein 1, the PF autoantigen, which becomes an IgG4 response of higher titer
against a more pathogenic epitope in disease.12 These
results suggest that some environmental agent (e.g.,
insects or other infectious disease agent) may trigger a
low-level autoantibody response that becomes pathogenic by intramolecular epitope spreading in genetically susceptible individuals. With this theory in mind,
it is interesting that 40%80% of patients from Brazil
with the insect-borne diseases onchocerciasis, leishmania, and Chagas disease have low-level antidesmo-
Aphthous ulcers
Candidiasis
Lichen planus
Behet disease
Erythema multiforme
Toxic epidermal necrolysis
Porphyria
Junctional or dystrophic epidermolysis bullosa
Pemphigus
::
Familial benign pemphigus (HaileyHailey disease)

Bullous impetigo, staphylococcal scalded-skin
MOUTH ULCERS/EROSION WITHOUT

AUTOANTIBODIES
Chapter 54
INTRAEPIDERMAL BLISTERING DISEASES

glein 1 antibodies, but patients with other infectious

diseases from Brazil rarely have such antibodies.15
Fogo selvagem occurs often in children and young
adults, unlike sporadic PF, which is a disease of mostly
middle-aged and older patients. Also unlike PF, fogo
selvagem occurs not infrequently in genetically related
family members, although it is not contagious. This
fact probably implies a common exposure, as well as
susceptibility. There is no known racial or ethnic predominance, and anyone moving into an endemic area
may be susceptible to disease. Again supporting the
presence of an environmental trigger, the development of the rural endemic areas of Brazil decreased the
incidence of disease. Certainly, this fascinating disease
holds clues to understanding how this autoimmune
response is triggered.
SEX RATIO
The sex ratio of pemphigus cases is difficult to estimate
accurately due to the overall low incidence. Larger epidemiologic studies (i.e., those identifying greater than
100 cases) have shown that the sex ratio of pemphigus in women versus men ranges from 1.33 or 2.25 to
1.7,9,1620 Notable exceptions are the predominance of
women (4:1) in an endemic focus of PF in Tunisia,6 and
a predominance of men (19:1) in an endemic focus of
PF in Colombia.21
587
AGE OF ONSET
The average age of disease onset also varies by region.
In Turkey, Saudi Arabia, Tunisia, and Iran, the mean
age of onset is approximately 40 years.6,16,18,22 Studies
in the United States and elsewhere in Europe demonstrate an average age of onset between 50 and 70
years.5,6,9,10,17,19,23,24,25 Pemphigus rarely occurs in children,26 except in regions of endemic disease.

Section 8
::
588
The discovery of pemphigus as an organ-specific, autoantibody-mediated disease of desmosomes highlights

the synergy between clinical care and basic science
research. The development of light microscopy and
electron microscopy allowed dermatologists to identify the morphology and immunopathology of disease.
Patient serum IgG served as a key reagent to help identify both the PF and PV antigens.2729 The cloning and
characterization of the pemphigus antigens have subsequently led to the development of enzyme-linked
immunosorbent assay (ELISA) tests to improve the
sensitivity and specificity of disease diagnosis, and
continued studies on pemphigus pathophysiology
aim to develop safer and effective therapies for these
potentially fatal diseases.
PEMPHIGUS AUTOANTIGENS
Pemphigus antigens are desmogleins, transmembrane
glycoproteins of desmosomes (cell-to-cell adhesion
structures, reviewed in Chapter 53).30,31 Desmogleins
are part of the cadherin superfamily of calciumdependent cell adhesion molecules. The original
members of this family (e.g., E-cadherin) demonstrate
homophilic adhesive interactions (binding between
like molecules). Desmogleins similarly demonstrate
homophilic binding but can also participate in heterophilic adhesion by binding desmocollins, the other
major transmembrane glycoprotein of desmosomes.32,33
The PF antigen (as well as the fogo selvagem antigen) is desmoglein 1, a 160-kDa protein.27,28,34 The PV
antigen is desmoglein 3, a 130-kDa protein that is 64%
similar and 46% identical in amino acid sequence to
desmoglein 1.29 All patients with PV have antidesmoglein 3 antibodies, and some of these patients also
have antidesmoglein 1 antibodies.35,36 Patients with
mucosal-dominant PV tend to have only antidesmoglein 3 antibodies, whereas those with mucocutaneous
disease usually have both antidesmoglein 3 and antidesmoglein 1 antibodies.3739 PF patients typically have
antibodies against only desmoglein 1.
Several lines of evidence indicate that antidesmoglein 1 and 3 antibodies in pemphigus patients directly
cause blisters and hence are the etiologic agents of disease. Passive transfer of PV or PF IgG to neonatal mice
or human skin causes blisters that clinically and histologically mimic the corresponding type of pemphigus in patients.4042 The antidesmoglein antibodies are
responsible for blister formation in the passive transfer
model, since affinity purified antidesmoglein 1 and 3

autoantibodies cause PF and PV blisters, respectively,
and adsorption of desmoglein-reactive autoantibodies from PF or PV IgG abrogates disease.4346 Similar
passive transfer experiments have been described in
humans, where mothers with even mild PV can pass
IgG autoantibodies to the fetus, causing blistering
oral and skin disease that resolves by approximately 6
months, concurrent with the disappearance of maternal IgG from the circulation.47
Desmoglein 4, which is expressed in the developing
hair cortex and the superficial epidermis, is a target of
some pemphigus antibodies.48 However, the antidesmoglein 4 antibodies in mucocutaneous PV and in PF
have been shown to be a result of cross-reactivity from
desmoglein 1 autoantibodies, and the desmoglein 4
reactivity has not been shown to be necessary or sufficient for acantholysis.49 Other cell surface molecules
such as acetylcholine receptors and E-cadherin have
also been identified as immunologic targets of pemphigus autoantibodies, although their direct involvement in the pathophysiology of pemphigus is similarly
unclear.50,51
PATHOPHYSIOLOGY OF
ACANTHOLYSIS
Unlike many other autoantibody-mediated diseases,
such as pemphigoid and epidermolysis bullosa acquisita, in which the constant region of the antibody is
required for blister formation to activate complement
or bind antibody receptors on inflammatory cells, in
pemphigus the variable region of the antibody is sufficient to cause blisters in neonatal mice or human
skin.42,6062 For this reason a significant amount of
research on disease pathophysiology has focused on
the epitopes bound by pathogenic autoantibodies, as
these regions are likely critical for maintaining desmosomal cell adhesion.
Epitope mapping studies have shown that pathogenic PV and PF autoantibodies bind calciumsensitive, conformational epitopes in the aminoterminal extracellular domains of desmogleins,
whereas nonpathogenic antibodies tend to bind more
membrane proximal extracellular domains.6366 The
amino-terminal domains bound by pathogenic autoantibodies are the same domains that are predicted to
form the key molecular interactions for desmoglein
intercellular adhesion, based on studies of cadherin
ultrastructure.67,68 This evidence is the primary basis
for the steric hindrance hypothesis, which proposes
that pathogenic antibodies directly interfere with desmoglein adhesive interactions, causing acantholysis.
Studies on cultured keratinocytes have indicated
that loss of intercellular adhesion by pathogenic autoantibodies leads to internalization and degradation
of desmogleins,6972 indicating that pemphigus antibody binding leads to loss of desmoglein function. If
this is the case, then other model systems with loss
of desmoglein function should mimic pemphigus.
Indeed, mice genetically deficient for desmoglein
Pemphigus
Compared to a matched population, patients with PV

have a markedly increased frequency of certain class
II major histocompatibility complex (MHC) antigens.
Among Ashkenazi Jews with PV, the serologically
defined HLA-DR4 haplotype is predominant, whereas
in other ethnic groups with PV, the DQ1 allele is more
common.83 However, the association with disease susceptibility becomes even more striking in an analysis
of these MHC alleles at a genetic level. Patients with
the DR4 serotype almost all have the unusual allele
DRB1*0402, and patients with the DQ1 serotype
almost all have the rare allele DQB1*0503. Similar, but
::
GENETIC RESTRICTION OF THE

PEMPHIGUS IMMUNE RESPONSE
less restricted, HLA-DR alleles are associated with

PF.84 The protein chains encoded by these PV MHC II
alleles vary from those found in HLA-DR4 and DQ1
controls without disease by only a few amino acids.
MHC class II alleles encode cell surface molecules
that are necessary for antigen presentation to the
immune system; therefore, it is hypothesized that PVassociated MHC class II molecules allow presentation
of desmoglein 3 peptides to T cells.85 Consistent with
this hypothesis, certain peptides from desmoglein 3,
predicted to fit into the DRB1*0402 peptide-binding
pocket, were found to stimulate T cells from patients.86
Other studies have confirmed that the immune
response in pemphigus is restricted to certain desmoglein peptides and MHC class II alleles.8789 An unexpected observation was that T cells of normal people
with the DRB1*0402 or DQB1*0503 respond just as well
as those of pemphigus patients to the same desmoglein
3 peptides,85,90 indicating that T-cell reactivity to desmoglein 3 peptides is not sufficient for disease onset.
The factor that may determine who gets pemphigus
and who does not has been proposed to be the presence of regulatory T cells that can suppress the autoimmune response in those who do not.91
Cloning of antidesmoglein antibodies from PV and
PF patients has indicated a marked restriction of antibody gene usage by the antidesmoglein antibodies,
most notably for the heavy chain variable region.61,62,92
These studies also show that pathogenic antibodies
from different patients bind at or near common epitopes on desmogleins and may share common idiotypes. In comparison to the restricted B-cell antibody
variable region gene usage, there is more heterogeneity
of the T-cell receptor variable gene usage in pemphigus
patients.90,93 If specific antibody or T-cell receptor gene
usage patterns are found to be shared among multiple
pemphigus patients, these may serve as clinical markers for targeting disease-specific immune cell populations in pemphigus patients.
Chapter 54
3 demonstrate suprabasal blisters in the oral mucosa

histologically identical to PV patients.73 Additionally,
cleavage of desmoglein 1 by staphylococcal exfoliative
toxin (in bullous impetigo or staphylococcal scalded
skin syndrome) causes blisters histologically identical
to those seen in PF patients.74
If inactivation of desmoglein isoforms results in blistering, then why do blisters in PV and PF have specific
tissue localizations that do not necessarily correlate
with the sites at which the antibodies bind by immunofluorescence? In PF, for example, the antidesmoglein 1
antibodies bind throughout the epidermis and mucous
membranes,75 yet blisters occur only in the superficial
epidermis. This apparent paradox can be explained
by desmoglein compensation, as outlined in Fig. 54-1.
The concept of desmoglein compensation originates in
the assumption that autoantibodies against one desmoglein isoform inactivate only that isoform and that
another isoform coexpressed in the same area can compensate in adhesion.7678 Desmoglein compensation
explains why neonatal PF is so unusual, because even
though the maternal antidesmoglein 1 antibodies cross
the placenta, in neonatal skin, but not in adult skin,
desmoglein 3 is coexpressed with desmoglein 1 in the
superficial epidermis, thereby providing protection
against the loss of desmoglein 1-based adhesion.77,79
Desmoglein compensation also offers an explanation
for the differing sites of blister formation in PV and
PF, both in regard to the histology (i.e., suprabasal
or superficial), as well as the areas of involvement
(mucosa and/or skin.)
In potential challenge to the steric hindrance hypothesis, several studies have suggested that modulation of
cell signaling pathways can prevent blister formation
after passive transfer of pemphigus IgG in the neonatal mouse model, including p38 mitogen activated protein kinase (MAPK) and GTPases, among others.8082
Whether signaling is upstream or downstream of the
loss of intercellular adhesion is controversial. Nevertheless, the current general consensus is that desmosomal adhesion is a dynamic process that is perturbed
by pemphigus autoantibodies. Therefore, therapies
that aim to strengthen keratinocyte adhesion by modulation of signaling pathways may have a beneficial
effect on pemphigus, regardless of whether cell signaling is a primary pathologic cause of disease.
CLINICAL FINDINGS
PEMPHIGUS VULGARIS
CUTANEOUS LESIONS. The skin lesions in PV
can be pruritic or painful. Exposure to ultraviolet
radiation may exacerbate disease activity.94,95 The primary lesion of PV is a flaccid blister, which may occur
anywhere on the skin surface, but typically not the
palms and soles (Fig. 54-2). Usually, the blister arises
on normal-appearing skin, but it may develop on erythematous skin. Because PV blisters are fragile, the
most common skin lesions observed in patients are
erosions resulting from broken blisters. These erosions
are often quite large, as they have a tendency to spread
at their periphery (Fig. 54-3).
A characteristic finding in pemphigus patients is
that erosions can be extended into visibly normal skin
by pulling the remnant of the blister wall or rubbing at
the periphery of active lesions; additionally, erosions
can be induced in normal-appearing skin distant from
589
Desmoglein (Dsg) compensation
Pemphigus foliaceus
Skin
Mucous membrane
1
Dsg1
Section 8
::
Pemphigus vulgaris
Skin
Mucous membrane
1
Dsg3
only
1
Skin
Mucous membrane
Dsg3
+
Dsg1
1
590
Figure 54-1 Desmoglein (Dsg) compensation. Triangles represent the distribution of Dsg1 and 3 in skin and mucous
membranes. Anti-Dsg1 antibodies in pemphigus foliaceus cause acantholysis only in the superficial epidermis of skin. In
the deep epidermis and in mucous membranes, Dsg3 compensates for antibody-induced loss of function of Dsg1. In early
pemphigus vulgaris, antibodies are present only against Dsg3, which cause blisters only in the deep mucous membrane
where Dsg3 is present without compensatory Dsg1. However, in mucocutaneous pemphigus, antibodies against both
Dsg1 and Dsg3 are present, and blisters form in both mucous membrane and skin. The blister is deep probably because
antibodies diffuse from the dermis and interfere first with the function of desmosomes at the base of the epidermis.
Figure 54-3 Pemphigus vulgaris. Extensive erosions due

to blistering. Almost the entire back is denuded. Note
intact, flaccid blisters at the lower border of eroded lesions.
MUCOUS MEMBRANE LESIONS. The mucous

membranes most often affected by PV are those of the
oropharyngeal cavity (see Fig. 54-2B). As with cutaneous lesions, intact blisters are rare. Oropharyngeal erosions can be so painful that the patient is unable to eat
or drink. The inability to eat or drink adequately may
require inpatient hospitalization for disease control
and intravenous fluid and nutrient repletion.
In the majority of patients, painful mucous membrane erosions are the presenting sign of PV and may
be the only sign for an average of 5 months before skin
lesions develop.3 However, the presenting symptoms
may vary; in a study from Croatia, painful oral lesions
were the presenting symptom in 32% of patients.20
Most of these patients progressed to a more generalized eruption in 5 months to 1 year; however, some
had oral lesions for more than 5 years before generalization. On the other hand, in Tehran, 62% of patients
presented with oral lesions only.7 Skin involvement
without mucous membrane involvement in PV is
less common, accounting in one study for 11% of PV
cases.99
Pemphigus
VEGETATING LESIONS. In certain patients, erosions have a tendency to develop excessive granulation tissue and crusting, referred to as vegetating
lesions (Fig. 54-4). This type of lesion tends to occur
more frequently in intertriginous areas, in the scalp,
or on the face (see Fig. 54-4A). Historically, patients

presenting with vegetating lesions have been split
out into different disease designations: pemphigus vegetans of Hallopeau and pemphigus vegetans of Neumann.
However, the subsequent analysis of vegetating skin
lesions by histology and immunofluorescence suggests that these cases are simply clinical variants of
PV.1,97 In the Hallopeau variant, vegetating and often
pustular lesions are present from the outset of disease, are not preceded by bullae, and favor flexural
regions (see Fig. 54-4B). Generally, the prognosis for
these patients is thought to be better, with milder disease and a higher chance of remission compared to
typical PV patients.98 In patients with the Neumann
variant, ordinary PV erosions heal with papillomatous formations, with prognosis related to the extent
of disease activity. The vegetating type of response
may also appear in certain lesions that tend to be
resistant to therapy and remain for long periods of
time in one place. Thus, vegetating lesions seem to
be one reactive pattern of the skin to the autoimmune
insult of PV.
::
active lesions by pressure or mechanical shear force.

This phenomenon is known as the Nikolsky sign.96
This sign helps differentiate pemphigus from other
blistering diseases of the skin such as pemphigoid
(Box 54-1); however, similar findings can also be elicited in staphylococcal scalded skin syndrome, Stevens
Johnson syndrome, and toxic epidermal necrolysis.
Chapter 54
Figure 54-2 Pemphigus vulgaris. A. Flaccid blisters. (Used with permission from Lawrence Lieblich, MD.) B. Oral erosions.
591
Section 8
::
Figure 54-4 A. Crusted, vegetating lesions in pemphigus vulgaris. B. Extensive, vegetating granulomatous lesions in
pemphigus vegetans.
lesions of small flaccid blisters are typically not found.

Disease may stay localized for years, or it may rapidly
progress to generalized involvement, resulting in an
exfoliative erythroderma (Fig. 54-5B). Like PV, PF may
be exacerbated by ultraviolet radiation.95,110,111 Patients
with PF often complain of pain and burning in the skin
lesions. In contrast to patients with PV, those with PF
very rarely, if ever, have mucous membrane involvement, even with widespread disease.
The colloquial term for Brazilian endemic pemphigus, fogo selvagem (Portuguese for wild fire), takes
into account many of the clinical aspects of this disease: the burning feeling of the skin, the exacerbation
of disease by the sun, and the crusted lesions that make
the patients appear as if they had been burned.
Gastrointestinal tract involvement with PV has been

described in the esophagus, stomach, duodenum, and
anus, although only biopsies of the esophagus have
been proven to be due to suprabasal acantholysis.7,100,101
Involvement of other mucous membranes can also
occur, including the vulvovaginal, nasal, laryngeal,
and conjunctival mucosa.102106 In women, cervicovaginal lesions may be found in up to 51% of patients with
active disease but these lesions may be asymptomatic.
Even without obvious lesions, Pap smears may be positive in women with pemphigus and the acantholytic
cells may be misinterpreted as indicative of cervical
dysplasia.107,108 There are rare case reports on corneal
erosions in PV patients, but no histologic confirmation
of acantholysis.109
PEMPHIGUS ERYTHEMATOSUS. In 1926, Francis Senear and Barney Usher described eleven patients
with features of a pemphiguslupus erythematosus
overlap (SenearUsher syndrome).112 Over the next several decades, debate over whether these patients had
lupus erythematosus, pemphigus, seborrheic dermatitis,
or features of all three disorders continued, with Senear
concluding that the disease is best considered a variant of pemphigus, termed pemphigus erythematosus.113
PEMPHIGUS FOLIACEUS
CUTANEOUS LESIONS. The characteristic clinical
lesions of PF are scaly, crusted erosions, often on an
erythematous base. In more localized and early disease, these lesions are usually well demarcated and
scattered in a seborrheic distribution, including the
face, scalp, and upper trunk (Fig. 54-5A). The primary
592
Figure 54-5 Pemphigus foliaceus. A. Scaly, crusted lesions on upper back. B. Exfoliative erythroderma due to confluent
lesions.
DRUG-INDUCED PEMPHIGUS
Although there are sporadic case reports of pemphigus associated with the use of several different drugs,
the association with penicillamine, and perhaps captopril, is the most significant.121 The prevalence of
pemphigus in penicillamine users is estimated to be
approximately 7%. PF (including pemphigus erythematosus) is more common than PV in these penicillamine-treated patients, although either may occur. The
findings of direct and indirect immunofluorescence are
positive in most of these patients. Three patients with
drug-induced PF and one with drug-induced PV have
been shown to have autoantibodies to the same molecules involved in sporadic pemphigus, namely, desmoglein 1 and desmoglein 3, respectively.122 Therefore,
by immunofluorescence and immunochemical deter-
Pemphigus
Infants born to mothers with PV may display clinical, histologic, and immunopathologic signs of PV.47,116
The degree of involvement varies from none to severe
enough to result in a stillbirth. If the infant survives,
disease tends to remit as maternal antibody is catabolized. Mothers with PF may also transmit their
autoantibodies to the fetus, but, as discussed in Section Pathophysiology of Acantholysis, neonatal PF
occurs only rarely.117119 Neonatal pemphigus should be
distinguished from PV and PF that occur in childhood,
which are similar to the autoimmune diseases seen in
adults.120
::
NEONATAL PEMPHIGUS
minations, these patients with drug-induced pemphigus resemble those with sporadic disease.
Both penicillamine and captopril contain sulfhydryl
groups that are postulated to interact with the sulfhydryl groups in desmoglein 1, 3, or both, thereby causing pemphigus either by directly interfering with these
adhesion molecules or, more likely, by modifying them
so that they become more antigenic. The use of these
drugs may also lead to a more generalized dysregulation of the immune response, allowing production of
other autoantibodies such as those resulting in myasthenia gravis. Most, but not all, patients with druginduced pemphigus go into remission after they stop
taking the offending drug.
Additionally, rare anecdotal reports have suggested
the association of dietary intake and pemphigus, proposing the hypothesis that thiol-containing foods
such as garlic, leeks, and onions may precipitate disease.123,124 Some patients may note that certain foods
aggravate oral lesions, but it is unlikely that dietary
intervention alone will remit disease in most patients.
Interestingly, anecdotal case reports have reported
improvement of PV with cigarette smoking,125 as well
as with the cholinergic agonists pyridostigmine, carbachol, and pilocarpine.126,127 Studies suggest that activation of cholinergic receptors may regulate signaling
pathways modulated by PV IgG, thereby affecting
cell adhesion.128 These results are intriguing given the
clinical benefit of nicotine noted in other inflammatory
diseases, such as ulcerative colitis.129
Chapter 54
As these observations were made prior to the development of immunofluorescence testing for both pemphigus and lupus, the diagnosis was primarily based
on the clinical presentation: crusted erosions in a seborrheic distribution, at times concurrent with more
lupus-like discoid lesions with carpet-tack scale.
Walter Lever noted that many patients initially categorized as pemphigus erythematosus went on to develop
systemic lupus, or more widespread PF, or even PV, in
some cases due to incorrect initial diagnosis. Therefore,
rather than perpetuate the use of one term for different
diseases, he proposed that pemphigus erythematosus
be used to describe a localized form of PF with better
prognosis.1 After the development of immunofluorescence and antinuclear antibody testing for pemphigus
and lupus, it was discovered that pemphigus erythematosus patients demonstrate immunologic overlap
features; by definition all demonstrate the cell surface
staining pattern classic for pemphigus, approximately
30% have positive antinuclear antibody titers, and 80%
have positive lupus band tests, although the latter test
is only positive in 20%40% of biopsies on nonsunexposed skin.114 As most patients with pemphigus
erythematosus do not develop systemic signs or symptoms of lupus, and some may progress from localized
disease to generalized PF,115 the diagnosis of pemphigus erythematosus is largely one of historic, rather
than clinical, significance.
ASSOCIATED DISEASES
Myasthenia gravis, thymoma, or both have been associated with PV and PF.130 Approximately one-half of
associated pemphigus cases are vulgaris; one-half, foliaceus or erythematosus. Most of these data, however,
were reported before the recognition of paraneoplastic pemphigus as a distinct entity. Therefore, although
thymoma may clearly be associated with PV and PF,
it may also be associated with paraneoplastic pemphigus (see Chapter 55). Myasthenia gravis is a tissuespecific autoantibody-mediated disease leading to
skeletal muscle weakness. Early disease usually affects
facial muscles, leading to symptoms of dysarthria, dysphagia, ptosis, or diplopia. Disease may then progress
to affect the larger muscles of the trunk and extremities, with potential fatal complications from respiratory
muscle involvement. Thymoma, in contrast, is typically asymptomatic in adults. In children, thymomas
are more likely to be symptomatic with cough, chest
pain, superior vena cava syndrome, dysphagia, and/
or hoarseness from localized tumor encroachment.
Myasthenia gravis would be best evaluated by
a neurologist, who can complete a full neurologic
examination and may test for the presence of serum
acetylcholine receptor autoantibodies. The course of
myasthenia gravis and pemphigus appear to be independent of each other. Likewise, thymic abnormalities
may either precede or follow the onset of pemphigus.
Thymic abnormalities include benign or malignant
thymoma and thymic hyperplasia. Posteroanterior
593
Section 8
Figure 54-6 Histopathology of pemphigus vulgaris. Suprabasilar acantholysis. The row of tombstones.
::
and lateral chest radiographs with or without computerized tomography follow-up can detect most
thymomas. Irradiation of the thymus or thymectomy,
although clearly beneficial for myasthenia gravis, may
not improve the pemphigus disease activity. Although
this association is reported in at least 30 cases, the finding of thymoma or myasthenia gravis in a patient with
PV or PF is still unusual.
LABORATORY TESTS
Diagnosis of pemphigus relies on skin biopsy of a fresh
lesion for histology to determine the site of blister formation, as well as a confirmatory immunochemical
study to document the presence of skin autoantibodies, either by direct immunofluorescence of perilesional skin, or indirect immunofluorescence or ELISA
of patient serum.
HISTOLOGY
The characteristic histopathologic finding in PV is a
suprabasal blister with acantholysis (Fig. 54-6). Just
above the basal cell layer, epidermal cells lose their
normal cell-to-cell contacts and form a blister. Often, a
few rounded up (acantholytic) keratinocytes are in the
594
blister cavity. The basal cells stay attached to the basement membrane, but may lose the contact with their
neighbors; as a result, they may appear to be a row of
tombstones, symbolic of the potentially fatal prognosis of this disease. Usually, the upper epidermis (from
one or two cell layers above the basal cells) remains
intact, as these cells maintain their cell adhesion. Pemphigus vegetans shows not only suprabasilar acantholysis, but also papillomatosis of the dermal papillae
and downward growth of epidermal stands into the
dermis, with hyperkeratosis and scale-crust formation.
In addition, pemphigus vegetans lesions may show
intraepidermal abscesses composed of eosinophils
and/or neutrophils.131 Early PV lesions may show
eosinophilic spongiosis.132
The histopathology of early blisters in PF patients
demonstrates acantholysis (loss of cell-to-cell contact)
just below the stratum corneum and in the granular
layer (Fig. 54-7A). The stratum corneum is often lost
from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another
frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity (Fig. 54-7B). Histologic findings in PF are
often indistinguishable from those seen in bullous
impetigo/staphylococcal scalded skin syndrome,
because blisters in these latter diseases also result from
dysfunction of desmoglein 1, in these cases due to proteolytic cleavage by staphylococcal exfoliative toxins.31
Therefore, immunochemical studies are essential to
confirm a diagnosis of PF, as these would be negative
in staphylococcal-mediated skin blisters. The site of
blister formation in pemphigus erythematosus is identical to PF. As in PV lesions, very early PF lesions may
show eosinophilic spongiosis.132
IMMUNOFLUORESCENCE
The hallmark of pemphigus is the finding of IgG autoantibodies against the cell surface of keratinocytes.
These autoantibodies were first discovered in patients
sera by indirect immunofluorescence techniques and
soon thereafter were discovered by direct immunofluorescence of patients skin.133
Figure 54-7 Histopathology of pemphigus foliaceus. A. Acantholysis in the granular layer. B. Subcorneal pustule with
acantholysis.
Chapter 54
Figure 54-8 Immunofluorescence in pemphigus. A. Direct immunofluorescence for immunoglobulin G (IgG) of perilesional skin from a patient with pemphigus vulgaris. Note cell surface staining throughout the epidermis. B. Indirect immunofluorescence with the serum from a patient with pemphigus foliaceus on normal human skin. Note IgG on the cell
surface throughout the epidermis.
::
INDIRECT IMMUNOFLUORESCENCE. Indirect

immunofluorescence is performed by incubating serial
dilutions of patients sera with epithelial substrates. It
is reported as a semiquantitative titer (indicating the
last dilution at which the serum demonstrates a positive cell surface staining pattern). The test is offered by
most major national laboratories and can remain positive for weeks to months after healing of skin lesions,
making it a good diagnostic test if a patient should
present with no active skin lesions, for example, due
to empiric treatment with prednisone by a referring
physician. Depending on the substrate used for indirect immunofluorescence, more than 80% of patients
with pemphigus have circulating antiepithelial cell
surface IgG (Fig. 54-8B).136 The substrate used to detect
pemphigus antibody binding in indirect immunofluorescence greatly influences the sensitivity of the test.
In general, monkey esophagus is more sensitive for
detecting PV antibodies, and guinea pig esophagus or
normal human skin is a superior substrate for detecting PF antibodies. Patients with early localized disease
and those in remission are most likely to have negative
findings on an indirect immunofluorescence test; for
these patients the increased sensitivity of ELISA may

help in diagnosis (see below).
Patients with PV and PF usually display similar
direct and indirect immunofluorescence findings with
IgG on the cell surface of epidermal cells throughout
the epidermis, despite the different autoantigen profiles in these two diseases. Therefore, it is usually not
possible to differentiate the two diseases by the pattern of immunofluorescence. There is a positive, but
imperfect, correlation between the titer of circulating
anticell surface antibody and the disease activity in
PV and in PF.137 Although this correlation may hold in
general, and although patients in remission often show
serologic remission with negative direct and indirect
immunofluorescence findings,138,139 disease activity in
individual patients does not necessarily correlate with
indirect immunofluorescence titer. Therefore, in the
day-to-day management of these patients, following
disease activity is more important than following antibody titer.
Pemphigus
DIRECT IMMUNOFLUORESCENCE. Essentially all patients with active PV or PF have a positive

finding on a direct immunofluorescence study, which
tests for IgG bound to the cell surface of keratinocytes
in perilesional skin (Fig. 54-8A).134 This is a nonquantitative test (either negative or positive). The diagnosis
of pemphigus should be seriously questioned if the
test result of direct immunofluorescence is negative.
It is important that the biopsy for direct immunofluorescence be performed on normal-appearing perilesional skin, as the immune reactants can be difficult
to detect in blistered inflamed epidermis (leading to
a false negative result). In some cases of pemphigus
erythematosus, IgG and C3 are deposited at the basement membrane zone of erythematous facial skin, in
addition to the epidermal cell surface IgG, representing a positive lupus band test in addition to the typical
pemphigus intercellular pattern.135
ENZYME-LINKED
IMMUNOSORBENT ASSAY
For diagnosis of disease, antigen-specific ELISAs have
been shown to be more sensitive and specific than
immunofluorescence, and their titer correlates better
than that of indirect immunofluorescence with disease activity.35,140 Additionally, ELISAs are easier to
perform and less subjective than immunofluorescence,
and may replace the latter as the preferred first diagnostic test for pemphigus, although currently some
major national laboratories do not offer desmoglein
ELISA. These assays use desmogleins 1 and 3 bound to
plates, which are then incubated with patient sera and
developed with antihuman IgG reagents (Fig. 54-9).
As an advantage over indirect immunofluorescence,
ELISAs can help differentiate between PV and PF
due to the different autoantigen profiles in these two
diseases.35,140,141,142 In most cases, ELISA is positive for
desmoglein 3 (but not desmoglein 1) in mucosal PV, is
595
Enzyme-linked immunosobent assay (ELISA)

for desmoglein 3
Irrelevant antibodies
Dsg3
Dsg3
HRP-anti-human IgG
Section 8
::
HRP-substrate
Figure 54-9 Enzyme-linked immunosorbent assay

(ELISA) for desmoglein 3. Anti-Dsg3 antibodies (Dsg3)
from pemphigus serum binds Dsg3 on the ELISA plate; irrelevant antibodies, that do not bind, are washed off. The
plate is then incubated with horseradish peroxidase (HRP)
conjugated antihuman IgG, which binds the anti-Dsg3 IgG
that is on the plate. HRP is an enzyme that turns a clear
substrate blue and the amount of color, read on spectrophotometer, correlates with the amount of pemphigus
(i.e., anti-Dsg3) antibody in the patients serum.
positive for both desmogleins 3 and 1 in PV with both
mucosal and significant skin involvement, and is positive for only desmoglein 1 in PF. PV has rarely evolved
into PF, and vice versa, as determined by clinical, histologic, and immunochemical criteria.143145 A small
minority of PF patients may also demonstrate autoantibodies to desmoglein 3146; therefore, diagnosis should
be made based on the clinicalserologic correlation.
Additionally, some patients (e.g., those with bullous
pemphigoid) may demonstrate a low level of antidesmoglein 3 autoantibodies,140 which are detectable due
to the high sensitivity of the ELISA. Therefore, a result
in the indeterminate range should be interpreted carefully, as this may represent a true positive or a false
negative, the latter presumably due to formation of
nonpathogenic bystander autoantibodies after epidermal damage. As with indirect immunofluorescence,
the correlation of ELISA index value with disease
activity is not perfect. In making treatment decisions,
a negative result on desmoglein ELISA is more helpful
than a positive result, as a patient with the former is
more likely to achieve remission off immunosuppressives, whereas a patient with the latter may or may
not. In other words, disease activity is the mainstay for
determining treatment.

596
Before the advent of glucocorticoid therapy, PV was

almost invariably fatal due to severe blistering of the
skin and mucous membranes leading to malnutrition,

dehydration, and sepsis. PF was fatal in approximately
60% of patients. PF was almost always fatal in elderly
patients with concurrent medical problems; however,
in other patients its prognosis, without therapy, was
much better than PV.147,148
The systemic administration of glucocorticoids
and the use of immunosuppressive therapy have
dramatically improved the prognosis for patients
with pemphigus; however, pemphigus is still a disease associated with a significant morbidity and
mortality.149,150 In the United States, the annual
mortality rate from pemphigus (age-adjusted to
the standard population) is estimated to be 0.023
deaths per 100,000.151 A study in the United Kingdom showed that the risk of death in PV patients is
3.3 times greater than for controls.9 Infection is often
the cause of death, and by causing the immunosuppression necessary in the treatment of active disease,
therapy is frequently a contributing factor.152 With
glucocorticoid and immunosuppressive therapy, the
mortality (from disease or therapy) of PV patients
followed from 4 to 10 years is approximately 10% or
less, whereas that of PF is probably even less. In a
study of 40 patients with PV, two patients (5%) died
of sepsis and 17%, after an average of 18 months
of therapy, went into a complete and long-lasting
(>4 years, average, thought to be permanent) remission requiring no further therapy.153 Another 37% of
patients achieved remission but relapsed at times
after therapy was stopped; most of these also eventually achieved long-lasting remissions. The remainder of patients required continual therapy. In a group
of 159 patients with PV from Croatia, only approximately 12% went into long-term remission after therapy with glucocorticoids and immunosuppressives,
but most relapsed.20 In a study from Tehran of 1,206
pemphigus patients seen over 20 years, 6.2% of PV
and 0.2% of PF patients died, mostly of septicemia;
only 9.3% were in complete remission without therapy.7 In some small studies, higher percentages of
patients were reported to go into complete remission
(see below). With the advent of rituximab therapy,
complete remission in pemphigus may become more
common.
TREATMENT
Despite the potentially fatal prognosis, there are currently no FDA-approved treatments. Approach to
therapy of pemphigus varies widely, even among
experts.154 It is generally agreed that PV, even if initially limited in extent, should be treated at its onset,
because it will ultimately generalize and the prognosis
without therapy is very poor. In addition, it is probably
easier to control early disease than widespread disease,
and mortality may be higher if therapy is delayed.155
Because PF may be localized for many years, and the
prognosis without systemic therapy may be good,
patients with this type of pemphigus do not necessarily require treatment with systemic therapy; the use of
topical corticosteroids may suffice. When the disease is

active and widespread, however, the therapy for PF is,
in general, similar to that for PV.
Recently, a consensus statement on disease definitions and endpoints was proposed by an international
committee of pemphigus experts.156 Additionally,
clinical instruments have been developed for tracking
disease activity.157,158 The standardization of disease
definitions and activity scoring will facilitate future
clinical trials for pemphigus.
CORTICOSTEROIDS
IMMUNOSUPPRESSIVE AGENTS
Pemphigus
AZATHIOPRINE. Azathioprine has historically

been considered as a first-line immunosuppressive
agent for pemphigus, with clinical remission rates of
approximately 50% in retrospective studies.139,167 In a
prospective randomized trial of high dose methylprednisolone (2.0 mg/kg/day) plus azathioprine (2.0 mg/
kg/day), 72% of patients achieved clinical remission
within a mean of 74 days, although 33% experienced
significant adverse effects of therapy, including hyperglycemia, dizziness, abnormal liver enzyme tests, and
infection.165
Azathioprine is a prodrug, which is converted to
active mercaptopurine, thioguanine, and thioinosine
metabolites, in part by thiopurine methyltransferase
(TPMT), an enzyme whose levels can vary widely in
the population. 89% of Caucasians demonstrate normal to high levels of TPMT, 11% are intermediate, and
0.3% are deficient for TPMT, the latter group representing those who do not tolerate azathioprine therapy.168
Additionally, 1%2% of Caucasians may have super
high levels of TPMT, which is correlated with both
treatment resistance as well as increased hepatotoxicity
from excessive metabolite production.169 Altogether, it
is estimated that 5% of patients will be azathioprine
intolerant, although the genotypephenotype correlation is imperfect.170
::
When greater than minimal doses of glucocorticoids

are required for disease control, or if there are contraindications to oral glucocorticoids, other immunosuppressive agents are used for pemphigus therapy. In
many cases, treatment regimens often begin with an
immunosuppressive agent and prednisone simultaneously. Prospective randomized studies have shown
that immunosuppressive agents such as mycophenolate mofetil, azathioprine, and cyclophosphamide
have a steroid-sparing effect; retrospective studies
suggest decreased mortality with use of adjuvants plus
steroids compared to steroids alone.147,165,166
Because patients may die from complications of
therapy, it is important to monitor all patients closely
for potential side effects, such as blood count, liver
and kidney laboratory abnormalities, gastrointestinal
ulcer disease, high blood pressure, diabetes, glaucoma,
cataracts, osteoporosis, and infection. The decision to
use immunosuppressive agents, particularly in young
patients, must also take into account the potential incidence of malignancies that might be associated with
the long-term use of these drugs, as well as the risks of
infertility (for cyclophosphamide) and teratogenicity
(for mycophenolate mofetil, azathioprine, and cyclophosphamide, which are all pregnancy category D).
Chapter 54
The systemic administration of glucocorticoids, usually prednisone, is the mainstay of therapy for pemphigus. Before adjuvant immunosuppressive therapy
was available, very high initial doses of prednisone
(>2.0 mg/kg/day) were used for treatment, although
such regimens have retrospectively been associated
with significant morbidity and mortality from therapy.152,159,160 In many patients the disease can be brought
under control with a 0.51.0 mg/kg/day single daily
dose, especially if used in combination with adjunctive immunosuppressive therapy, which is thought to
result in fewer complications and decreased mortality as compared to higher dose glucocorticoid regimens.161,162 For patients who do not initially respond or
worsen, splitting the dose using a twice or three times
daily schedule may achieve disease control. The full
systemic dose of glucocorticoids has been defined in
the consensus guidelines as 1.5 mg/kg/day of prednisone equivalent for 3 weeks. Therefore, patients whose
total daily prednisone dose exceeds approximately
100 mg should be considered for adjunctive treatments, discussed below. Some experts still recommend
controlling initial refractive disease with escalating
doses of prednisone (increasing by 50% every 1 to 2
weeks until disease control or prohibitive side effects
occur), with total daily doses as high as 240 mg.148,163
Once disease activity is controlled, tapering prednisone to as low a dose as possible should be the goal.
Minimal therapy is defined as 10 mg daily of prednisone equivalent. Although there are no set guidelines,
if disease activity can be fully controlled on minimal
dose prednisone or lower, then glucocorticoid monotherapy may be feasible depending on the patients
other comorbidities and contraindications to alternative immunosuppressive agents. If patients have
continued relapses with daily prednisone doses of 10
mg or higher, adjunctive immunosuppressive agents
should be considered.
Interestingly, prednisone can control blistering
within days, at a time when the autoantibody titer
would be unchanged. A possible explanation is that
prednisone may increase the synthesis of desmogleins or other cell adhesion molecules or change
their posttranscriptional processing to prolong their
half-life.164 If pemphigus IgG depletes desmosomes of
desmogleins, then prednisone could counteract this
effect.
Topical corticosteroids may be used as monotherapy
in mild forms of disease, or as adjunctive therapy to
help heal new lesions. Patients with mucosal disease

may benefit from the use of glucocorticoid elixirs as a
swish and spit or dental trays to help apply class I corticosteroid gels or ointments to the gingiva. Additionally, class IIV corticosteroids can be used as topical
therapy to help resolve new blisters, even in patients
on systemic glucocorticoids.
597
Section 8
::
598
In patients with normal TPMT levels, the consensus dosing regimen that defines treatment failure
is 2.5 mg/kg/day for 12 weeks.156 From a practical
standpoint however, not all laboratories offer TPMT
testing. Additionally, since patients with normal levels of TPMT may also experience azathioprine toxicity, it is reasonable to start all patients at a lower dose
(e.g., 50100 mg daily) and titrate upward until clinical
remission, the target dose of 2.5 mg/kg/day, or unacceptable side effects result. Frequent blood and liver
monitoring should continue, particularly over the first
812 weeks when delayed toxicity from the accumulation of metabolites may emerge.
MYCOPHENOLATE MOFETIL. Mycophenolate

mofetil is also considered to be a first-line immunosuppressive agent for pemphigus. In 2006, the
FDA granted orphan drug status to mycophenolate
mofetil for the treatment of PV, thereby increasing
the feasibility of a new drug approval. Typical doses
range from 3040 mg/kg/day dosed twice daily (2.0
3.0 g/day), although certain patients such as the
elderly may achieve disease control with doses as low
as 1.0 g/day.
In case series, mycophenolate mofetil has been
shown to have a rapid effect in lowering pemphigus
antibody titers and decreasing disease activity, even
in patients whose disease is unresponsive to azathioprine.171,172 A prospective randomized trial comparing
methyprednisolone (2.0 mg/kg/day) with azathioprine (2.0 mg/kg/day) or mycophenolate mofetil
(2.0 g/day) in pemphigus patients showed 72% in the
azathioprine group and 95% in the mycophenolate
mofetil group went in clinical remission in a mean of
74 and 91 days, respectively.165 19% of patients experienced significant side effects of mycophenolate mofetil
therapy, compared to 33% in the azathioprine group.
None of these differences was statistically significant.
Another prospective randomized study indicated that
azathioprine was significantly more effective than
mycophenolate mofetil as a steroid sparing agent,
although this study compared a full dose of azathioprine (2.5 mg/kg/day) to a partial dose of mycophenolate mofetil (2.0 g/day).166 Caution with use of
mycophenolate mofetil is warranted, as fatal infection
and sepsis occurred in 2%5% of transplant patients
receiving mycophenolate mofetil, and increased risk
of infection with or reactivation of cytomegalovirus,
herpes zoster, atypical mycobacteria, tuberculosis, and
John Cunningham (JC) virus (in progressive multifocal
leukoencephalopathy) have been noted in postmarketing surveillance.173 Interestingly, mycophenolate
mofetil may offer protection against Pneumocystis carinii infection.174
CYCLOPHOSPHAMIDE.
Cyclophosphamide,
although more toxic than azathioprine or mycophenolate mofetil, is thought to be very effective in controlling severe disease, with one report of 19 of 23 patients
with pemphigus achieving complete remission in a
median time of 8.5 months.175 A variety of small case
series have evaluated different cyclophosphamide
regimens for pemphigus, including daily oral ther-
apy (1.12.5 mg/kg/day), daily oral therapy (50 mg)

with intermittent high-dose intravenous dexamethasone and cyclophosphamide, and immunoablative
intravenous cyclophosphamide.167,175179 All methods
were effective in the short-term, although none were
curative. Significant side effects, including hematuria, infection, and transitional cell carcinoma of the
bladder, were observed with higher dose regimens,
although one study using a lower daily dose of cyclophosphamide (1.11.5 mg/kg/day) did not report a
significantly different safety profile compared with
other immunosuppressive agents. Together with the
risk of infertility, cyclophosphamide is not generally
considered a first-line agent in the treatment of PV.
DAPSONE. In a case series and randomized double-blind trial, dapsone demonstrated a trend toward
efficacy as a steroid-sparing drug in maintenance
phase PV, although these results were not statistically
significant.180,181 Dapsone may be used in conjunction
with other immunosuppressive agents, particularly
rituximab (discussed below), where it offers the additional benefit of Pneumocystis pneumonia prophylaxis.
ADDITIONAL THERAPIES
There are additional therapies that can be used when
the more standard treatments, discussed previously,
are not effective.
RITUXIMAB. A very effective therapy for pemphigus that is refractory to more standard therapy is a
monoclonal anti-CD20 antibody rituximab, approved
for therapy of B-cell malignancies. In pemphigus
patients, this monoclonal antibody presumably targets B cells, the precursors of antibody-producing
plasma cells. The B cell also acts to process autoantigen and present it to T cells that provide help in
stimulating the autoantibody response.182 Rituximab
is infused intravenously at a dose of 375 mg/m2 once
weekly for 4 weeks. Alternatively, the rheumatoid
arthritis dosing regimen can be used (1,000 mg intravenously on day 1 and day 15). The course can be
repeated in approximately 6 months for patients with
more refractory disease, although a single cycle of
rituximab has been shown to be highly effective, with
86% of patients experiencing complete remission lasting 34 months or greater.183 Disease activity usually
begins to remit within 12 months after the course of
therapy. Some experts consider rituximab the therapy of choice for severe pemphigus uncontrolled by
corticosteroids and azathioprine or mycophenolate
mofetil or who have contraindications to corticosteroids.183,184 However, fatal infections with rituximab
therapy have been observed, including Pneumocystis
pneumonia, reactivation of hepatitis B, and JC virus
infection or reactivation causing progressive multifocal leukoencephalopathy.185188 Although these
complications are rare, some experts recommend
Pneumocystis prophylaxis for 1 year following rituximab infusion.
INTRAVENOUS IMMUNOGLOBULIN. Another
PULSED INTRAVENOUS HIGH-DOSE GLUCOCORTICOIDS. Intravenous, pulse adminis-
tration of methylprednisolone, 2501,000 mg given

over approximately 3 hours daily for 45 consecutive
days, can result in long-term remissions and decrease
the total dose of glucocorticoids necessary to control

1. Lever WF: Pemphigus and Pemphigoid. Springfield, IL,
Charles C. Thomas, 1965
12. Aoki V et al: Environmental risk factors in endemic
pemphigus foliaceus (fogo selvagem). J Investig Dermatol
Symp Proc 9:34, 2004
27. Koulu L et al: Human autoantibodies against a desmosomal core protein in pemphigus foliaceus. J Exp Med
160:1509, 1984
28. Stanley JR et al: A monoclonal antibody to the desmosomal glycoprotein desmoglein I binds the same
polypeptide as human autoantibodies in pemphigus
foliaceus. J Immunol 136:1227, 1986
41. Anhalt GJ et al: Induction of pemphigus in neonatal mice
by passive transfer of IgG from patients with the disease.
N Engl J Med 306:1189, 1982
76. Mahoney MG et al: Explanation for the clinical and
microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest 103:461, 1999
140. Amagai M et al: Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for
serodiagnosis of pemphigus. Br J Dermatol 140:351, 1999
165. Beissert S et al: A comparison of oral methylprednisolone
plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Arch Dermatol 142:1447, 2006
183. Joly P et al: A single cycle of rituximab for the treatment
of severe pemphigus. New Engl J Med 357:545, 2007
194. Amagai M et al: A randomized double-blind trial of
intravenous immunoglobulin for pemphigus. J Am Acad
Dermatol 60:595, 2009
Pemphigus
Plasmapheresis is sometimes used for severe pemphigus, or for pemphigus

that is unresponsive to a combination of prednisone
and immunosuppressive agents. Although one controlled study found it to be ineffective,197 other studies have found that it both reduces serum levels of
pemphigus autoantibodies and controls disease activity.198 Plasmapheresis plus intravenous pulse therapy
with cyclophosphamide has been reported to result
in remissions of PV.199 For maximum effectiveness, it
is probably necessary to perform plasmapheresis on
patients taking immunosuppressive agents to prevent
the antibody-rebound phenomenon that can follow
the removal of IgG. Protein A immunoadsorption,
which removes IgG selectively from plasma, has also
been used.200
::
PLASMAPHERESIS.
KEY REFERENCES
Chapter 54
method of decreasing serum autoantibodies is the

intravenous use of -globulin (IVIg) in high doses. IVIg
is thought to function by saturating circulating neonatal Fc receptor, thereby increasing catabolism of the
patients serum antibodies, which include the pathogenic autoantibodies.189191 It may be useful as adjuvant
therapy in those pemphigus patients whose condition
does not respond to more conventional therapy.192,193 A
multicenter, randomized, placebo-controlled, double
blind study has confirmed its efficacy in pemphigus,194
but it is expensive and probably requires continued
infusions for maintenance of remission. There can also
be significant side effects with this therapy, including stroke, deep venous thrombosis, and renal failure
with sucrose-containing formulations.195 Some centers
will use IVIg to establish initial control of blistering in
severely affected patients because it does not increase
risk of infection as much as corticosteroids and immunosuppressants. IVIg has also been used in combination with rituximab,196 although it is unclear whether
the combination is safer or more effective compared to
either alone.
disease.201 Although the purpose of this therapy is to

decrease the incidence of complications of long-term
steroid use, it can result in all the usual glucocorticoid complications, as well as cardiac arrhythmias
with sudden death, and its use is controversial.202 Furthermore, a controlled trial found that adjuvant oral
dexamethasone pulse therapy in addition to standard
therapy with prednisolone and azathioprine for PV is
not beneficial.203 It may be that simply giving divided
lower doses of prednisone could accomplish the same
result with fewer side effects.
All in all, there has been a tremendous advance in the
armamentarium of therapies for pemphigus since the
time before the development of glucocorticoids when
PV was a fatal disease. Thanks to these advances, the
row of tombstones seen in the pathology of PV no
longer alludes to its prognosis.
599
Chapter 55 :: Paraneoplastic Pemphigus

:: Grant J. Anhalt & Daniel Mimouni
PARANEOPLASTIC PEMPHIGUS
AT A GLANCE
Rare complication of malignancy, most
commonly non-Hodgkins lymphoma,
chronic lymphocytic leukemia, or Castleman
disease.
Section 8
::
Painful, erosive stomatitis and

polymorphous cutaneous lesions that
may be blistering and erosive (resembling
erythema multiforme), morbilliform, or
lichenoid.
Serum autoantibodies directed against

plakin proteins that are detected by indirect
immunofluorescence against rodent bladder
epithelium.
High mortality rate, with death due to
sepsis, complications of treatment, or
bronchiolitis obliterans.
No consistently effective therapy, but some
success with the combined use of rituximab,
systemic corticosteroids, and other
immunosuppressive agents.
Paraneoplastic pemphigus (PNP) is an autoimmune

disorder that is almost always linked to an underlying
lymphoproliferative disorder. The following features
define PNP:
1. Painful stomatitis and a polymorphous
600
cutaneous eruption with lesions that may be

blistering, lichenoid, or resemble erythema
multiforme.
2. Histologic findings that reflect the variability
of the cutaneous lesions, showing acantholysis,
lichenoid, or interface change.
3. Direct immunofluorescence findings of
immunoglobulin G (IgG) and complement
deposition in the epidermal intercellular
spaces and, often, granular/linear complement
deposition along the epidermal basement
membrane zone.
4. Serum autoantibodies that bind to the cell
surface of skin and mucosae in a pattern typical
of pemphigus, but in addition, bind to simple,
columnar, and transitional epithelia.
5. The serum autoantibodies identify desmogleins
1 and 3, in addition to members of the
plakin family of epithelial proteins, such as
desmoplakins, envoplakin, and periplakin.1
Non-Hodgkins lymphoma (NHL), chronic lymphocytic leukemia (CLL), and Castleman disease are the
neoplasms most commonly associated with PNP.
There is no regularly effective treatment. Most patients
die from complications of the disease, including pulmonary involvement with respiratory failure.
EPIDEMIOLOGY
The incidence of PNP is unknown, although it is less
common than pemphigus vulgaris or foliaceus (see
Chapter 54). In an adverse events reporting analysis
including 100,000 patients with known NHL and CLL,
12 were found to have PNP. Only three of them were
identified by the reporting physician, and the remainder were identified only by retrospective data analysis, suggesting that the majority of cases of PNP are
not being properly diagnosed. In this series, the most
common misdiagnoses were erythema multiforme,
StevensJohnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction.

In almost all cases, PNP is associated with a limited
number of lymphoproliferative neoplasms. On the
basis of 140 cases of PNP confirmed by immunoprecipitation findings of the characteristic autoantibody
profile, the estimated frequencies of specific neoplasms
are 44% NHL, 19% CLL, 16% Castleman disease (giant
follicular hyperplasia), 8% thymoma (malignant and
benign), 7% sarcomas that are retroperitoneal and
often poorly differentiated, 4% Waldenstrms macroglobulinemia, and in 2% the neoplasms were too
poorly differentiated to categorize (Fig. 55-1). The
Tumors associated with paraneoplastic pemphigus
Castleman
disease
Thymoma
Retroperitoneal
sarcoma
Waldenstom
Other
Chronic
lymphocytic
leukemia
Non-Hodgkin
lymphoma
Figure 55-1 Tumors associated with paraneoplastic pemphigus.
Paraneoplastic Pemphigus
CLINICAL FINDINGS
::
Castleman disease and is currently being studied in

clinical trials.8
It had also been proposed that the autoantibody may
derive from the lymphoid tumor itself. Cultures of
Castleman tumors have been shown to contain B cells
that produce specific autoantibody.9 However, Castleman tumors are unique in that they are not clonal
neoplasms, and these studies showed the expansion
of several immunologically active B-cell clones within
the tumors. In Waldenstrms macroglobulinemia, the
autoantibody is polyclonal and IgG class, not IgM, and
therefore, cannot be produced by the tumor cells.
Almost all patients with PNP have autoantibodies against desmogleins, demonstrable by enzymelinked immunosorbent assay (ELISA), and when the
desmoglein autoantibodies from these patients are
affinity purified and injected into neonatal mice, acantholytic skin lesions are induced.10 However, none of
features of the disease that appear to be induced by
cell-mediated autoimmunity are recreated by the
immunoglobulin injections. No internal organs, like
the lungs, are involved, and there are no findings of
lymphocyte-mediated lichenoid or interface epithelial
injury. This is another indication that humoral immunity alone reproduces features of acantholysis, but passive transfer of autoimmune cells from these patients
may be necessary to induce the complete spectrum of
the disease in animals.
Chapter 55
isproportionate representation of Castleman disease

d
is notable, given its overall rarity. In children with PNP,
Castleman disease is almost always the underlying
neoplasm.2 Before the description of PNP, many cases
of Castleman disease associated with atypical forms
of pemphigus had been reported, and we suspect that
most were PNP. A study of archived clinical material in
one such case confirmed the presence of autoantibodies specific for PNP.
With very rare exceptions, more common cancers,
such as adenocarcinomas of breast, bowel, and lung,
or basal cell and squamous cell carcinoma of skin, have
not been associated with PNP. There are a few reports
of PNP and squamous cell carcinoma, but in most of
them, the diagnosis was made with immunofluorescent techniques only, which have a significant false
positive and false negative rate, and were not confirmed immunochemically, so the association remains
unproven.
The mechanisms by which these tumors induce
autoimmunity against epithelial proteins remain speculative. One hypothesis states that the tumors constitutively or anomalously express epithelial proteins.
These proteins are targeted by the antitumor immune
response that cross-reacts with normal constitutive
epithelial proteins of the host. This mechanism occurs
in several neurologic paraneoplastic syndromes.3
This antitumor immune response may be initiated by
reactivity against plakin proteins, and the antitumor
immune response may cross-react with normal constitutive proteins of epithelia. However, to date, there are
no data to support this hypothesis.
It is more likely that this autoimmune disease is
a result of more complex interactions between the
tumor cells, the immune system, and specific genetic
background. In many autoimmune diseases, specific
genetic predispositions have been found, and HLA
studies performed on two different series of PNP
patients revealed a significant predominance of HLAclass II DRB*03 and HLA-class I Cw*14 genes. It is
interesting to note that these two HLA molecules are
not those associated with development of pemphigus
vulgaris, providing another argument to consider PNP
as a distinct entity.4,5
There is evidence that dysregulated cytokine production by tumor cells drives the development of
autoimmunity. Patients with PNP have evidence of
markedly elevated levels of interleukin 6 (IL-6).6 It
has been observed that in a subset of cases of NHLs,7
CLL, and Castleman tumors, the tumor cells secrete
massive amounts of IL-6 in vitro. IL-6 is known to promote B-cell differentiation and to drive immunoglobulin production, and dysregulated IL-6 production
has been implicated in certain autoimmune diseases.
Castleman tumors are known to be associated with
other autoimmune phenomena such as myasthenia
gravis and autoimmune cytopenias, and these patients
also have high serum levels of IL-6. Symptoms attributable to Castleman tumors are routinely reversed by
complete excision of the affected node(s), and, coincidentally, serum IL-6 levels revert to normal. Administration of anti-IL-6 receptor monoclonal antibodies
also effectively reverses systemic manifestations of
HISTORY
CUTANEOUS LESIONS. The most constant clinical feature of the disease is the presence of intractable
stomatitis (Figs. 55-2A and 55-2B). It is the earliest presenting sign and the one feature that persists throughout the course of the disease, even after treatment and
is extremely resistant to therapy. This finding is so consistent that in its absence, PNP should not be considered in the differential diagnosis.
This stomatitis consists of erosions and ulcerations
that can affect all surfaces of the oropharynx. The
lesions differ from those seen in pemphigus vulgaris
in that they show more necrosis and lichenoid change.
They also preferentially localize to the lateral borders
of the tongue, and characteristically extend onto and
involve the vermilion of the lips. Occasionally, oral
lesions are the only manifestation of the disease.
The cutaneous lesions of PNP are quite variable, and
different morphologies may occur in an individual
patient according to the stage of the disease (see Fig.
55-2C and 55-2D). The initial patients reported with
the syndrome had episodes of waves of blistering
affecting the upper trunk, head and neck, and proximal extremities. These lesions consisted of blisters that
ruptured easily, leaving erosions. The blisters on the
extremities were sometimes quite tense, resembling
those seen in bullous pemphigoid, or they had surrounding erythema, clinically resembling erythema
multiforme (see Fig. 55-2D). On the upper chest and
601
Section 8
::
Figure 55-2 A. Extensive erosions involving the vermillion of the lips in a patient presenting with paraneoplastic pemphigus and an occult lymphoma. The characteristic severe stomatitis, accompanied by polymorphous cutaneous lesions,
is the most consistent feature of the disease. B. Painful ulcerations tend to localize to the lateral border of the tongue.
C. Lesions of the trunk from the same patient pictured in A. Erythematous macules and papules coalesce and become
erosive on the upper chest as the cutaneous lesions evolve. D. Lesions from the forearm of the same patient. These
lesions clinically resemble erythema multiforme, but biopsy shows a mix of individual cell necrosis, interface change, and
acantholysis.
602
LABORATORY TESTS
The key finding is the serologic identification of polyclonal IgG autoantibodies against plakin proteins and,
in most cases, desmogleins 1 and 3. The plakins are a
group of sequence-related proteins that form the intra-
PNP is the only form of pemphigus that involves nonstratified squamous epithelium. Approximately 30%
40% of cases develop pulmonary injury, often with a
fatal outcome.13 The earliest symptoms are progressive
dyspnea associated initially with an absence of findings on chest radiography. Pulmonary function studies
show airflow obstruction in large and small airways.
Inflammation of the large airways evolves and is evidenced by endoscopic biopsy showing acantholysis of
bronchial respiratory epithelium. Pulmonary function
deteriorates in most cases despite immunosuppressive therapy, and radiologic, histologic, and functional changes characteristic of bronchiolitis obliterans
develop.
::
RELATED CLINICAL FINDINGS
cellular plaque of desmosomes and hemidesmosomes,

and mediate attachment of cytoskeletal intermediate
filaments to transmembrane adhesion molecules such
as the desmogleins (see Chapter 53). Autoantibodies
against these proteins are the most characteristic surrogate markers for the disease. The pattern of antigens
recognized by individual patients shows considerable
variability, but the most characteristic and consistently
recognized plakin antigens are envoplakin14 and periplakin15 (210 and 190 kDa, respectively; Fig. 55-3). The
next most frequently detected are antibodies against
desmoplakin I and desmoplakin II (250 and 210 kDa,
respectively). Less commonly, patients recognize bullous pemphigoid Ag 1 (230 kDa), plectin (400 kDa), and
plakoglobin (82 kDa). The identity and frequency of
an antigen band at 170 kDa are not well defined. PNP
patients may also have clinical and serologic evidence
of other autoimmune phenomena such as myasthenia
gravis and autoimmune cytopenias (see Fig. 55-3).
To screen for PNP autoantibodies, one can test for
IgG autoantibodies by indirect immunofluorescence
reactive with rodent urinary bladder epithelium. A
positive result implies the presence of plakin autoantibodies; however, the sensitivity and specificity of this
serologic test are only approximately 75% and 83%,
respectively.16 Recently, ELISA kits using recombinant
proteins containing subdomains of envoplakin and
periplakin have been developed and have demonstrated high sensitivity and specificity for the diagnosis of PNP.17,18 More specific and sensitive tests, which
are more time consuming, technically demanding, and
of limited availability, include immunoblotting against
epidermal cell extracts that can effectively detect antibodies against envoplakin, periplakin and desmoplakin, and immunoprecipitation, using radiolabeled
keratinocyte extracts, which can detect antibodies
against any of the plakin proteins.
The PNP autoantibody profile is more complex than
that observed in pemphigus vulgaris or foliaceus,
where there are autoantibodies produced only against
the desmogleins. The humoral immunity in PNP may
represent an example of epitope spreading in which
patients develop autoantibodies against structurally
related plakin proteins and structurally unrelated
transmembrane cell surface proteins (the desmogleins)
that are physically linked to the plakin proteins in the
desmosome and hemidesmosome.
Chapter 55
back, confluent erosive lesions can develop, producing a picture resembling TEN. The similarity of the
mucocutaneous features to erythema multiforme and
TEN explains why this is the most common differential diagnosis for PNP. However, it is important to note
that erythema multiforme and TEN are self-limited
events that evolve and resolve over several weeks,
whereas PNP is a relentlessly progressive and evolves
continuously over months.
Cutaneous lichenoid eruptions are very common,
and they may be the only cutaneous signs of the disease, or may develop in lesions that had previously
been blistered. When cutaneous lichenoid lesions are
present, severe stomatitis is also invariably present.
In the chronic form of the disease and after treatment,
this lichenoid eruption may predominate over blistering on the cutaneous surface. The common presence of
both blisters and lichenoid lesions affecting the palms
and the soles as well as the paronychial tissues helps to
distinguish PNP from pemphigus vulgaris, in which
acral and paronychial lesions are uncommon.
There are a small number of patients who appear
to have PNP but who do not have demonstrable circulating autoantibodies.11 These patients tend to have
predominantly lichenoid skin and mucosal lesions,
but behave in every other way like antibody-positive
patients. They have the same underlying neoplasms,
and frequently develop bronchiolitis obliterans.
Because the definition of the disease relies so heavily
on demonstration of the specific autoantibody markers, further study is required to determine the exact
classification of what is presently termed the lichenoid
variant of PNP.
The disease has also been identified in a horse and
two dogs. In animal species, the disease is associated
with the same neoplasms and has the same clinical
outcomes.12
HISTOPATHOLOGY
The histopathology of PNP is distinctive from pemphigus vulgaris and foliaceus for two reasons. First,
because the lesions can be clinically very polymorphous, there is substantial variability in the histologic
findings.19 Second, findings due to cell-mediated cytotoxicity are frequently observed.
Owing to the severe mucositis, many biopsies of oral
lesions yield nonspecific changes of inflammation and
ulceration. If one can biopsy perilesional epithelium, a
lichenoid mucositis with variable degrees of individual cell necrosis and suprabasilar acantholysis can be
observed.
603
Section 8
::
604
Figure 55-3 Diagnosis of paraneoplastic pemphigus (PNP) depends on the demonstration of antiplakin antibodies.
A. This can be accomplished by indirect immunofluorescence of patient serum on rodent urinary bladder demonstrating
binding of immunoglobulin G to the cell surface of transitional epithelial cells. A positive result implies the presence of
antiplakin antibodies. This technique, although easily performed, has the lowest sensitivity and specificity. B. Immunoblotting against epidermal cell extracts is much more sensitive and specific. This shows detection of envoplakin (210 kDa)
and/or periplakin (190 kDa) in 15 patients with PNP. Lane 16 is a normal control, and lane 17 shows a monoclonal antibody against periplakin. This technique uses denatured antigen extracts, so it does not reliably detect some of the PNP
antigens, but antibodies against the most characteristic plakin antigens, envoplakin and periplakin, are easily detected.
C. Immunoprecipitation using radiolabeled, nondenatured epidermal extracts and serum from a patient with PNP and
pemphigus vulgaris (PV). In this case, the PNP patients serum identifies all of the plakin antigens. Envoplakin and desmoplakin II migrate as a doublet at 210 kDa. This technique is the most sensitive and specific test for demonstration of antiplakin antibodies in PNP, but has limited availability. Although this technique readily detects the antiplakin antibodies, desmoglein 3 is not always efficiently identified, and this is best shown by using enzyme-linked immunosorbent assay (ELISA).
When evaluating biopsies from skin lesions, one

must recognize that lesions with different clinical
morphologies yield differing histologic findings. In
noninflammatory cutaneous blisters, suprabasilar
acantholysis is expected to be more prominent than
the interface/lichenoid change (Fig. 55-4A). When
erythematous macules and papules are sampled, interface and lichenoid dermatitis is predominant (see Figs.
55-4B and 55-4C). Lesions with a mixed clinical pattern also show mixed histologic features of concomitant suprabasilar acantholysis and interface/lichenoid
dermatitis.
There is also observed variability of the interface

and lichenoid dermatitis. The spectrum of changes can
include: (1) individual keratinocyte necrosis with lymphocytic infiltration into the epidermis, reminiscent of
that seen in erythema multiforme or graft-versus-host
disease; (2) vacuolar interface change with sparse lymphocytic infiltrate of the basilar epithelium, resembling
cutaneous lupus erythematosus or dermatomyositis; and (3) a thick lichenoid band along the dermal
epidermal junction similar to that seen in lichen planus. Although most of the specimens show a complex
overlap of histologic patterns, there is a relatively good
Chapter 55
::
correlation between the clinical and the predominant

histologic pattern.
The histopathologic variability of this disease may
be related to the fact that it is a presumed antitumor immune response. If this speculation is correct,
one would expect to observe a combination of both
humoral and cell-mediated immunity that is aberrantly
directed against normal epithelium. In such a setting,
one would expect to see changes of the sort described
in the previous paragraph. This degree of cell-mediated immunity is not seen in pemphigus vulgaris or
foliaceus (see Chapter 54); hence the unique histopathologic features, and, presumably, the unique clinical features as well. The presence of T-cell-mediated
epithelial cytotoxicity has been recently demonstrated
in histologic studies.20
IMMUNOPATHOLOGY
Patients with PNP should have evidence of IgG autoantibodies bound to the cell surface of affected epithelium by direct immunofluorescence. However, false
negatives are more common in PNP than in pemphigus vulgaris, and repeated biopsies may be necessary,
Figure 55-4 A. Histopathology of a blistering cutaneous lesion in paraneoplastic pemphigus. This demonstrates the
characteristic presence of vacuolar interface change and suprabasilar acantholysis [Hematoxylin and eosin (H&E), 200].
B. Macular and papular lesions may show just vacuolar interface change (H&E, 100). C. Lichenoid lesions demonstrate
lichenoid infiltrates on histologic examination (H&E, 40). The presence of these varied histologic findings help differentiate paraneoplastic pemphigus from pemphigus vulgaris. D. Direct immunofluorescence can be negative in a significant
number of cases, but when positive, the most characteristic changes are those of deposition of immunoglobulin G and
complement components on both the surface of basilar and suprabasilar keratinocytes and along the epidermal basement membrane zone (Immunofluorescence with fluoresceinated anti-immunoglobulin G, 200).
as well as careful investigation of the adnexal structures which may be the only positive site.21 In a minority of cases, one might also see a combination of both
cell surface and basement membrane zone deposition
of IgG and complement components, but the absence
of this combined cell surface/basement membrane
zone staining does not negate the diagnosis (see Fig.
55-4D).
SPECIAL TESTS
Approximately one-third of patients have an occult
malignancy at the time they develop PNP. Neoplasms
that would not be detected by routine complete blood
count, serum chemistries, and physical examination are
most likely to be intra-abdominal lymphoma, intrathoracic or retroperitoneal Castleman tumors, or retroperitoneal sarcomas. The most effective and efficient method
for screening for these tumors is either computer-aided
tomography or magnetic resonance imaging of the
body from the neck to the base of the bladder. If available, Positron emission tomography/ computer tomography (PET/CT) using fluorodeoxyglucose (FDG) as a
biologically active molecule can be more specific in the
605
Approach to patient with paraneoplastic pemphigus
Clinical
evaluation
Section 8
Laboratory
evaluation
::
Special
testing
Therapy
Painful
stomatitis
Absent
Diagnosis excluded
Present
Diffuse epithelial necrosis,

tongue and vermilion of lips
Skin
lesions
Blisters & erosions often resembling erythema

multiforme or toxic epidermal necrolysis, lichenoid
Biopsy
for histology
Acantholytic, lichenoid or vacuolar interface change
Direct
immunofluorescence
Immunoglobulin G and C3 on cell surfaces and along

the basement membrane (false negatives common)
Indirect
immunofluorescence
Cell surface binding on monkey esophagus and murine

bladder epithelium (negative result - possibly lichenoid variant)
Immunochemical
testing
Antibodies against desmoglein 1 & 3,

desmoplakins 1 & 2, envoplakin & periplakin
No known tumor
Imaging of chest, abdomen, & pelvis (most common tumors non-Hodgkin lymphoma, chronic lymphocytic leukemia,
Castleman disease, retroperitoneal sarcoma, or thymoma
Pre-existing
neoplasm
Castleman tumor,
thymoma, or sarcoma
Non-Hodgkin
lymphoma and
chronic lymphocytic
leukemia
Excise completely if possible, followed by

immunosuppressive therapy for up to 2 years
Reducing tumor does not stop autoimmune disease
Immunosuppressive therapy with prednisone, rituximab,
or other agents
High mortality rate - best treatment regimen still unclear
Figure 55-5 Approach to a patient with paraneoplastic pemphigus.
identification of an occult lymphoma. Other studies,

such as endoscopy, are not required.

DIAGNOSIS
The diagnosis can best be made if the algorithm shown
in Fig. 55-5 is followed. The clinical differential diagnosis is summarized in Box 55-1.

COURSE
606
Proceed to treatment
It is not known why PNP is so refractory to the type of

immunosuppressive treatments that are usually effective
in pemphigus vulgaris and other autoimmune diseases.
In those patients who do succumb, death has been
attributed in individual cases to multiple factors,

of Paraneoplastic Pemphigus
Oral lesions
Pemphigus vulgaris
StevensJohnson syndrome
Mucous membrane pemphigoid
Oral lichen planus
Chemotherapy-induced stomatitis
Major aphthous stomatitis
Cutaneous lesions
Erythema multiforme/StevensJohnson
syndrome/toxic epidermal necrolysis

Pemphigus vulgaris
Drug eruption
Lichen planus
Subepidermal blistering disorders
of detectable tumor burden at the time of his death,

but died from pulmonary injury secondary to PNP. It
is notable that the patient underwent autologous bone
marrow transplantation, and therefore received his
own memory T cells, or possibly individual malignant
lymphoid cells that were not detectable by routine
autopsy methods.
TREATMENT
::
(See Box 55-2)

Individuals with benign or encapsulated tumors
such as Castleman tumors or thymoma should have
them surgically excised. If the entire lesion is removed,
the disease generally improves substantially or goes
into complete remission. The remission of the autoimmune disease may take 12 years after surgery, so
continued immunosuppression during this period
is required. The usual treatment involves combined
use of prednisone and rituximab.23 In pediatric cases
with respiratory disease, the persistent autoimmunity immediately after surgery can cause ongoing
pulmonary injury, and lung transplantation might be
required for long-term survival.24
In patients with malignant neoplasms, there is no consensus regarding a therapeutic regimen that is consistently effective. Despite scattered individual reports of
long-term survivors, almost all patients with NHL or CLL
succumb in a period of 1 month to 2 years after diagnosis.
Oral corticosteroids in a dose of 0.51.0 mg/kg produce
partial improvement, but not complete resolution of
lesions. Cutaneous lesions respond quickly to therapy,
but the stomatitis is generally quite refractory to any
treatment. Systemic corticosteroids and many other
agents have been tried in individual cases, but none has
proven to be particularly effective. Methods that have
been tried and often failed include immunosuppression with cyclophosphamide, mycophenolate mofetil
or azathioprine, gold, dapsone, plasmapheresis, and
Chapter 55
including sepsis, gastrointestinal bleeding, multiorgan failure, and respiratory failure. Patients with
autoimmune disease associated with B-cell neoplasms
are known to have a high frequency of autoimmune
cytopenias, and some fatal episodes of sepsis are suspected to have occurred because of sudden and unexplained neutropenia, possibly due to this mechanism.
Respiratory failure is a common terminal event. The
development of shortness of breath with obstructive disease progressing to bronchiolitis obliterans is
a terminal complication in most cases. Because these
patients have autoantibodies that react with desmoplakins, and because desmoplakins are present in
respiratory epithelium, respiratory failure may be due
to autoantibody-mediated injury to bronchial epithelium, with plugging of terminal bronchioles, resulting in airflow obstruction and ventilation/perfusion
abnormalities. Additionally, direct damage to alveolar
epithelium could cause a diffusion barrier and subsequent intractable hypoxia. One autopsy study showed
an absence of autoantibodies and a marked infiltration of bronchioles with cytotoxic T cells in a patient
who died from PNP and bronchiolitis obliterans. This
shows that there may be similar complex humoral and
cell-mediated autoimmune injury to the lung, similar
to what is seen in the skin. The pulmonary injury does
not respond well to medical treatment, and the development of shortness of breath and hypoxia in a patient
with this syndrome is an ominous prognostic sign.
In patients with malignant neoplasms there is no
definite correlation between tumor burden and the
activity of the autoimmune syndrome. Treatment of
the primary malignancy does not affect the activity of
the autoimmune disease. It seems that once the process is initiated by the malignancy, the autoimmunity
progresses independently. An example of the disconnect between tumor burden and autoimmunity is
found in the case reported by Fullerton et al,22 in which
PNP occurred after successful autologous bone marrow transplantation for NHL. This patient was free
Box 55-2 Treatments for Paraneoplastic Pemphigus

First line
Drug
Usual Dose
Other Dosing
Prednisone
0.51.0 mg/kg
Rituximab
375 mg/m2 IV weekly 4 week,

repeat every 6 months
2 mg/kg IV weekly 4 week,
then every other week indefinitely
20 mg IV on day 0 and day 4,
repeat every 34 months
Methylprednisolone, 1,000 mg
IV daily 3 days
1,000 mg IV weekly 2 week
Daclizumab
Basiliximab
Second line
Cyclosporine
Cyclophosphamide
High-dose IV immunoglobulin
Plasmapheresis
5 mg/kg daily
2.5 mg/kg daily
1,000 mg PO bid
2 g/kg IV, repeat q 34 week
Every other day for six total
treatments
607
photopheresis. A small number of patients have shown

a good response to combination treatment directed at
both humoral and cell-mediated autoimmunity. These
patients received oral prednisone, rituximab, and daclizumab or basiliximab (both are nondepleting monoclonal antibody against CD25, the high affinity IL-2
receptor of T cells). This appears to be a less toxic way
of downregulating both humoral and cell-mediated
autoimmunity, with promising early results.
PREVENTION
Section 8
::
There is no known intervention that may prevent the

development of PNP in a patient with a known lymphoid malignancy. Although there has been individual
case reports of PNP perhaps being triggered by certain
drugs, radiation therapy, or cytokine administration, it
is still not clear that any of these treatments triggered
the autoimmune disease, and it appears more likely
that the neoplasm itself triggers the autoimmunity.

1. Anhalt GJ et al: Paraneoplastic pemphigus: An autoimmune mucocutaneous disease associated with neoplasia.
N Engl J Med 323:1729, 1990
3. Posner JB. Immunology of paraneoplastic syndromes:
Overview. Ann N Y Acad Sci 998:178, 2003
6. Nousari HC et al: Elevated levels of interleukin-6 in paraneoplastic pemphigus. J Invest Dermatol 112:396, 1999
13. Nousari HC et al: The mechanism of respiratory failure in
paraneoplastic pemphigus. N Engl J Med 340:1406, 1999
14. Kim SC et al: cDNA cloning of the 210-kDa paraneoplastic pemphigus antigen reveals that envoplakin is a component of the antigen complex. J Invest Dermatol 109:365,
1997
23. Borradori L et al: Anti-CD20 monoclonal antibody (rituximab) for refractory erosive stomatitis secondary to
CD20(+) follicular lymphoma-associated paraneoplastic
pemphigus. Arch Dermatol 137:269, 2001
Chapter 56 :: Bullous Pemphigoid

:: Donna A. Culton, Zhi Liu, & Luis A. Diaz
BULLOUS PEMPHIGOID AT A GLANCE
Usually occurs in elderly patients.
Yearly mortality varies from 6% to 40%.
Pruritic urticarial lesions and tense large
blisters. Oral mucous membrane erosions in
minority of patients.
Skin pathology shows subepidermal blisters
with eosinophils.
Direct immunofluorescence shows
immunoglobulin (Ig) G and C3 at epidermal
basement membrane of perilesional skin,
indirect immunofluorescence shows IgG
antibasement membrane autoantibodies in
the serum.
The autoantigens BPAg1e and the
BP180 are proteins of the keratinocyte
hemidesmosome, a basal cellbasement
membrane adhesion structure.
Therapy includes topical and systemic
corticosteroids and immunosuppressives.
608
KEY REFERENCES
Bullous pemphigoid was originally classified as a

unique disease with distinctive clinical and histologic features by Walter Lever in 1953.1 Its separation from pemphigus was important, because at the
time pemphigus vulgaris was often fatal, whereas
bullous pemphigoid had a comparatively good
prognosis. The separation of bullous pemphigoid
from pemphigus was confirmed and fully justified
by the characteristic immunopathologic features
of these diseases described approximately 12 years
later.2,3
EPIDEMIOLOGY
Bullous pemphigoid typically occurs in patients over
60 years of age, with a peak incidence in the 70s.4
There are several reports of bullous pemphigoid in
infants and children, although this is rare.58 There
is no known ethnic, racial, or sexual predilection for
developing bullous pemphigoid. The incidence of bullous pemphigoid is estimated to be 7 per million per
year in both France and Germany, and 14 per million
per year in Scotland.4,911 A recent large cohort study
suggests that the incidence of bullous pemphigoid
may be as high as 43 per million per year in the United
Kingdom with incidence increasing over the last several years.12

IMMUNOPATHOLOGY
BULLOUS PEMPHIGOID ANTIGENS
Bullous pemphigoid is an autoimmune inflammatory

disease. The distinctive feature of bullous pemphigoid is the presence of circulating and tissue-bound
autoantibodies against BP180 and BP230. Anti-BP180
autoantibodies of various immunoglobulin isotypes
and IgG subclasses are present in bullous pemphigoid
sera with IgG being predominant, followed by IgE.4446
Serum levels of anti-BP180-NC16A IgG and IgE correlate well with disease activity in bullous pemphigoid
patients.24,26,40 Inflammatory cells are present in the
upper dermis and bullous cavity, including eosinophils
(the predominant cell type), neutrophils, lymphocytes,
and monocytes/macrophages. Both intact and degranulating eosinophils, neutrophils, and mast cells (MC)
are found in the dermis.4750 Local activation of these
cells may occur via the multiple inflammatory mediators present in the lesional skin and/or blister fluid.5159
Several proteinases are found in bullous pemphigoid
blister fluid, including plasmin, collagenase, elastase,
and MMP-9,6067 which may play a crucial role in subepidermal blister formation by their ability to degrade
extracellular matrix proteins.
Both in vitro and in vivo data demonstrate that
autoantibodies, particularly those against BP180, are
pathogenic. In vitro studies using normal human
skin sections indicate that bullous pemphigoid IgG is
capable of generating dermalepidermal separation in
the presence of complement and leukocytes.68,69 Early
attempts to demonstrate the pathogenicity of patient
autoantibodies by a passive transfer mouse model
were unsuccessful because bullous pemphigoid antiBP180-NC16A autoantibodies fail to cross-react with
the murine BP180.70 To overcome this difficulty, rabbit
antibodies were raised against the epitope on mouse
BP180. Passive transfer of these rabbit antibodies to
neonatal mice induces blisters that resemble some key
Bullous Pemphigoid
PATHOPHYSIOLOGY OF
SUBEPIDERMAL BLISTERING
::
Immunofluorescence (IF) techniques demonstrate that

patients with bullous pemphigoid exhibit circulating and tissue-bound autoantibodies directed against
antigens of the cutaneous basement membrane zone
(BMZ).3 Immunoelectron microscopy studies localize
bullous pemphigoid antigens to the hemidesmosome,
an organelle that is important in anchoring the basal
cell to the underlying basement membrane.13 These
autoantibodies bind to both the intracellular plaque
of the hemidesmosome and the extracellular face of
the hemidesmosome. Bullous pemphigoid autoantibodies recognize two distinct antigens with molecular weights of 230 kDa and 180 kDa by immunoblot
analysis of human skin extracts.14 The 230-kDa molecule is termed BP230, BPAG1, or BPAG1e.1417 BPAG1e
belongs to a gene family that includes desmoplakin
I, a desmosomal plaque protein that is important in
anchoring keratin intermediate filaments to the desmosome.18,19 By immunoelectron microscopy BPAG1e
is located in the intracellular plaque of the hemidesmosome, exactly where keratin intermediate filaments
insert.20 Analysis of BPAG1e-deficient mouse strains
generated by transgenic knockout technology further
demonstrates that the function of BPAG1e is to anchor
keratin intermediate filaments to the hemidesmosome.21 Mice lacking BPAG1e show fragility of basal
cells due to collapse of the keratin filament network,
but no epidermaldermal adhesion defect. Interestingly, an alternatively spliced form of BPAG1e (termed
BPAG1n) is expressed in neural tissue. BPAG1n stabilizes the cytoskeleton of sensory neurons,22,23 just
as BPAG1e stabilizes the cytoskeleton of epidermal
cells. The lack of dermalepidermal separation in the
BPAG1e-null mice indicates that pathogenic autoantibodies in bullous pemphigoid do not act simply by
inhibiting the function of BPAG1e.
The 180-kDa BP autoantigen is termed BP180, BPAG2,
or type XVII collagen.2426 BP180 is a transmembrane
protein with an intracellular amino-terminal domain
and an extended carboxyl-terminal domain that spans
the lamina lucida and projects into the lamina densa of
the basement membrane.2731 Its cytoplasmic domain
is located in the plaque of the hemidesmosome and
its extracellular domain is linked to anchoring fila-
Chapter 56
The hallmarks of bullous pemphigoid include the

presence of subepidermal blisters, lesional and perilesional polymorphonuclear cell infiltrates in the
upper dermis, and immunoglobulin (Ig) G autoantibodies and C3 bound to the dermal epidermal junction. Remarkable advances have been made in the last
decades characterizing the antigens as hemidesmosomal components and developing an animal model
that demonstrates the pathogenicity of bullous pemphigoid autoantibodies.
ments.3234 The extracellular domain of BP180 contains

a series of 15 collagen regions interrupted by 16 noncollagen sequence.29 The NC16A subdomain, adjacent
to the membrane-spanning region, harbors the major
autoantibody-reactive epitopes.35,36 These features
make the BP180 antigen a prime target for pathogenic
autoantibodies. As discussed in Section Pathophysiology of Subepidermal Blistering, antibodies against
the NC16A domain are capable of inducing subepidermal blisters in mice. Moreover, an enzyme-linked
immunosorbent assay (ELISA) to measure antibodies
against the BP180 NC16A domain is both sensitive and
specific for a diagnosis of bullous pemphigoid3739 and
its titers correlate with disease activity.40 Further evidence that BP180 mediates dermalepidermal adhesion comes from analysis of the gene defect in patients
with the junctional subepidermal blistering disease,
non-Herlitz junctional epidermolysis bullosa (JEBnH), previously known as generalized atrophic benign
epidermolysis bullosa. These patients have recessively
inherited mutations in the BP180 gene that result in a
missing or dysfunctional protein.4143
609
Proposed mechanism of subepidermal blister formation in mouse model of BP
BK
1
7
Blistering
Ab binding
C activation C5a
-BP180 IgG
BP180
MC
C5aR
FcRI
FcRIII
3
Section 8
::
610
NE, MMP-9,
plasmin, ROS
6
BMZ injury
MC activation
TFN, etc
PMN
activation
4
FcRIII
5
Fc-FcR
binding
PMN recruitment
PMN
Figure 56-1 Proposed mechanism of subepidermal blister formation in mouse model of BP. Subepidermal blistering is
an inflammatory process that involves the following steps: 1, anti-BP180 IgG binds to the pathogenic epitope of BP180
antigen on the surface of basal keratinocytes (BK); 2, the molecular interaction between BP180 antigen and anti-BP180
IgG activates the classical pathway of the complement system (C); 3, C activation products C3a and C5a cause mast cells
(MC) to degranulate; 4, TNF- and other proinflammatory mediators released by MC recruit neutrophils (PMN); 5, infiltrating PMNs bind to the BP180anti-BP180 immune complex via the molecular interaction between Fc receptor III (FcRIII)
on neutrophils and the Fc domain of anti-BP180 IgG; 6, the interaction between Fc and FcRIII activates PMNs to release
neutrophil elastase (NE), gelatinase B (MMP-9), plasminogen activators (PAs), and reactive oxygen species (ROS); 7, Proteolytic enzymes and ROS work together to degrade BP180 and other extracellular matrix proteins, leading to subepidermal
blistering.
features of human bullous pemphigoid, including in
situ deposition of rabbit IgG and mouse C3 at the BMZ,
dermalepidermal separation, and an inflammatory
cell infiltrate.70 These studies demonstrate that experimental blistering in animals requires activation of the
classical pathway of the complement system, mast
cell degranulation, and neutrophil infiltration (Fig.
56-1).7175 A well-orchestrated proteolytic event occurs
during the disease progression. Plasmin activates proenzyme MMP-9 and activated MMP-9 then degrades
1-proteinase inhibitor, the physiological inhibitor of
neutrophil elastase. Unchecked neutrophil elastase
degrades BP180 and other extracellular matrix components, resulting in dermalepidermal junction separation.7679 To directly test the pathogenicity of anti-BP180
IgG autoantibodies from bullous pemphigoid patients,
humanized BP180 mouse strains were generated, in
which the human BP180 or NC16A domain replaces
the murine BP180 or corresponding domain.80,81 These
humanized mice, upon injection with anti-BP180 IgG
from bullous pemphigoid patients, develop subepidermal blisters.80,81 Like the rabbit antimurine BP180
IgG-induced model, the humanized NC16A mouse
model of bullous pemphigoid also requires complement, MC, and neutrophils (Fig. 56-2).80
IgE anti-BP180 autoantibodies may also play a role in

blister formation. Human skin grafted onto immunedeficient mice injected with an IgE hybridoma to the
extracellular portion of BP180 or total IgE from bullous
pemphigoid patients sera exhibit histological dermal
epidermal separation,82,83 suggesting that anti-BP180
IgE antibodies may also participate in pathogenesis
of bullous pemphigoid through activating MC and
recruiting eosinophils.
Although animal model studies clearly show that
an inflammatory cascade is triggered by BP180specific antibodies and is essential for blister formation, direct interference of hemidesmosome-mediated
cellcell matrix adhesion by anti-BP180 autoantibodies
may be another disease mechanism.84 Involvement of
anti-BP230 autoantibodies in bullous pemphigoid blistering is also implicated in some animal model studies,85,86 but direct evidence in humans is lacking.
In addition to the humoral response, bullous pemphigoid patients also mount a cell mediated autoimmune response. Autoreactive T and B lymphocytes
recognize BP180.8789 These studies suggest that bullous pemphigoid is a T- and B-cell-dependent and antibody-mediated skin autoimmune disease. As in most
autoimmune diseases, the initial trigger for induction
Humanized BP180NC16A mouse model of BP
NC16A
Collagen domains
hBP180
NC14A
mBP180
NC16A
hmBP180
Chapter 56
::
(a) Clinical
(b) lgG
(c) C3
(e) MC
(f) PMN
Bullous Pemphigoid
(d) DermalEpidermal
Separation
Figure 56-2 Humanized BP180NC16A mouse model of BP. A. Human BP180 (top panel) is a transmembrane protein of
basal keratinocytes. It contains a single transmembrane domain. The extracellular region is consisted of 15 interrupted
collagen domains (yellow bars) and 16 noncollagen domains (black lines). The NC16A domain (red line) harbors immunodominant epitopes recognized by BP autoantibodies. The extracellular region of mouse BP180 (middle panel) contains
13 collagen domains (blue bars) and 14 noncollagen domain (black lines). In humanized BP180NC16A mice, the mouse
BP180NC14A domain was replaced by the human NC16A domain (lower panel). B. Neonatal NC16A mice injected i.d. with
BP180NC16A-specific IgG autoantibodies developed clinical blistering (a). Direct IF showed BMZ deposition of human
IgG (b) and murine C3 (c). Histological sections of lesional skin showed dermalepidermal separation (d). Examination of
toluidine blue-stained skin sections revealed degranulating mast cells (MC) (e). Hematoxylin/Eosin (H/E) staining showed
infiltrating neutrophils (PMN) in the upper dermis (400 magnification) (f ). E = epidermis; D = dermis; V = vesicle; arrows in
panels bd = basal keratinocytes.
611
of autoreactive lymphocytes and autoantibody production in bullous pemphigoid remains unknown.

Several other subepidermal blistering diseases also
show autoimmune responses to BP180. These include
pemphigoid gestationis (or herpes gestationis), cicatricial pemphigoid (or mucous membrane pemphigoid),
linear IgA bullous dermatosis, and lichen planus pemphigoid.90100 It is possible that they may share some
common immunopathological mechanisms with bullous pemphigoid.
CLINICAL FINDINGS
Section 8
HISTORY
::
Most cases of bullous pemphigoid occur sporadically

without any obvious precipitating factors. However,
there are several reports in which bullous pemphigoid appears to be triggered by ultraviolet (UV) light,
either UVB or following PUVA therapy, and radiation
therapy.101103 Certain medications have also been associated with the development of bullous pemphigoid
including penicillamine, efalizumab, etanercept, and
furosemide.104109
CUTANEOUS LESIONS
The classic form of bullous pemphigoid is characterized
by large, tense blisters arising on normal skin or on an
erythematous base (Fig. 56-3A).110,111 These lesions are
most commonly found on flexural surfaces, the lower
abdomen, and thighs, although they may occur anywhere. The bullae are typically filled with serous fluid,
but may be hemorrhagic. The Nikolsky and Asboe
Hansen signs are negative. Eroded skin from ruptured
blisters usually heals spontaneously without scarring,
although milia can sometimes occur. Once the lesions
heal they leave hyperpigmented patches that may last
for several months. Pruritus may be intense in some
patients, but minimal in others.
612
Nonbullous lesions are the first manifestation of bullous pemphigoid in almost half of patients.112 Often,
urticarial type lesions precede the more classic tense
bullae, and patients may present with these lesions
early in the course of disease (Fig. 56-3B). The erythematous component in some bullous pemphigoid
patients may appear eczematoid, serpiginous, or targetoid with erythema multiforme-like lesions.
Mucous membrane lesions occur in approximately
10% of patients and are almost always limited to the
oral mucous membranes, particularly the buccal
mucosa.110,113115 Intact oral mucosa blisters are rare, with
erosions more commonly seen. The lesions heal without scarring and are fairly limited. Unlike erythema
multiforme, the vermillion border of the lips is rarely
involved. There are rare reports of esophageal involvement.116,117 The presence of scarring is more suggestive
of cicatricial pemphigoid as discussed in Chapter 57.
In addition to the more classic findings, unusual
clinical presentations can be seen.118 In these cases,
the diagnosis is confirmed by IF and ELISA studies. For example, localized bullous pemphigoid
often presents as tense bullae restricted to localized
areas of involvement, most commonly on the lower
legs.119,120 Patients with localized disease have antibodies against the same pemphigoid antigens as
patients with more generalized disease.119121 The
lesions may remain localized for years or progress to
generalized bullous pemphigoid. Childhood bullous
pemphigoid often presents as localized disease with
acral distribution being common.58,122 Localized vulvar and perivulvar disease has also been described
in young girls.123,124 Other reports of localized bullous
pemphigoid suggest that changes induced by radiation, trauma, or surgery (colostomy, urostomy, or skin
graft donor site) at a particular site may precipitate
disease in these areas.125133
Other less common presentations include erythroderma, prurigo nodularis-like or vegetating lesions,
and dyshidrotic dermatitis-like lesions. Again, the
antibodies from these patients show typical IF localization and bind the pemphigoid antigens.121,134142
Figure 56-3 Bullous pemphigoid. A. Large, tense bullae and erythematous patches studded of small vesicles on the
thighs and lower legs. B. Urticarial lesions of bullous pemphigoid with overlying tense vesicles and bullae in the axilla.
In addition to atypical clinical presentations, bullous

pemphigoid may also coexist with other cutaneous diseases. Lichen planus pemphigoides describes the coexistence of bullous pemphigoid and lichen planus with
typical clinical, histologic, and immunopathologic features of both diseases.143146 Lichen planus pemphigoides more often presents in middle-aged patients (mean
age of onset 3545 years of age) and is more localized
to the extremities with a less severe clinical course
when compared to classic bullous pemphigoid. In rare
instances, bullous pemphigoid has also been reported
to coexist with pemphigus.147150
The diagnosis of bullous pemphigoid is made based

upon clinical, histologic, and IF features as described
below. Other laboratory studies play a small supporting role. Approximately half of patients will have
elevated total serum IgE levels, which often correlate
with titers of bullous pemphigoid IgG autoantibodies by IF and pruritus.51,161,162 Approximately one-half
of patients have peripheral blood eosinophilia, which
does not correlate with serum IgE levels.162,163
HISTOPATHOLOGY
Biopsy of an early small vesicle is diagnostic with
histology revealing a subepidermal blister with a
superficial dermal infiltrate consisting of eosinophils,

neutrophils lymphocytes, and monocytes/macrophages (Fig. 56-4).110 The infiltrate ranges from intense
to sparse, but it characteristically contains some eosinophils, which may also be seen in the blister cavity.
The blister roof is usually viable without evidence of
necrosis. Histology of urticarial lesions may only show
a superficial dermal infiltrate of lymphocytes, monocytes/macrophages, and eosinophils with papillary
dermal edema. These urticarial lesions may also display
degranulating eosinophils at the dermalepidermal
junction, with early separation of individual basal cells
from the basement membrane and/or eosinophilic
spongiosis.164
Bullous Pemphigoid
LABORATORY TESTS
Figure 56-4 Histopathology of bullous pemphigoid. Subepidermal blister with an inflammatory cell infiltrate containing eosinophils in the superficial dermis (100 magnification).
::
Neurological disease is seen more frequently in bullous pemphigoid patients and it appears that patients
with neurological disease (especially those over
80 years of age) have a significantly higher risk of
developing bullous pemphigoid than those without
neurological disease.151153 In rare instances, bullous
pemphigoid may be seen in association with acquired
hemophilia due to acquired Factor VIII inhibitor.
Cutaneous clinical manifestations include ecchymoses, hematomas, and hemorrhagic bullae in addition
to more systemic findings such as gastrointestinal
bleeding.154156
There have been many case reports of bullous pemphigoid associated with malignancy. However, casecontrol studies suggest that there is no increase, or a
very small increase, in the frequency of malignancy
in bullous pemphigoid patients compared with agematched controls.152,157159 There may be an increased
frequency of malignancy in bullous pemphigoid
patients with negative indirect IF studies as compared
with those with positive findings.113,160 The perceived
association may be explained by the fact that both bullous pemphigoid and malignancy occur more commonly in elderly patients. While a thorough review of
systems and symptom-guided workup is indicated in
patients with a new diagnosis of bullous pemphigoid,
extensive screening for an asymptomatic malignancy
is not warranted.
Chapter 56
DISEASE ASSOCIATIONS
ELECTRON MICROSCOPY
Ultrastructural studies demonstrate that early blister formation in bullous pemphigoid occurs in the
lamina lucida, between the basal cell membrane
and the lamina densa (Fig. 56-5A and 56-5B).165 In
areas of blister formation, there is loss of anchoring
filaments and hemidesmosomes. Degranulation of
eosinophils, neutrophils, and MC in the lesional/
perilesional skin has also been observed by electron
microscopy.49
SPECIAL TESTS
Direct IF of perilesional skin shows linear IgG (usually
IgG1 and IgG4, although all IgG subclasses and IgE
have been reported) and C3 along the basement membrane.2,3,113,162,166 In approximately 70% of patients, there
are circulating IgG and IgE autoantibodies that bind
the BMZ on normal human skin or monkey esophagus
by indirect IF.45,113,162,163,166169 Using 1 M NaCl split skin,
which separates the epidermis from the dermis at the
lamina lucida, an even higher percentage of patients
will have detectable circulating anti-BMZ autoantibodies.170,171 In addition to being more sensitive, the other
613
Indirect IF
Immuno-EM
Section 8
::
Figure 56-5 A. Indirect immunofluorescence of bullous

pemphigoid serum shows a linear pattern of immunoglobulin G binding to the epidermal dermal junction of
normal skin. B. Binding of bullous pemphigoid antibodies to human basal cell hemidesmosomes as described
by Mutasim et al: J Invest Dermatol 84:47-53, 1985. A
small rectangle of linear indirect IF staining and the arrow
depicts the immunolocalization of the reactive antibodies
to the hemidesmosome (white asterisks).
advantage of the 1 M NaCl-split skin substrate is that

bullous pemphigoid antibodies bind the roof of the
artificially induced blister (i.e., the bottom of the basal
cells). This finding differentiates bullous pemphigoid
antibodies from epidermolysis bullosa acquisita (EBA)
autoantibodies, which bind the base or the floor of the
split skin (i.e., dermal side; Figs. 56-6A and 56-6B). In
614
contrast to pemphigus, in bullous pemphigoid the

indirect IF antibody titer does not usually correlate
with disease extent or activity.172
Recently, ELISA techniques have proven to be useful
in both clinical and research settings for the detection
of circulating antigen specific IgG and IgE antibodies. Commercial kits are available for detection of both
BP-180 (NC16A and total) and BP-230 IgG antibodies.
A sensitivity of 89% and specificity of 98% when used
with appropriate cutoff values are reported with these
assays.37 As many as 75% of patients also have antigen
specific IgE with anti-BP180 and anti-BP230 IgE antibodies detectable by IF and ELISA.44,46,168,173176 Those
patients with anti-BP180 IgE antibodies may have a
more severe form of disease.174 Antigen specific IgE antibodies may account for the early urticarial type lesions
and likely play a role in recruiting eosinophils to skin
lesions.82,173
Recent studies have shown that approximately 7%
of the normal population has anti-BP180 antibodies
detectable by ELISA in the absence of clinical and histologic features of disease without age or gender predilection. The predictive relevance of these circulating
antibodies in healthy individuals is unknown as longterm follow-up is not available. However, this finding underscores the importance of using the ELISA
in appropriate clinical settings and not as a screening
tool in patients who lack other features of disease.177
The differential diagnosis for bullous pemphigoid
includes other blistering diseases, such as linear IgA
disease, dermatitis herpetiformis, erythema multiforme, EBA, and pemphigus. Histology and IF can
easily distinguish bullous pemphigoid from these diseases (Box 56-1). Distinguishing bullous pemphigoid
from EBA and cicatricial pemphigoid may be difficult
as histology and direct IF may be identical.115,178 EBA
can usually be distinguished from bullous pemphi-
Figure 56-6 Indirect immunofluorescence on normal skin previously incubated in 1 M NaCl to induce a split through the
lamina lucida of the dermalepidermal junction. A. IgG antibodies from bullous pemphigoid serum binds to the roof of
the artificial blister (hemidesmosomes). B. IgG antibodies from epidermolysis bullosa acquisita (EBA) serum binds to the
floor of the split (collagen VII of anchoring fibers).

of Bullous Pemphigoid
WITH AUTOANTIBODIES


Pemphigus

Allergic contact dermatitis (e.g., rhus dermatitis)
Bullous impetigo, staphylococcal scalded-skin
syndrome
Friction blisters
goid by indirect or direct IF on salt-split skin as stated

above.179 Confirmation of EBA may be accomplished
by ELISA assays using type VII collagen, the EBA
antigen (discussed in Chapter 60). Immunoelectron
microscopy also distinguishes these diseases because
the IgG in EBA is below the lamina densa on the
anchoring fibrils (type VII collagen), whereas the IgG
in bullous pemphigoid is closely associated with the
basal cell hemidesmosomes.180
As opposed to bullous pemphigoid, cicatricial
pemphigoid usually presents with mucosal lesions
predominantly, if not exclusively (see Chapter 57).
Cicatricial pemphigoid is characterized by desquamative gingivitis as well as inflammation and scarring of
conjunctiva. If there is blistering of the skin, it may be
transient and may result in scarring. Large, tense blisters, which are characteristic of bullous pemphigoid,
are usually not seen in cicatricial pemphigoid.
COMPLICATIONS
Complications in untreated patients include skin
infection developing within denuded bullae, dehy-
Bullous pemphigoid is characterized by a waxing and

waning course with occasional spontaneous remission
in the absence of treatment. Localized disease often
resolves spontaneously, but spontaneous remission
can even occur in patients with more generalized disease. For example, prior to the availability of systemic
corticosteroids, Lever reported that 8 of 30 adults with
bullous pemphigoid went into remission after approximately 15 months (range, 338 months) of active disease.110 In treated patients, the length of disease ranges
from 9 weeks to 17 years with a median treatment
period of 2 years and 50% remission rates in patients
followed for at least 3 years.181 Clinical remission with
reversion of direct and indirect IF to negative has been
noted in patients, even those with severe generalized
disease, treated with oral corticosteroids alone or with
azathioprine.162,182 High ELISA titers and, to a lesser
degree, positive direct IF at the time of therapy cessation has been associated with a high risk of relapse
within the first year following cessation of therapy.182
At least one of these tests should be performed before
therapy is discontinued.
Old age, poor general health, and the presence
of anti-BP180 antibodies have been associated with
a poor prognosis.183186 Early mortality rates in
untreated patients were reported to be 25%.110 Newer
studies have shown the 1-year mortality of patients
with bullous pemphigoid to be between 19% and
40% in Europe, but lower (less than 6%12%) in the
United States.12,183185,187190 The factors underlying
this discrepancy in mortality rates between Europe
and the United States are not clear. While mortality rates remain relatively low in the United States,
recent studies have confirmed a slow steady increase
in mortality over the last 24 years in the United
States.191
Bullous Pemphigoid

WITH AUTOANTIBODIES
::
Erythema multiforme and toxic epidermal necrolysis

Porphyria
Epidermolysis bullosa (genodermatoses)
Chapter 56
Pemphigoid gestationis
Epidermolysis bullosa acquisita (EBA)
Linear immunoglobulin A disease
Bullous lupus erythematosus, described as an EBA
phenotype
dration, electrolyte imbalance, and possibly death

from sepsis.
TREATMENT
Treatment of bullous pemphigoid depends greatly on
the extent of disease. Localized bullous pemphigoid
often can be treated successfully with topical corticosteroids alone (Box 56-2).162,166,192 Topical tacrolimus has
also been reported to be useful in a few cases of localized pemphigoid.192196
More extensive disease is usually treated with oral
prednisone.192,197,198 Despite the lack of randomized
controlled trials, oral prednisone remains the mainstay of therapy. Some recent studies suggest that
potent topical steroids, such as clobetasol proprionate cream 0.05% applied twice daily, are also effective
in both moderate and severe bullous pemphigoid
and may be safer than oral prednisone.189 Thus, these
patients received a daily dose of 40 g of clobetasol
propionate that was applied twice daily to the entire
surface of the body until 15 days after control of the
615
Box 56-2 Treatments for Bullous

Pemphigoid
CORTICOSTEROIDS
High potency topical steroids
Prednisone
OTHER IMMUNOSUPPRESSIVE AGENTS

Azathioprine
Others: methotrexate, cyclophosphamide
Section 8
::
616
MODULATORS OF ANTIBODY LEVELS

Intravenous -globulin
Plasmapheresis
OTHER
Tetracycline or erythromycin and nicotinamide
Dapsone
Topical tacrolimus
mon approach to therapy. High-dose pulse therapy

with intravenous methylprednisolone also has been
reported to be effective in rapidly controlling active
blister formation in bullous pemphigoid.210 Once
the development of blisters has been arrested and
the erythema has subsided, a careful tapering of the
prednisone is recommended. A weekly lowering
of 5 mg to reach 30 mg is commonly used. Lowering this dose must be done according to the clinical
response of the patient. The majority of patients may
be controlled with small amounts of prednisone and
immunosuppressive drugs. Sulfones may be effective in a minority of patients. Dapsone and sulfapyridine have been reported to control disease activity
in 15%44% of bullous pemphigoid patients.198,211213
Reports have described successful treatment of some
bullous pemphigoid patients with tetracycline and nicotinamide or variations on this theme, such as erythromycin and nicotinamide or tetracycline alone.214216
In small numbers of patients, other therapies reported
to be effective include plasmapheresis,217 intravenous
immunoglobulins,218220 methotrexate,205,207,221 leflunomide,222 and chlorambucil.223
KEY REFERENCES
disease had been attained. High-potency topical
treatment did result in significant systemic absorption and therefore may act via local and systemic
effects.199 Such topical therapy can be expensive and
difficult to apply, which may prove prohibitive in
many patients.
In elderly patients, the complications of systemic
glucocorticoid therapy (such as osteoporosis, diabetes, and immunosuppression) may be especially
severe.200 Therefore, it is important to try to minimize
the total dose and duration of therapy with oral glucocorticoids. Starting doses of prednisone of 0.751.0
mg/kg/day or even less may be adequate for disease
control.201 In addition, immunosuppressive agents
such as azathioprine, mycophenylate mofetil, and
methotrexate (and less often cyclophosphamide) are
often used in conjunction with prednisone for their
potential steroid-sparing effects,192,198,202209 although
very few controlled trials have addressed this com-

19. Stanley JR et al: Isolation of complementary DNA for
bullous pemphigoid antigen by use of patients autoantibodies. J Clin Invest 82(6):1864, 1988
28. Diaz LA et al: Isolation of a human epidermal cDNA
corresponding to the 180-kD autoantigen recognized by
bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome. J
Clin Invest 86(4):1088, 1990
75. Liu Z: Bullous pemphigoid: Using animal models to
study the immunopathology. J Investig Dermatol Symp
Proc 9(1):41, 2004
165. Lever WF: Pemphigus and pemphigoid. A review of the
advances made since 1964. J Am Acad Dermatol 1(1):2,
1979
167. Beutner EH, Jordon RE, Chorzelski TP: The immunopathology of pemphigus and bullous pemphigoid. J Invest
Dermatol 51(2):63, 1968
197. Patton T, Korman NJ: Bullous pemphigoid treatment
review. Expert Opin Pharmacother 7(17):2403, 2006
Chapter 57 :: Cicatricial Pemphigoid

:: Kim B. Yancey
CICATRICIAL PEMPHIGOID
AT A GLANCE
A chronic autoimmune subepithelial
blistering disease characterized by erosive
lesions of mucous membranes and skin that
result in scarring.
Immunopathologic studies of perilesional

mucosa and skin demonstrate in situ
deposits of immunoreactants in epithelial
basement membranes; circulating
antibasement membrane autoantibodies are
detected in sera of some but not all patients.
A variety of different autoantigens are
recognized by autoantibodies from patients,
suggesting that cicatricial pemphigoid is not
a single nosologic entity but rather a disease
phenotype.
Autoantibodies directed against autoantigens in epidermal basement membrane are held responsible for
the pathogenesis of cicatricial pemphigoid (Fig. 57-1).15
A variety of different autoantigens are recognized by
circulating autoantibodies from these patients.1,1631
These and other findings have led to the idea that cicatricial pemphigoid is not a single nosologic entity but
rather a disease phenotype. Autoantigens recognized
by immunoglobulin G (IgG) autoantibodies from
patients with cicatricial pemphigoid are summarized
in Table 57-1. While autoantibodies directed against
some of these autoantigens have been shown to be
pathogenic in vivo (Table 57-1), it is conceivable that
other mechanisms may contribute to the pathogenesis
of cicatricial pemphigoid. For example, recent studies
have demonstrated high stromal expression of IL-13 in
CD3+ T cells from patients with ocular cicatricial pemphigoid and that these cells may contribute both profibrotic and proinflammatory stimuli to conjunctival
fibroblasts.39
Bullous pemphigoid antigen 2 (BPAG2) appears to
represent a major cicatricial pemphigoid autoantigen;
other autoantigens of particular interest include laminin 332, integrin subunit 4, integrin subunit 6, type
VII collagen, and bullous pemphigoid antigen 1. Other
patients with cicatricial pemphigoid have IgA antibasement membrane autoantibodies (alone or in conjunction with IgG antibasement membrane autoantibodies);
the best characterized IgA autoantigen linked to the cicatricial pemphigoid phenotype is bullous pemphigoid
antigen 2.1,4042
Cicatricial Pemphigoid
A progressive disorder that may result in

serious complications (e.g., blindness, loss of
the airway, esophageal stricture formation).
::
A rare disorder, occurring in one person per

million annually; females are affected 1.52.0
times as often as males.
71 to 77 of the DQB1 protein may represent a disease

susceptibility marker.1,1014
Chapter 57
Lesions commonly involve the oral and ocular

mucosae; other sites that may be involved
include the nasopharyngeal, laryngeal,
esophageal, genital, and rectal mucosae.
Cicatricial pemphigoid (alternate designation: mucous

membrane pemphigoid) is a rare chronic autoimmune
subepithelial blistering disease characterized by erosive lesions of mucous membranes and skin that result
in scarring of at least some sites of involvement.16
EPIDEMIOLOGY
Cicatricial pemphigoid has been estimated to occur in
approximately 1 person per million annually; females
are affected 1.52.0 times as often as males.79 Cicatricial pemphigoid has a mean age of onset of the early
to middle 60s.9 Although there is no known racial or
geographic predilection, the HLADQB1*0301 allele has
been shown to be significantly increased in frequency
in patients with oral, ocular, and generalized bullous
pemphigoid; amino acid residues at positions 57 and
Figure 57-1 Direct immunofluorescence microscopy of

normal-appearing perilesional skin from a patient with
cicatricial pemphigoid shows continuous linear deposits
of C3 in the epidermal basement membrane.
617
TABLE 57-1
Major Cicatricial Pemphigoid Autoantigens

MW (kDa)
Location SSS/Ultra
BPAG1
230
Epid/HD
BPAG2
180
Epid/HDaf
Integrin 4
205
Epid/HDaf
Integrin 6
120
Epid/HDaf
Laminin 332
400440
Derm/LLLD interface
Exp IgG (intact IgG and Fab fragments alone) vs. laminin 332
create subepid blisters in newborn and adult mice that resemble
those seen in patients with AECP.34
Patient IgG creates subepid blisters in human skin grafts on
immunodeficient adult mice that resemble those seen in
patients with AECP.35
Type VII collagen
290
Derm/AF
Exp and patient IgG vs. the NC1 domain of type VII collagen
create subepid blisters in adult mice that resemble those seen in
patients with EBA.3638
Section 8
Autoantigen
::
618
Passive Transfer Studies

IgG vs. the NC16A domain of BPAG2 creates subepid blisters in
newborn mice that resemble those seen in patients with BP.32,33
AECP = antiepiligrin cicatricial pemphigoid; AF = anchoring fibril; BP = bullous pemphigoid; BPAG1 = bullous pemphigoid antigen 1; BPAG2 =
bullous pemphigoid antigen 2; Derm = dermal; EBA = epidermolysis bullosa acquisita; Epid = epidermal; Exp = experimental; HD = hemidesmosome; HDaf = hemidesmosomeanchoring filament complexes; IgG = immunoglobulin G; LLLD interface = lamina lucidalamina densa interface; Location SSS/Ultra = localization in 1 M NaCl-split skin/ultrastructural localization in epidermal basement membrane; MW (kDa) = molecular
weight in kilodaltons; subepid = subepidermal.
CLINICAL FINDINGS
HISTORY
Patients typically describe the onset of painful, erosive,
and/or blistering lesions on one or more mucosal surfaces. A few skin lesions on the upper body are also
sometimes noted. Associated symptoms are site specific as detailed later.
MUCOSAL AND CUTANEOUS LESIONS

The mouth is the most frequent site of involvement in
patients with cicatricial pemphigoid; it is often the first
(and only) site affected. Lesions often involve the gingiva, buccal mucosa, and palate (Fig. 57-2); other sites
such as the alveolar ridge, tongue, and lips are also
susceptible.9,43 A frequent oral manifestation is desquamative gingivitis. Other lesions may present as tense
blisters that rupture easily or as mucosal erosions that
form as a consequence of epithelial fragility. Lesions
in the mouth may result in a delicate white pattern of
reticulated scarring. In severe disease, adhesions may
develop between the buccal mucosa and the alveolar
process, around the uvula and tonsillar fossae, and
between the tongue and the floor of the mouth. Gingival involvement can result in tissue loss and dental
complications (e.g., caries, periodontal ligament damage, and loss of bone mass and teeth).
Ocular involvement in patients with cicatricial pemphigoid is common and may become sight threatening (Figs. 57-3 and 57-4). 44,45 Ocular lesions typically
manifest as conjunctivitis that progresses insidiously
to scarring. Early ocular disease can be quite subtle

and nonspecific. Although disease is usually bilateral,
it often begins unilaterally and progresses to both eyes
within several years. Patients may complain of burning, dryness, or a foreign-body sensation in one or both
eyes; frank blisters on conjunctival surfaces are rarely
seen. Early disease is best appreciated by slit-lamp
examination. Because disease may be localized to the
upper tarsal conjunctiva, it may escape detection without eversion of the eyelids. Chronic ocular involvement
can result in scarring characterized by shortened fornices, symblepharons (i.e., fibrous tracts between bulbar and palpebral conjunctival surfaces), and, in severe
disease, ankyloblepharons (i.e., fibrous tracts fusing the
Figure 57-2 Denuded and inflamed sites on the oral

mucosa are seen in association with sites of gingiva recession and loss.
Figure 57-6 The scalp displays scarring alopecia and a

focal hemorrhagic crust as a consequence of involvement
with cicatricial pemphigoid.
Figure 57-4 Ocular involvement has resulted in conjunctivitis, a shortened conjunctival fornix, and symblepharon
formation.
crust formation, impaired airflow, chronic sinusitis,

scarring, and tissue loss. Laryngeal involvement may
present as hoarseness, sore throat, or loss of phonation.
Chronic laryngeal erosions, edema, and scarring may
result in supraglottic stenosis and airway compromise
that eventually necessitates tracheostomy.46 Esophageal involvement may result in stricture formation,
dysphagia, odynophagia, weight loss, and/or aspiration. Moreover, it has been suggested that esophageal
dysfunction and gastroesophageal reflux may elicit or
exacerbate laryngeal disease and/or bronchospasm
in such patients. Although involvement of the genital and/or rectal mucosae in patients with cicatricial
pemphigoid is rare, it can be a source of substantial
pain and morbidity (Fig. 57-5). Rare cases of urethral
stricture, vaginal stenosis, and anal narrowing have
developed as a consequence of this disease.
The skin is involved in 25%35% of patients with
cicatricial pemphigoid. The most frequently affected
areas are the scalp, head, neck, and upper trunk (Fig.
57-6). Lesions typically consist of small vesicles or bullae situated on erythematous and/or urticarial bases.
Lesions rupture easily and are often seen as small,
crusted papules or plaques. The extent and number of
::
superior and inferior palpebral conjunctivae with obliteration of the conjunctival sac). Conjunctival scarring
also can cause entropion and trichiasis (i.e., in-turning
of the eyelashes) that result in corneal irritation, superficial punctate keratinopathy, corneal neovascularization, corneal ulceration, and/or blindness. Additional
ocular complications include scarring of the lacrimal
ducts, decreased tear secretion, and loss of mucosal
goblet cells leading to decreased tear mucus content
and unstable tear films. It is very important for patients
with suspected ocular involvement to be examined by
an ophthalmologist, because early disease may be subtle, is only identified by slit-lamp examination, and can
result in severe complications. Cicatricial pemphigoid
may be limited to the eyes.
Other sites that may be affected by cicatricial pemphigoid include the nasopharyngeal, laryngeal,
esophageal, and anogenital regions. Nasopharyngeal
lesions can result in discharge, epistaxis, excessive
Figure 57-5 Scalloped erosions and sites of denuded

vulvar and vaginal mucosae.
Chapter 57
Figure 57-3 The medial aspects of the lower conjunctival fornix and eyelid show shortening, fibrosis, and malaligned eyelashes.
619
cutaneous lesions are generally small; lesions sometimes recur in the same areas.
Section 8
::
SYSTEMIC ASSOCIATIONS. A cohort of 35

patients with antiepiligrin cicatricial pemphigoid (also
called antilaminin 332 cicatricial pemphigoid) was
shown to have an increased relative risk for cancer.47,48
Ten patients in this cohort had solitary solid cancers
(three lung, three gastric, two colon, two endometrial);
eight patients developed cancer after the onset of cicatricial pemphigoid (six within a year, seven within
14 months). The time between blister onset and cancer
diagnosis was approximately 14 months in nine of the
ten patients. Eight patients in this cohort died as a consequence of their cancer. All deaths occurred within 21
months. This form of cicatricial pemphigoid appears to
have a relative risk for malignancy that approximates
that for adults with dermatomyositis; as is true for the
latter, the risk for cancer appears to be particularly
high in the first year of disease. Other patients with
this form of cicatricial pemphigoid and cancer have
been described more recently.4957 Interestingly, recent
studies have suggested that the relative risk for cancer
among patients with ocular or oral cicatricial pemphigoid and autoantibodies versus integrin subunit 4 or
integrin subunit 6, respectively, may be reduced.58,59
BRUNSTINGPERRY PEMPHIGOID. In 1957,
Brunsting and Perry described seven patients with
locally recurrent and scarring subepidermal blistering lesions of the head or neck that for many years
was thought to be a form of cicatricial pemphigoid.60
Although these patients are typically elderly and demonstrate deposits of immunoreactants in epidermal
basement membranes like other patients with cicatricial
pemphigoid, BrunstingPerry pemphigoid predominates in men and lacks mucous membrane involvement. More recently, patients with the same clinical,
histologic, and immunopathologic features have been
reported to have autoantibodies directed against type
VII collagen (or rarely to bullous pemphigoid antigens).3,61 Identification of similar patients with blister
planes beneath the lamina densa further suggests that
individuals with this phenotype usually have localized
forms of epidermolysis bullosa acquisita.
LABORATORY TESTS
LIGHT MICROSCOPY
620
Although the findings of light microscopy studies of

lesional skin or mucosa from patients with cicatricial
pemphigoid often are nonspecific, they characteristically show a subepidermal blister and a dermal
leukocytic infiltrate composed of lymphocytes and histiocytes as well as variable numbers of neutrophils and
eosinophils.2,3,62,63 Plasma cells often are seen in mucosal lesions, whereas eosinophils and neutrophils are
seen most commonly in skin lesions. Biopsy specimens
of older lesions may be relatively cell poor and show

features that correlate with the noninflammatory character of such sites clinically. Light microscopy studies
of older lesions often show fibroblast proliferation and
lamellar fibrosis (i.e., fibrosis characterized by collagen
bundles ordered parallel to the surface epithelium).
ELECTRON MICROSCOPY
Ultrastructural studies of lesional skin or mucosa from
patients with cicatricial pemphigoid show that blisters
typically develop within the lamina lucida and eventuate in partial or complete destruction of the basal lamina in older lesions.6266 A generally held impression is
that blisters form below those of bullous pemphigoid,
because scarring is more common in patients with this
disease. Reports of patients with blisters in the sublamina densa region are thought to represent mucosapredominant forms of epidermolysis bullosa acquisita.
IMMUNOFLUORESCENCE
MICROSCOPY
Direct immunofluorescence microscopy of normalappearing perilesional tissue from patients with
cicatricial pemphigoid shows continuous deposits
of immunoreactants in epithelial basement membranes.5,66 The most commonly detected immunoreactants are IgG and C3 (see Fig. 57-1); the predominant
subclass of these autoantibodies is IgG4.67 IgA, IgM,
and/or fibrin are found in some patients.68 One study
of skin and mucosal samples from ten patients found
immunoreactants more commonly in perilesional
mucosal biopsy specimens, which suggests that
mucous membranes are the preferred biopsy site for
direct immunofluorescence microscopy studies.66
Splitting tissue samples with 1 M NaCl increases the
sensitivity of direct immunofluorescence microscopy
and facilitates identification of immunoreactants as
well as their relative distribution within epithelial
basement membranes.69,70
Indirect immunofluorescence microscopy studies
using intact skin or mucosa often find low-titer IgG
(and/or IgA) antibasement membrane autoantibodies
in patients with cicatricial pemphigoid.1,3,5,71 The use of
1 M NaCl-split skin as a test substrate in these studies
substantially increases the detection of such autoantibodies.27,72,73 In such studies, IgG (and/or IgA) binding is usually directed against the epidermal side of
1 M NaCl-split skin, although combined epidermal
and dermal or exclusively dermal binding can occur.
In fact, this heterogeneity in autoantibody binding
patterns was one of the first clues that cicatricial pemphigoid is a disease phenotype that is associated with
different autoantigens (see Table 57-1). Although some
studies have suggested that the use of human mucosal
tissue substrates increases the likelihood of detecting
autoantibodies in patients with cicatricial pemphigoid,
other studies have not obtained similar results.6,66
Patients with both IgG and IgA antibasement membrane autoantibodies appear to have a worse prognosis
as defined by requirements for medications to control

disease as well as overall clinical severity score.33,35
SPECIALIZED TESTS
Site-specific complications of cicatricial pemphigoid

were outlined earlier and are summarized in Table 57-2.

COURSE
Cicatricial pemphigoid is typically a chronic and
progressive disorder, although involvement may be
limited to a given anatomic site (e.g., the mouth, the
conjunctivae) for many years. Cicatricial pemphigoid
rarely goes into spontaneous remission; its treatment is
largely determined by its severity and sites of involvement. Scarring can only be prevented in these patients;
it cannot be reversed.
Always Rule Out

Pemphigus (specifically, pemphigus vulgaris, paraneoplastic pemphigus)
Other subepidermal immunobullous diseases
Erythema multiforme
Lupus erythematosus
Lichen planus
COMPLICATIONS
Consider
Drug-induced hypersensitivity reaction
Lichen sclerosus (especially in the anogenital area)
::
The diagnosis of cicatricial pemphigoid is suggested when

patients present with bullous or erosive lesions of mucous
membranes and continuous deposits of immunoreactants
are demonstrated in epithelial basement membranes of
perilesional tissue. Distinguishing cicatricial pemphigoid
from other autoimmune bullous diseases can be difficult
and may require specialized immunopathologic studies
and/or immunoelectron microscopy. Disorders that must
be differentiated from cicatricial pemphigoid include
lichen planus, erythema multiforme, lupus erythematosus, lichen sclerosus, andin the case of ocular disease
cicatrizing or inflammatory conjunctivitis that results
from long-term use of certain ophthalmologic preparations (e.g., pilocarpine, guanethidine, or ephedrine used
in the treatment of glaucoma or idoxuridine used as an
antiviral) or biologics that inhibit epidermal growth factor receptor tyrosine kinase (Box 57-1).37,74 It also has been
reported that some cases of ocular cicatricial pemphigoid
develop after an acute episode of severe ocular inflammatory injury secondary to StevensJohnson syndrome75 (see
Chapter 40). Interestingly, the time between the appearance of StevensJohnson syndrome and the onset of ocular cicatricial pemphigoid in these patients can range from
a few months to more than 30 years.
Most Likely
Pemphigus
Pemphigus vulgaris
Other subepidermal immunobullous diseases
Bullous pemphigoid
Linear immunoglobulin A dermatosis
Erythema multiforme
Lupus erythematosus
Lichen planus
Chapter 57
Selected cases may require specialized immunochemical

studies (e.g., immunoblot studies of keratinocyte or skin
extracts, immunoprecipitation studies of biosynthetically
radiolabeled keratinocytes) to identify the autoantigen
targeted by patient antibasement membrane autoantibodies. Perilesional tissue from seronegative patients
may be further characterized by immunoelectron microscopy studies to determine if in situ deposits of immunoreactants reside above or below the lamina densa of
epidermal basement membrane.

of Cicatricial Pemphigoid
TREATMENT
The following overview (Box 57-2) is representative of
most treatment regimens.4,7678
Mild lesions of the oral mucosa and skin can often
be treated effectively with topical glucocorticoids (or
calcineurin inhibitors such as tacrolimus) in a gel or
ointment base applied two to four times each day.77,79,80
Blotting lesional sites dry with a soft disposable tissue can enhance the adherence and effectiveness of
topical agents applied to lesional sites in the mouth.
These agents are particularly effective before bed,
because oral secretions diminish during sleep. Because
it is difficult to maintain contact of topical agents with
mucous membranes (and because lesions often are
localized to the gingiva), customized delivery trays to
occlude topical glucocorticoids over lesional sites in
the mouth are also useful.81 This approach also facilitates interactions with professionals who can manage
other complications in these patients (e.g., dental complications). Mouthwash (dexamethasone 100 g/mL,
5 mL per rinse) used in a swish-and-spit regimen
for 5 minutes two to three times each day represents
another approach for topical therapy. For oral disease
resistant to topical glucocorticoids, these agents can
(in some instances) be administered intralesionally.
In addition to these measures, patients should follow
a strict regimen of oral hygiene that includes regular brushing, flossing, and cleaning of teeth. Use of
toothpastes and mouthwashes that lack sodium lauryl
621
TABLE 57-2
Potential Complications of Cicatricial Pemphigoid

Site
Mouth
Mucosa
Gingiva
Eyes
Conjunctivae
Section 8
Eyelids
Cornea
Tear ducts
Potential Complications
Painful, erosive scarring lesions; adhesions between the buccal mucosa and the alveolar process; the uvula and
the tonsillar fossae; the tongue and the floor of the mouth
Loss of gingival tissue, caries, periodontal ligament damage, loss of alveolar bone, loss of teeth
Painful, erosive conjunctivitis; foreign-body sensations; photophobia; scarring; shortened fornices; loss of goblet
cells; decrease in tear mucus content, unstable tear film; symblepharons; ankyloblepharons
Ectropion, trichiasis, ankyloblepharons
Corneal irritation, superficial punctate keratinopathy, corneal neovascularization, corneal ulcers, blindness
Scarring, occlusion, secondary infection
::
Nose
Discharge, epistaxis, excessive crust formation, impaired airflow, recurrent and chronic sinusitis, scarring,
tissue loss
Larynx
Hoarseness, impaired phonation, loss of voice, scarring, supraglottic stenosis, airway compromise, and loss
Esophagus
Dysphagia, odynophagia, impaired swallowing, aspiration, stricture formation, weight loss
Anogenital
region
Painful erosions, stenosis, stricture, secondary infection
sulfate and alcohol, respectively, often facilitates

patient compliance with such activities.
A number of reports have suggested that dapsone
(50200 mg by mouth daily) may be effective.38,82 Others have found that cicatricial pemphigoid does not
respond to this agent. Systemic glucocorticoids can be
administered alone (e.g., 2060 mg of prednisone by
mouth each morning) or in combination with dapsone.
Because of potentially severe complications, ocular,
Box 57-2 Treatments for Cicatricial Pemphigoid

MILD INVOLVEMENT
Sites
Mouth
Anogenital region
Skin
Local Care Measures

Topical corticosteroid (gels or ointments) bid/qid; topical corticosteroids
under occlusion (e.g., dental trays); topical calcineurin inhibitors; intralesional
corticosteroids
Irrigation with isotonic saline bid/tid; nasal lubricants; topical corticosteroids
(e.g., via sprays, inhalers)
Topical corticosteroids; topical calcineurin inhibitors
Topical corticosteroids; topical calcineurin inhibitors
MODERATE INVOLVEMENT
Sites
Mouth, eyes, nose, larynx, esophagus, anogenital region
Therapeutic Options
Local care measures outlined above plus dapsone 50200 mg daily, prednisone 2060 mg each morning, or both of these agents simultaneously
Nose
SEVERE INVOLVEMENT
Sites
Mouth, eyes, nose, larynx, esophagus, anogenital region
622
laryngeal, esophageal, and/or anogenital involvement

requires aggressive management by teams of physicians familiar with specialized care of these organ
systems. For mild or moderate ocular involvement,
systemic glucocorticoids (e.g., 2060 mg of prednisone
by mouth each morning) alone or in conjunction with
daily dapsone may be effective. Patients whose ocular
disease is complicated by trichiasis may benefit from
epilation, although this decision is best made by an
Therapeutic Options
Local care measures outlined above plus prednisone (1 mg/kg each morning),
intravenous immunoglobulin (2 g/kg body weight over 23 days every 26 week
for 46 months), or both of these agents simultaneously in conjunction with azathioprine (22.5 mg/kg/day), mycophenolate mofetil (12.5 g/day), cyclophosphamide (12 mg/kg/day), or rituximab (375 mg/m2 weekly 4 then every 46
months as needed, or 1000 mg on days 1 and 15 and then 500 mg at month 6).
tap water as well as the use of topical emollients. Esophageal involvement requires medical management to avert
dysphagia, pain, tissue loss, and secondary complications such as gastroesophageal dysfunction and reflux,
stricture formation, aspiration, laryngeal irritation, or
bronchospastic pulmonary disease. All patients with cicatricial pemphigoid require long-term follow-up because
of the possibility for this chronic disease to relapse.
KEY REFERENCES
Rare blistering disease with onset typically

after fourth decade of life.
Rarely seen in association with malignancy,

specifically lymphoid.
Linear band of immunoglobulin A at the

dermalepidermal basement membrane.
Histology shows subepidermal collection of

neutrophils at the basement membrane, often
collecting in papillary tips with subepidermal
blisters.
May occur in association with many drugs,

including vancomycin.
May occur in association with inflammatory
bowel diseases but only rarely associated
with gluten sensitive enteropathy.
Linear Immunoglobulin A Dermatosis and Chronic Bullous
LINEAR IMMUNOGLOBULIN A DERMATOSIS AT A GLANCE
::
2. Chan LS et al.: The first international consensus on mucous membrane pemphigoid: Definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic
indicators. Arch Dermatol 138:370, 2002
3. Fleming TE, Korman NJ: Cicatricial pemphigoid. J Am
15. Olasz EB, Yancey KB: Bullous pemphigoid and related
subepidermal autoimmune blistering diseases. Curr Dir
Autoimmun 10:141, 2008
47. Egan CA et al: Anti-epiligrin cicatricial pemphigoid: Clinical findings, immunopathogenesis, and significant associations. Medicine (Baltimore) 82:177, 2003
76. Kirtschig G et al: Interventions for mucous membrane
pemphigoid/cicatricial pemphigoid and epidermolysis
bullosa acquisita: A systematic literature review. Arch Dermatol 138:380, 2002
Chapter 58 :: L
inear Immunoglobulin
A Dermatosis and Chronic Bullous
Disease of Childhood

:: Caroline L. Rao & Russell P. Hall III
Clinical presentations may mimic dermatitis

herpetiformis, bullous pemphigoid, and
cicatricial pemphigoid.
Chapter 58
ophthalmologist. For severe disease affecting the ocular, pharyngeal, or urogenital epithelia, a combination
of systemic glucocorticoids and an additional immunosuppressive is indicated. In such cases, azathioprine
(2.02.5 mg/kg/day), mycophenolate mofetil (1.02.5
g/day), or cyclophosphamide (12 mg/kg/day)
are often used in conjunction with daily prednisone
(1 mg/kg/day).77,8386 In this regimen, daily prednisone
is tapered gradually over approximately 6 months,
and the patient is maintained on the alternate agent
alone for an additional 612 months. Such combined
regimens have had success in halting the progression
of severe ocular disease, limiting scarring, and producing long-term remissions. In an effort to avoid adverse
effects and complications produced by prolonged
treatment with immunosuppressive agents, some
groups treat patients with intravenous immunoglobulin (i.e., intravenous immunoglobulin 2 g/kg of body
weight administered over 23 days every 26 weeks
for 46 months).8790 Another emerging trend in the
management of patients with particularly severe disease is the use of biologic agents that antagonize tumor
necrosis factor- (e.g., etanercept, infliximab) or bind
CD20 (rituximab).91,92
Involvement of the nasopharynx or esophagus potentially has severe complications and requires aggressive
and specialized care. Nasal lesions often benefit from
twice-daily irrigation of the nasal passages with saline or
Most patients respond dramatically to treatment

with dapsone; some require adjunctive systemic
corticosteroids.
Prognosis variable with both spontaneous
remissions and long-standing disease.
623
::
Linear immunoglobulin A (IgA) dermatosis is a rare

immune-mediated blistering skin disease that is
defined by the presence of homogeneous linear deposits of IgA at the cutaneous basement membrane (Fig.
58-1). Although in the original description of patients
with linear IgA dermatosis it was considered to be a
manifestation of dermatitis herpetiformis (DH), it has
now been clearly separated from DH on the basis of
its immunopathology, immunogenetics, and lack of
consistent association with a gluten-sensitive enteropathy.14 Patients with linear IgA dermatosis can present with lesions suggestive of epidermolysis bullosa
acquisita (EBA), DH, bullous pemphigoid (BP), lichen
planus, prurigo nodularis, or cicatricial pemphigoid.16
Drug-induced linear IgA was initially described in
association with vancomycin and has subsequently
been associated with a wide variety of drugs.711 Druginduced linear IgA has been found to differ somewhat
from classic linear IgA in clinical presentation with a
wider variety of clinical presentations including morbilliform, erythema multiforme like, and toxic epidermal necrolysis like.714
Chronic bullous disease of childhood (CBDC) is a
rare blistering disease that occurs predominantly in
children younger than 5 years of age and has an identical pattern of homogeneous linear IgA deposits at
the epidermal basement membrane.15,16 Recent studies
have demonstrated that in some patients CBDC and
linear IgA dermatosis represent different presentations
of the same disease process.17,18
Section 8
Figure 58-1 Direct immunofluorescence of normal-appearing perilesional skin from a patient with linear immunoglobulin A dermatosis. A homogeneous band of immunoglobulin A is present at the dermalepidermal junction.
EPIDEMIOLOGY
624
Linear IgA dermatosis occurs most often after puberty,

with most patients presenting after the fourth decade
of life.2,4,19 A slight predominance of females has been
noted in several studies.2,4,20 In contrast, CBDC presents
most often before the age of 5 years.20As in patients
with linear IgA dermatosis, there is a slight female predominance in patients with CBDC.16,20
Evaluation of the HLA association in patients with
linear IgA dermatosis and CBDC has yielded conflicting results. Some investigators have found an
increased frequency of the human histocompatibility

antigen HLA-B8 in patients with linear IgA dermatosis,
whereas others have found no increased frequency.2123
In CBDC, an increased frequency of HLA-B8 has been
noted, with up to 76% of patients expressing HLA-B8.20
Collier et al demonstrated an increased frequency of
HLA-B8, -DR3, and -DQ2 in CBDC that was not seen in
adults with linear IgA dermatosis.21 These authors suggested that these haplotypes may have a role in earlier
disease presentation. In addition, the TNF2 allele was
found with increased frequency in both adults and
children with linear IgA disease when compared with
unaffected subjects. There was, however, no increase
seen in either adults or children when compared with
HLA-DR3+ controls.
CHRONIC BULLOUS DISEASE OF

CHILDHOOD AT A GLANCE
Rare blistering disorder of childhood
presenting predominantly in children less
than 5 years of age.
Linear IgA at the dermalepidermal
basement membrane.
Clinical presentation of tense bullae, often
in perineum and perioral regions, giving a
cluster of jewels appearance. New lesions
sometimes appear around the periphery of
previous lesions with a collarette of blisters.
Histology shows subepidermal collection
of neutrophils at the basement membrane,
similar to linear IgA bullous dermatosis.
Most patients respond dramatically to
treatment with dapsone.
Spontaneous remissions, often within 2
years, are frequent.
ETIOLOGY AND PATHOGENESIS:

IMMUNOPATHOLOGY
Linear IgA dermatosis and CBDC are defined by the
presence of a homogeneous linear band of IgA at
the dermalepidermal basement membrane zone. A
minority of patients in both groups have additional
deposits of other immunoreactants, most often IgG
and occasionally the third component of complement
(C3).20 Because IgA is the predominant Ig of the secretory immune system, numerous investigators have
attempted to determine if the IgA present in the skin of
these patients is of mucosal origin. Characterization of
the IgA subclass in the skin has revealed almost exclusively IgA1 and not the subclass most often associated
::
epidermal side of 1 M NaCl-split normal human skin,

as shown by indirect immunofluorescence.32 They
found that serum IgA from patients with either CBDC
or linear IgA dermatosis bound to a 97-kDa protein. Immunoelectron microscopy revealed that the
97-kDa antigen is present in the lamina lucida, below
the hemidesmosome of normal human skin, in a location similar to where the IgA is localized in patients
with CBDC and linear IgA dermatosis.33 Subsequently, Zone et al determined that the 97-kDa linear
IgA bullous disease antigen is identical to a portion
of the extracellular domain of the 180-kDa BP antigen (BPAG2 or collagen XVII), which is essential in
anchoring basal keratinocytes to the epidermal basement membrane.34 The BP antigen (BPAG2) consists
of a 180-kDa transmembrane protein and 120-kDa
portion that corresponds to the collagenous ectodomain. Roh et al and Schumann et al have reported
that autoantibodies in patients with linear IgA dermatosis recognize the soluble 120-kDa ectodomain
of type XVII collagen35,36 The 120-kDa antigen target
is not unique to linear IgA dermatosis because it is
also the antigen targeted by autoantibodies in some
patients with cicatricial pemphigoid and BP.35,36 Furthermore, IgA antibodies and T cells from patients
with linear IgA bullous dermatosis have been found
to be directed against the NC-16A region of collagen
type XVII, which is the same region against which the
IgG and T cells from patients with BP are directed.37,38
This may explain in part the overlap in clinical and
histologic features of these conditions. Wojnarowska
et al have identified another possible target antigen in
patients with linear IgA dermatosis and CBDC using
sera from patients in whom the IgA bound to the epidermal side of 1 M NaCl-split skin on routine indirect
immunofluorescence. They found that IgA in the sera
of some patients with these diseases bound to a 285kDa protein (LAD 285) that was not the 230-kDa BP
antigen or type VII collagen, the EBA antigen.39Allen
and Wojnarowska have analyzed the sera of over 70
patients with both linear IgA dermatosis and CBDC
and found that the predominant antigenic target in
these patients is the BP180 antigen (collagen XVII),
but that some patients react with multiple antigens
including the BP230, LAD 285, and other yet to be
identified proteins.40 Ishtii et al described a patient
with Linear IgA who had antibodies directed at the
NC16a domain of BP180 without evidence of antibody formation to 120-kDa LAD 1.41 In many patients,
IgA appears to bind to several different antigenic targets, suggesting the possibility that there is epitope
spreading. The clinical significance of these findings
however, has not been established.40
Chapter 58
with mucosa, IgA2.19,24,25 In addition, neither secretory

piece nor J chain, both of which are present in secretory IgA, have been found in the IgA present in the
skin of patients with linear IgA deposits.26 Although
these data have led to suggestions that the IgA is not
of mucosal origin, the true origin of the IgA deposits in
the skin of these patients is not known.
Initially it was thought that patients with linear IgA dermatosis and CBDC rarely had circulating IgA antibodies against the epidermal basement
membrane. Indirect immunofluorescence, using 1 M
NaCl-split normal human skin as a substrate, demonstrates that the majority of patients with CBDC have
low-titer circulating antibodies against the epidermal side of the split skin.19 Circulating low-titer IgA
antibodies directed against the epidermal basement
membrane also have been found in adults with linear IgA dermatosis.20,27 Others have reported binding
of IgA antibodies from some patients to the dermal
side of normal human split skin, suggesting that
more than one antigen may be the target for the IgA
antibasement membrane antibodies.2729 Immunoelectron microscopic studies have been performed to
determine the exact location of the IgA in the skin of
patients with both linear IgA dermatosis and CBDC.
Immunoelectron microscopy of the skin of patients
with linear IgA deposits has revealed three distinct
patterns of immunoreactants. In some patients with
linear IgA dermatosis, the IgA deposits are found in
the lamina lucida region of the basement membrane
zone, similar to the location of immunoreactants present in the skin of patients with BP.28,29 A second pattern
of IgA deposition has been detected in which the IgA
deposits are present at and below the lamina densa
in a pattern similar to that seen in EBA.2830 Prost et
al have described a third pattern of immunoreactants
in some patients with linear IgA dermatosis in which
the IgA deposits are found both above and below the
lamina densa.29 In a similar manner, immunoelectron
microscopic studies of skin of patients with CBDC
have shown the IgA immunoreactants to be in either
the lamina lucida or a sublamina densa location.17,30
These findings further support the probability that
multiple antigens may be involved as the targets in
both adults and children with linear IgA deposits in
the skin. Horiguchi et al reviewed 213 cases of linear
IgA in Japan and found a strong association between
older age of onset and both IgG/IgA type and dermal binding. IgG was found in approximately 9% of
patients with the infantile (CBDC) type whereas in
adults (>16 years) IgG was found in 24% of patients.
Interestingly, when comparing the different groups
based on patterns of antigen binding (e.g., dermal vs.
epidermal and IgA vs. IgG/A) no significant clinical
differences were found.31
Although the relatively low titer of IgA antibodies
against the basement membrane present in the sera of
patients with both linear IgA dermatosis and CBDC
has complicated the search for specific antigenic targets for the IgA, several investigators have made significant observations regarding the antigenic targets
in these diseases. Zone et al studied sera from patients
who had circulating IgA antibodies that bound to the
CLINICAL FINDINGS
CUTANEOUS MANIFESTATIONS
The clinical manifestations of linear IgA dermatosis are
heterogeneous and often indistinguishable from those
seen in patients with DH.2,4,20,42 Patients may present
625
Section 8
::
626
Figure 58-2 Patient with linear immunoglobulin A dermatosis with crusted erosions, papules, and vesicles on
the back and neck.
with combinations of annular or grouped papules, vesicles, and bullae (Figs. 58-2 and 58-3). Typically, these
lesions are distributed symmetrically on extensor surfaces, including elbows, knees, and buttocks. Lesions
Figure 58-3 Patient with linear immunoglobulin A dermatosis with annular erythematous plaques on the thighs.
Figure 58-4 Patient with linear immunoglobulin A dermatosis with grouped urticarial papules on the back with
scattered crusted erosions.
most often are very pruritic, resulting in numerous
crusted papules (Fig. 58-4). The clinical presentation
can be difficult to distinguish from that seen in patients
with DH. However, the degree of pruritus seen in
patients with linear IgA dermatosis is variable and, in
general, less severe than that seen in patients with DH.
Some patients with linear IgA dermatosis present with
larger bullae, in a pattern more consistent with that
seen in patients with BP, or occasionally with cutaneous findings similar to those seen in patients with EBA.
Patients with drug-induced linear IgA bullous dermatosis have been reported with erythema multiformelike findings and a toxic epidermal necrolysis-like
presentation, with widespread bullae.7,11,13 Localized
palmar and morbilliform variants have also been
described.12,14 While vancomycin is most closely associated with the drug-induced linear IgA, a number of
other medications have also been implicated including
lithium, phenytoin, sulfamethoxazole/trimethoprim,
furosemide, atorvastatin, captopril, and diclofenac.13
In addition, a localized linear IgA in the setting of an
acute contact dermatitis has been reported.43 Recovery
has been reported with discontinuation of the offending agent alone, but these patients may benefit from
dapsone therapy (see Section Treatment and Prognosis).7,11,44
The clinical presentation of CBDC is characterized
most often by the development of tense bullae, often
on an inflammatory base.15 These lesions occur most
frequently in the perineum and perioral region and
often may occur in clusters, giving a cluster of jewels appearance (Figs. 58-558-7). New lesions sometimes appear around the periphery of previous lesions,
with a resulting collarette of blisters. Patients often
Chapter 58
::
Figure 58-7 Extensive chronic bullous disease of childhood. Note tense and flaccid blisters without notable inflammation.
report significant pruritus and/or a burning of the

skin with the development of skin lesions. Patients
with CBDC often present with the acute development
of large numbers of tense blisters, which may rupture
and become secondarily infected. CBDC differs from
linear IgA bullous dermatosis of adults in its typical
clinical appearance, relative paucity of serious mucosal involvement, and good prognosis.31
Rarely, patients with linear IgA dermatosis may
present with an acute febrile illness with arthritis,
arthralgias, and generalized malaise.45,46 The pres-
ence of multiple papules and vesicles in a patient

with systemic signs and symptoms has led to the
evaluation of these patients for systemic infections,
including viral infections. Routine direct immunofluorescence, however, has revealed linear deposits
of IgA, and these patients have responded to conventional therapy.
Figure 58-6 Chronic bullous disease of childhood. Tense

blisters on erythematous bases in the pubic and inguinal
areas.
MUCOSAL INVOLVEMENT
Mucosal involvement is an important clinical manifestation seen in patients with linear IgA dermatosis
and CBDC. This involvement can range from largely
asymptomatic oral ulcerations and erosions to severe
oral disease alone as well as to severe conjunctival
and oral disease typical of that seen in cicatricial pemphigoid.20,47,48 Oral lesions may occur in up to 70%
of patients with linear IgA disease.20 Mucosal invasion with complication is less often seen in CBDC.31
Although most patients with linear IgA dermatosis
and mucosal involvement have significant cutaneous
disease, cases have been reported in the literature in
which the presenting and predominant clinical manifestations are lesions of the mucous membranes.48,49
These patients may present with desquamative gingivitis and oral lesions consistent with those seen in
patients with cicatricial pemphigoid (see Chapter 57).
Patients also may present with conjunctival disease
and scar formation typical of that seen in patients
with cicatricial pemphigoid (see Chapter 57). Mucosal involvement also appears to be less prominent in
patients with drug-induced linear IgA.13 Patients with
linear IgA bullous dermatosis have also been reported
to present with severe laryngeal and pharyngeal
involvement before the development of more typical
cutaneous manifestitations.50
Figure 58-5 Patient with chronic bullous disease of childhood. Tense bullae and crusted papules are present on the
abdomen, with a clustering of bullae noted in the perineal
region.
627
Section 8
::
628
DISEASE ASSOCIATIONS
The similar clinical presentation of many patients with
linear IgA disease to that seen in patients with DH led
to the investigation of patients with linear IgA disease for an associated gluten-sensitive enteropathy.
Although some investigators have found evidence of
minimal inflammatory changes in the small bowel of
patients with linear IgA disease, numerous investigators have been unable to show that the majority of
patients with linear IgA disease have significant evidence of the villous atrophy characteristically seen in
patients with DH.3,51 In addition, the clinical manifestations of linear IgA disease have not been controlled
by the use of a gluten-free diet.52 Circulating autoantibodies against tissue transglutaminase, which occur
in high frequency in patients with untreated glutensensitive enteropathy and DH, have not been found in
most patients with linear IgA diseases.53
Other conditions have been reported in association
with linear IgA disease. One example is ulcerative colitis
(UC) and Crohns disease, which can result in a clinical
syndrome where the activity of both diseases is linked
(i.e., as one disease flares, so does the other).54,55 Paige
and coworkers reviewed 70 patients with linear IgA bullous dermatosis and found 7.1% had associated UC. The
extent and reason for this association has yet to be established. Perhaps, the abnormal mucosal IgA1 production
seen in patients with UC may play a role.55 In patients
with CBDC, Horoguchi reported associated systemic
disease in only 13 of 213 cases reviewed.31 CBDC also has
been reported in association with acute mononucleosis
and Paecilomyces lung infection in the setting of chronic
granulomatous disease.56 The relationship between these
conditions and CBDC has yet to be established.
The relatively acute onset of clinical, histologic, and
immunopathologic findings consistent with linear IgA
disease has been seen in patients who have been taking
a variety of drugs, including vancomycin, lithium phenytoin, sulfamethoxazole/trimethoprim, furosemide,
atorvastatin, captopril, and diclofenac.79,13,44 Vancomycin is the most common drug that is associated with
the development of linear IgA bullous dermatosis. Linear IgA dermatosis has similarly been described with
interferon 2a and was temporally related to the influenza vaccine. While these may reflect an induction of
a previously unrecognized autoimmune process, in
both cases the eruption was self-limited, in contrast to
classic linear IgA, which follows a chronic, waxing and
waning course.57,58 The mechanism of this interaction is
not known; however, a small number of patients with
vancomycin-induced linear IgA disease have been
reported to have circulating IgA antibodies directed
against the BP180, BP230, and LAD 285 antigens.59,60
In one case of vancomycin-induced linear IgA bullous
dermatosis, rechallenge with vancomycin in a gradual
manner did not result in a recurrence of the eruption.61
Linear IgA disease also has been associated rarely
with a variety of malignancies. Patients with linear
IgA disease have been reported with both lymphoid
and nonlymphoid malignancies.62,63 Godfrey et al
reported three cases of lymphoid malignancies in 70
patients with linear IgA disease followed for a mean

of 8.5 years. This represented an increase over the predicted number of 0.2 cases in an age- and sex-matched
population.62 No increase in the rate of nonlymphoid
malignancies was seen. These findings suggest a small
risk of lymphoid malignancy in these patients. However, larger population-based studies need to be done
to confirm these findings.
HISTOPATHOLOGY
Routine histopathology of an early lesion in patients
with linear IgA dermatosis and CBDC reveals a subepidermal bulla with collections of neutrophils along
the basement membrane, often accumulating at the
papillary tips (Fig. 58-8). A mild lymphocytic infiltrate
may be present around the superficial dermal blood
vessels without any evidence of neutrophilic vasculitis. Occasionally, the inflammatory infiltrate is composed of eosinophils, but most frequently neutrophils
are the major component of the subepidermal inflammation.20,64,65 Electron microscopic examination of the
blisters found in patients with both linear IgA dermatosis and CBDC has revealed that the blister forms
either within the lamina lucida or in a sublamina densa
location.17,28 Most often the histopathology seen in linear IgA disease is difficult to distinguish from that seen
in patients with DH. Smith et al65 reported that patients
with linear IgA disease tended to have fewer papillary
microabscesses and a more diffuse infiltrate of neutrophils at the basement membrane zone. However, Blenkinsopp et al found no significant difference between
the histopathology found in patients with linear IgA
disease and those with DH.64 In general, the histopathology of blisters in linear IgA disease, CBDC, and
DH is virtually indistinguishable.
Linear IgA dermatosis often closely mimics the clinical
pattern seen in patients with DH. Some patients may
Figure 58-8 Histopathology of lesional skin from a patient

with linear immunoglobulin A dermatosis showing a subepidermal blister filled with neutrophils. (Used with permission from Kim B. Yancey, MD.)
Box 58-1 Linear Immunoglobulin

A Bullous Dermatosis

Bullous pemphigoid
Bullous eruption of systemic lupus erythematosus
Lichen planus

3. Lawley TJ et al: Small intestinal biopsies and HLA types in
dermatitis herpetiformis patients with granular and linear
IgA skin deposits. J Invest Dermatol 74:9-12, 1980
16. Jablonska S et al: Linear IgA bullous dermatosis of childhood (Chronic bullous dermatosis of childhood). Clin Dermatol 9:393-401, 1992
20. Wojnarowska F et al: Chronic bullous disease of childhood, childhood cicatricial pemphigoid and linear IgA
disease of adults: A comparative study demonstrating
clinical and immunopathologic overlap. J Am Acad Dermatol 19:792-805, 1988
32. Zone JJ et al: Identification of the cutaneous basement
membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest
85:812-820, 1990
34. Zone JJ et al: The 97 kDa linear IgA bullous disease antigen is identical to a portion of the extracellular domain of
the 180 kDa bullous pemphigoid antigen, BPAg2. J Invest
Dermatol 110:207-210, 1998
46. Leigh G, Marsden RA, Wojnarowska F: Linear IgA dermatosis with severe arthralgia. Br J Dermatol 119:789-792,
1988
52. Leonard JN et al: Experience with a gluten free diet in the
treatment of linear IgA disease. Acta Derm Venerol (Stockh)
67:145-148, 1987
Adults with linear IgA dermatosis have an unpredictable course.4,20 Many patients have disease that continues for years, with few, if any, episodes of remission.
Occasionally, patients may have a spontaneous remission with loss of clinical features of the disease and
disappearance of the linear IgA deposits in the skin.
Patients with severe mucosal disease, especially of the
eyes, may have persistent problems with symblepharon formation and resulting structural problems with
the eyelids and cornea, even after active blistering has
remitted. Untreated ocular involvement can lead to
cicatrix and loss of vision.66
Patients with linear IgA disease most often respond
dramatically to dapsone or sulfapyridine. This response
usually occurs within 2448 hours, in a manner similar
to that seen with DH; as such, it is not a helpful diagnostic sign for linear IgA disease.2,4,20 Although most
patients are well controlled with dapsone or sulfapyridine alone, some patients require low-dose prednisone
therapy to suppress blister formation.20 In patients
who are unresponsive or intolerant of these medications, mycophenolate mofetil has been useful as a ste-
::
TREATMENT AND PROGNOSIS
KEY REFERENCES
Chapter 58
have findings that resemble those seen in patients with

BP, cicatricial pemphigoid, EBA, and, rarely, toxic epidermal necrolysis. In a similar manner, patients with
CBDC must be differentiated from those with DH of
childhood and childhood BP. The findings of linear IgA
deposits at the basement membrane by direct immunofluorescence, most often in the absence of IgG and
the C3, can distinguish this disease from BP, cicatricial
pemphigoid, and EBA, whereas granular IgA deposits
are found at the basement membrane in patients with
DH (Box 58-1).
roid-sparing agent.67 Trimethoprim/sulfamethoxazole

has been reported to be helpful when used in conjunction with other immunosuppressives.68 The majority
of patients with linear IgA disease cannot control their
skin disease with a gluten-free diet.52
CBDC is most often a self-limited disease, with most
children going into remission within 2 years of the onset
of the disease.15,16,20 Occasionally, the disease persists
well into puberty but often is less severe than the initial
eruption. Patients with CBDC respond in a similar dramatic fashion to dapsone or sulfapyridine.15,16,20 Many
children, however, require the addition of relatively
small doses of prednisone to bring the disease under
control.15,16 Mycophenolate mofetil has been used as a
steroid-sparing agent in isolated cases.69 Intravenous
immunoglobulins have also been proposed in the rare
patient not responding to, or intolerant of, dapsone
therapy.70,71 Topical tacrolimus may also be a useful tool
in minimizing systemic therapy.72 Several case reports
suggest that some patients with CBDC may respond
to antibiotics, including sulfonamides, dicloxacillin,
and erythromycin.73,74 In one case series, seven children
with linear IgA disease treated with flucloxacillin demonstrated improvement, with four achieving remission
within 3 months.75 However, spontaneous remission in
these patients cannot be ruled out.
629
Chapter 59 :: P
emphigoid Gestationis
(Herpes Gestationis)

:: Jeff K. Shornick
PEMPHIGOID GESTATIONIS
AT A GLANCE
Acute-onset, intensely pruritic, vesiculobullous
eruption of pregnancy or the immediate
postpartum period.
::
Histopathology: dermalepidermal
separation with numerous eosinophils.
Section 8
Rare, occurring in roughly 1 in 50,000

pregnancies.
Direct immunofluorescence: linear

deposition of C3, with or without
immunoglobulin (Ig) G, along the basement
membrane zone of the epidermal fragment
of salt-split skin.
Enzyme-linked immunosorbent assay for
pemphigoid gestationis antibody (BP180)
commercially available.
No significant maternal morbidity or mortality.
Associated with a slight increase in premature
and small-for-gestational-age births.
EPIDEMIOLOGY
Pemphigoid gestationis (PG) is the least common, yet
best-characterized, dermatitis specific to pregnancy.1 It
classically presents as an intensely pruritic, urticarial
rash during the later part of pregnancy or the immediate postpartum period, then rapidly progresses to a
pemphigoid-like, vesiculobullous eruption. The rash
may wax and wane during pregnancy, only to flare
during labor and delivery. PG appears to be mediated
by a specific immunoglobulin (Ig) G directed against
the cutaneous basement membrane zone (BMZ).
PG occurs in approximately 1 in 50,000 pregnancies.2,3
It is associated with HLA-DR3 and -DR4, and it appears
likely that the incidence in various ethnic groups parallels the frequency of these genes in different populations.4
630
PG appears to be caused by an anti-BMZ antibody that

induces C3 deposition along the dermalepidermal
junction. The PG autoantibody (formerly called HG
factor) is an IgG that is infrequently found by direct
immunofluorescence (IF), although indirect, complement-added IF reveals the circulating IgG in the majority of patients. In salt-split skin, staining remains with
the epidermal fragment. An enzyme-linked immunosorbent assay (ELISA) for the PG antibody is commercially available, and when this highly sensitive test is
used, antibody titers appear to correlate with disease
activity.5 The PG autoantibody appears to belong to
the IgG1 subclass and fixes complement via the classical complement pathway.6 T cells also show selective
NC16A reactivity in PG, although their role in disease
development remains to be elucidated.7
Nearly all patients with PG [and most patients with
bullous pemphigoid (BP)] have demonstrable antibodies to BP180 (type XVII collagen), a 180-kDa transmembrane protein with its N-terminal end embedded
within the intracellular component of the hemidesmosome and its C-terminal end located extracellularly
(see Chapter 53). The extracellular section contains a
series of 15 collagenous components alternating with
16 short, noncollagenous domains. The sixteenth noncollagenous segment closest to the plasma membrane
of the basal keratinocyte is designated NC16A and
contains the BP180 immunoreactive site.8,9 The PG
autoantibody is assumed to be pathogenic for several
reasons: (1) It is found in essentially all patients. (2) In
vitro, purified antibodies to BP180 cause chemoattraction to the dermalepidermal junction with subsequent
degranulation and dermalepidermal separation.10 (3)
BP180 antibodies cause keratinocytes to lose cell adhesion in tissue culture.11 (4) Rabbit antibodies to BP180
in animal models induce subepidermal blisters when
infused into neonatal mice or hamsters.12,13
The BP180 protein differs significantly from the BP230
protein recognized by the majority of BP sera.14,15 The
230-kDa protein is coded for on the short arm of chromosome 6.16 Its complementary DNA (cDNA) has been
sequenced17 and codes for an intracellular protein18 that
shows considerable homology with desmoplakin I.19 The
180-kDa protein is coded on the long arm of chromosome
10.20 Its cDNA shows no homology with the 230-kDa
cDNA but rather encodes a protein with two domains
showing the primary structure of trihelical collagen.21
What initiates the production of autoantibody
remains unclear, but because gestational pemphigoid is exclusively a disease of pregnancy, attention
has focused on immunogenetics and the potential for
cross-reactivity between placental tissue and skin.
Immunogenetic studies reveal an increase in HLA
antigens DR3 or DR4, and curiously, nearly 50% of
patients have the simultaneous presence of both.22 The
extended haplotype HLA-A1, B8, DR3 is known to
be in linkage disequilibrium with a deletion of C4A (the
C4 null allele or C4QO). Indeed, 90% of patients have
either a C4AQO or a C4BQO.23 However, whether the
C4QO association is the primary genetic marker for PG
The typical lesions of PG are urticarial or arcuate

plaques that rapidly progress toward a mixed dermatitis, including tense, pemphigoid-like blisters (Figs. 59-1
Pemphigoid Gestationis (Herpes Gestationis)
CUTANEOUS LESIONS
::
tion de novo. Up to one-quarter of patients initially

present during the immediate postpartum period.
Newborns may be affected up to 10% of the time, but
the disease is typically mild and self-limited. IF of newborn skin may yield positive findings despite a lack of
clinically apparent disease, which suggests that more
than C3 deposition alone is required to induce lesions.33
Because of clinical and IF similarities with BP, and
because of the considerable confusion over the term
herpes gestationis (particularly outside dermatology),
most authors have accepted the revised terminology
of PG.34 However, there are several differences worth
bearing in mind: (1) BP is a disease of the elderly and
shows no gender bias. PG is exclusively associated
with pregnancy. (2) PG shows a strong association with
HLA-DR3, -DR4, and a C4 null allele. BP does not. (3)
Indirect IF in BP yields positive results in the majority
of patients, and the titer of anti-BMZ antibody is often
high. The titer of anti-BMZ antibody in PG is usually
so low that antibody cannot be detected without the
use of complement-added or ELISA techniques. (4)
The majority of BP sera react to an intracellular 230to 240-kDa component of the hemidesmosome. Sera
from most PG patients react to a 180-kDa transmembrane protein with a collagenous domain coded for on
a different chromosome. Until such time as nosology
is driven by pathologic mechanism instead of clinical
observation, naming is likely to remain fungible.
Chapter 59
or the presence of a C4QO is even clinically relevant to

complement function remains to be shown.
It is worth noting that patients with neither DR3
nor DR4 may have disease clinically indistinguishable
from those with classic HLA findings; the presence of
HLA-DR3, -DR4, or the concurrent presence of both is
neither necessary nor sufficient to produce disease.22
Essentially, 100% of women with a history of PG
have demonstrable anti-HLA antibodies.24,25 Because
the only source of disparate HLA antigens is typically the placenta (which is primarily of paternal
origin), the universal finding of anti-HLA antibodies implies a high frequency of immunologic insult
during gestation. Indeed, a slight increase in HLADR2 in the husbands of women with PG has been
reported.24 It has been suggested that immunologically primed women may simply react more strongly
to tissue with disparate HLA antigens. Whether antiHLA antibodies represent phenomenon or epiphenomenon remains to be clarified.
The autoantibody of gestational pemphigoid binds
to amniotic basement membrane, a structure derived
from fetal ectoderm and antigenically similar to
skin.26,27 Women with PG also show an increased
expression of major histocompatibility complex class
II antigens (DR, DP, DQ) within the villous stroma of
chorionic villi but not skin.28,29 Therefore, it has been
proposed that PG is a disease initiated by the aberrant
expression of major histocompatibility complex class
II antigens (of paternal haplotype) within the placenta
that serves to initiate an allogeneic response to placental BMZ, which then cross-reacts with skin.30
On the other hand, PG has also been reported in association with hydatidiform moles31 and choriocarcinomas.32 This is an intriguing clinical observation, because
most hydatidiform moles are produced by a diploid
contribution of paternal chromosomes and contain neither fetal tissue nor amnion. There are no case reports
of a PG-like rash in males with choriocarcinoma. Unlike
its counterpart in women, choriocarcinoma in males
is strictly syngeneic tissue. Because choriocarcinoma
in women is entirely derived from placental tissue (of
paternal derivation), the suggestion is that the development of PG is somehow dependent on the state of partial
allograph, not necessarily on the presence of amnion.
CLINICAL FINDINGS
PG is exclusively associated with pregnancy. It typically presents during late pregnancy with the abrupt
onset of intensely pruritic urticarial lesions. Fifty percent of patients experience first onset on the abdomen,
often within or immediately adjacent to the umbilicus.
The other half present with typical lesions, but in an
atypical distribution (extremities, palms, or soles).
Rapid progression to a generalized, pemphigoid-like
eruption, sparing only the face, mucous membranes,
palms, and soles is the rule (although any site may be
involved). Flares occur with delivery in approximately
75% of patients and may be dramatic. The explosive
onset of blistering may occur within hours of delivery,
either as a flare of preexisting disease or as presenta-
Figure 59-1 Pemphigoid gestationis. Polymorphic lesions

on dorsa of feet.
631
Section 8
::
632
SPECIAL TESTS
Figure 59-2 Pemphigoid gestationis. Erythematous urticarial and bullous lesions on the chest and shoulders.
and 59-2, and eFig. 59-2.1 in online edition). Blisters may
arise within urticarial plaques or on otherwise normalappearing skin. Pruritic urticarial papules and plaques
of pregnancy (see Chapter 108) can show microvesiculation but not the tense, subepidermal blisters of PG.

PG is seen exclusively in women and only in the presence of pregnancy (or trophoblastic tissue). Any other
setting is inconsistent with this diagnosis.
LABORATORY TESTS
Results of routine laboratory investigations are normal.
Histopathology classically reveals a subepidermal vesicle with a perivascular infiltrate of lymphocytes and
eosinophils (Fig. 59-3). Eosinophils may be lined up
along the dermalepidermal junction and typically fill
the vesicular space. However, classic findings are seen
only in the minority of cases. A nonspecific mixed cellular infiltrate containing a variable number of eosinophils is more common. The presence of eosinophils is
the most constant histologic feature of PG.
Figure 59-3 Pemphigoid gestationis. Subepidermal

vesicle formation; dermal edema; infiltrate consisting of
lymphocytes, histiocytes, eosinophils, and a few neutrophils; and focal basal cell necrosis. Note bulbous, teardroplike vesicles.
The sine qua non for a diagnosis of PG is the finding

of C3, with or without IgG, in a linear band along the
BMZ of perilesional skin (eFig. 59-3.1 in online edition). In salt-split skin specimens, antibody deposition
is found along the bottom of the epidermal fragment, a
finding similar to that seen in BP. Indirect IF only occasionally detects circulating IgG deposition. However,
complement-added indirect IF reveals the circulating
anti-BMZ IgG in nearly all patients. The PG ELISA
now available may replace IF over time, though not all
patients react with the BP180 antibody alone, and such
a narrow focus may miss cases where the relevant antigen is outside the NC16A site.
Anti-BMZ antibody titers correlate with the extent
and severity of disease, but only if ELISA tests are
used.5 There is no apparent correlation between HLA
type and clinical activity.22 An increased incidence of
antithyroid antibodies has been documented in those
with a history of PG, but clinically apparent thyroid
dysfunction appears rare.35 Antinuclear antibodies are
not seen, and serum complement levels are normal.
Since early lesions of PG can be urticarial, the most
frequent frustration is differentiating PG from pruritic
urticarial papules and plaques of pregnancy, otherwise
known as polymorphous eruption of pregnancy (see Chapter 108). PG usually progresses rapidly, which makes the
clinical diagnosis apparent. Allergic contact dermatitis
and drug eruptions might also be difficult to distinguish.
Where doubt exists, IF (or ELISA) is the key to differentiation and is particularly relevant in helping patients
plan for future pregnancies (Fig. 59-4 and Box 59-1).
COMPLICATIONS
No increase in maternal morbidity or mortality has
been documented, although the impression of such
remains from a review of published case reports.
Cutaneous disease in the newborn is typically selflimited and rarely requires intervention. Although
there is an increased risk of premature and small-forgestational-age births,33 there are no data to suggest
that treatment with systemic corticosteroids alters
the risk of premature delivery. That being the case,
it is imperative that the risks of therapy be balanced
against the severity of the symptoms.
Women with a history of PG appear to be at increased
risk for the subsequent development of Graves disease.35

COURSE
The clinical presentation and course of disease may be
extremely variable. Many patients experience spontaneous resolution during the later part of gestation
Approach to patient with pemphigoid gestationis
Rash in pregnancy
Coincidental
Related to pregnancy
Non-compatible with
pemphigoid gestationis
Compatible with
pemphigoid gestationis
Enzyme-linked
immunosorbent assay results
Positive
Chapter 108
Pemphigoid
gestationis
::
Negative
Chapter 59
Other eruptions
in pregnancy
only to experience a flare, sometimes dramatically, at

the time of delivery. Others develop relatively trivial
urticarial lesions during one pregnancy, only to suffer
characteristic blistering during a subsequent gestation.
Still others develop classic disease during one pregnancy, then no disease during the next. The frequency
of such skip pregnancies approximates 5% to 10%.36
Recurrences associated with menstruation are common, particularly during the first several months after
delivery, and flares during the subsequent use of oral
contraceptives occur in at least 25% of patients.
Most disease remits spontaneously over weeks to

months following delivery, although there are isolated reports of protracted postpartum involvement. It
has often been said that once gestational pemphigoid
develops, it tends to occur earlier and with greater
severity during subsequent gestations, but there are no
data to support this contention.
No clear pattern of paternal contribution, if there is
one, has yet been elucidated. First onset during both
primiparous and multiparous pregnancies has been
reported, with and without a change in partners.
Pemphigoid Gestationis (Herpes Gestationis)
Figure 59-4 Approach to the patient with pemphigoid gestationis.
TREATMENT
of Pemphigoid Gestationis
Most Likely
Urticarial pemphigoid gestationis
Pruritic urticarial papules and plaques of pregnancy
Other eruptions of pregnancy (see Chapter 108)
Contact dermatitis
Drug eruption
Consider
Urticaria
Erythema multiforme
Rule Out
Pemphigus vulgaris
Varicella
Gestational pemphigoid is sufficiently rare that no

controlled studies are available. Nonetheless, there is
general consensus that treatment with topical corticosteroids and antihistamines is ineffective. Systemic
corticosteroids remain the cornerstone of therapy.
Most patients respond to 0.5 mg/kg of prednisone
(prednisolone) daily. Maintenance therapy, generally at a lower dosage, may or may not be required
throughout gestation. As noted earlier, many patients
experience spontaneous disease regression during the
third trimester, only to experience flare during parturition.
In individual cases, alternatives to corticosteroids
(dapsone, pyridoxine, cyclosporine, rituxan) or adjuvants (gold, methotrexate, cyclophosphamide, plasmapheresis) have been tried. None, with the possible
exception of cyclosporine, is useful prior to term, and
the experience with each has been variable at best.
There are obvious concerns with the use of any of these
products during pregnancy.
633
PREVENTION
Section 8
Only a small percentage of women who express DR3,

DR4, or the combination of DR3 and DR4 ever develop
PG, and the role of the paternal tissue in the development of disease (if any) is far from clear. With no predictive test available, prevention is not possible.
Those with a history of PG face the likelihood (but
not the assurance) of recurrent involvement during
subsequent gestations and are likely to develop symptoms during the use of oral contraceptives. Women
who have experienced PG need not avoid additional
pregnancies. However, they should be counseled that
recurrent disease is the rule.
KEY REFERENCES
1. Ambros-Rudolph C et al: The specific dermatoses of pregnancy revisited and reclassified: Results of a retrospective
two-center study on 505 pregnant patients. J Am Acad Dermatol 54:395, 2006
30. Kelly SE, Black MM, Fleming S: Pemphigoid gestationis:
A unique mechanism of initiation of an autoimmune response by MHC class II molecules? J Pathol 158:81, 1989
::
Chapter 60 :: Epidermolysis Bullosa Acquisita

:: David T. Woodley & Mei Chen
EPIDERMOLYSIS BULLOSA
ACQUISITA AT A GLANCE
Rare, autoimmune subepidermal bullous
disease due to immunoglobulin (Ig) G
autoantibodies to type VII collagen.
Etiology is unknown.
Skin fragility, subepidermal blisters, residual
scarring, and milia formation. Common sites
are trauma-prone areas such as hands, feet,
elbows, knees, sacrum, nails, and mouth.
Related features may include an underlying
systemic disease such as inflammatory
bowel disease. May have erosions of the
mucosa and esophageal stenosis.
Pathology shows subepidermal bulla,
fibrosis, milia formation, and positive direct
immunofluorescence for IgG deposits at the
dermalepidermal junction.
Treatment options are limited and often
difficult.
EPIDEMIOLOGY
634
Epidermolysis bullosa acquisita (EBA) is a sporadic

autoimmune bullous disease of unknown etiology and
with no gender, ethnic, or geographic predisposition.
Although EBA does not have a Mendelian pattern type
of inheritance, there may be some genetic predisposi-
tion to EBA and autoimmunity in African-Americans

who live in the southeastern part of the United States.1
African-American patients in the southeastern part
of the United States who have either EBA or bullous
systemic lupus erythematosus (SLE) have a high incidence of the HLA-DR2 phenotype. The calculated
relative risk for EBA in HLA-DR2+ individuals is 13.1
in these patients. These results also suggest that EBA
and bullous SLE are immunogenetically related and
that either the HLA-DR2 gene is involved with autoimmunity to anchoring fibril collagen or is some sort
of a marker for some other gene that exists in linkage
disequilibrium with it.1

EBA is a chronic, subepidermal blistering disease
associated with autoimmunity to the collagen (type
VII collagen) within anchoring fibril structures that
are located at the dermalepidermal junction (DEJ).
Although the precise etiology of EBA is unknown,
most of the evidence suggests an autoimmune etiology. The immunoglobulin (Ig) G autoantibodies
to type VII collagen are associated with a paucity of
normal-anchoring fibrils at the basement membrane
zone (BMZ) separating the epidermis from the dermis
and poor epidermaldermal adherence. Although it
is an acquired disease that usually begins in adulthood, it was placed in the category epidermolysis
bullosa (EB) approximately 100 years ago because
physicians were struck by how similar the clinical
lesions of EBA were to those seen in children with
hereditary dystrophic forms of EB. Direct immunofluorescence (DIF) of perilesional skin biopsies from
EBA patients reveals IgG deposits at the DEJ.2 EBA
antibodies bind to type VII collagen within anchoring fibrils (see Chapter 53).3,4
::
Epidermolysis Bullosa Acquisita
antigen, they develop widespread skin blisters and fall

into a subset of SLE called bullous SLE.12 This experiment of nature suggests that EBA autoantibodies
are pathogenic and capable of inducing disadherence
between the epidermis and dermis. Secondly, direct
proof that EBA autoantibodies are pathogenic comes
from recent passive transfer studies. We immunized
rabbits and raised a high titer antiserum to the NC-1
domain of human type VII collagen. We injected this
antibody into hairless immune competent mice, and
the mice developed bullous skin disease with many of
the features of EBA in humans.13 The mice developed
subepidermal blisters and lost nails on their feet. They
also had circulating NC-1 antibodies in their blood
and anti-NC-1 IgG antibody deposits at their DEJ. In
addition, the mice had murine complement deposits at the DEJ induced by the autoantibodyantigen
complex.13 Another study by Sitaru and colleagues14
showed that the injection of rabbit polyclonal antibodies to the NC-1 domain of mouse type VII collagen into
mice also induced subepidermal skin blisters that were
reminiscent of human EBA.14 Further, we have also
affinity purified human EBA autoantibodies against an
NC-1 column and injected them into mice. The mice
then developed clinical, histologic, immunologic, and
ultrastructural features akin to human EBA.15 Taken
together, these successful passive transfer experiments
and the observations with bullous SLE strongly suggest that EBA autoantibodies are pathogenic and
capable of causing epidermaldermal separation in
skin.
In addition to a passive transfer animal model of
EBA, Sitaru and colleagues16 have established an
active EBA animal model by immunizing certain
strains of mice with fragments of the noncollagen
domain (NC-1) of murine type VII collagen. In these
animal models, activation of complement by the alternative pathway and NADPH oxidase for neutrophil
action are required for the development of murine
EBA.17,18 The murine models of EBA with these requirements for components of inflammation may better
reflect the inflammatory subsets of EBA than the classical noninflammatory mechanobullous EBA phenotype
since it is known that not all EBA patients have complement-fixing antibodies or a pathology involving neutrophils. Alternatively, the murine model could reflect
early processes in the development of all EBA that is
later modulated in certain EBA patients by their intrinsic immune regulatory processes. The next advance in
understanding the pathogenesis of EBA will be linking the pathogenic mechanistic steps involved in the
disease with the patients clinical phenotype of disease
(see Section Clinical Findings).
Chapter 60
Anchoring fibrils anchor the epidermis and its

underlying BMZ to the papillary dermis. Patients with
hereditary forms of dystrophic EB (see Chapter 62)
and EBA have decreased numbers of anchoring fibrils
in their DEJ. This paucity of anchoring fibrils is associated with two similar clinical phenotypes, EBA and
dystrophic forms of hereditary EB, because both diseases are characterized by skin fragility, subepidermal
blisters, milia formation, and scarring. Although both
EBA and hereditary forms of dystrophic EB are etiologically unrelated in terms of their underlying pathogenesis, they share the common feature of decreased
anchoring fibrils. In the case of dystrophic forms of
hereditary EB, the cause of decreased or absent anchoring fibrils is a genetic defect in the gene that encodes
for type VII collagen chains that ultimately results in
small, nonfunctional, or decreased anchoring fibrils.5,6
The gene coding for type VII collagen is located on
the short arm of chromosome 3, approximately 21 cm
from zero.7 The gene defects involved in hereditary
forms of dystrophic EB have been identified at variable locations, but the severity of the disease appears
to correlate with the degree of type VII collagen and
anchoring fibril perturbations.6 In EBA, the IgG autoantibodies binding to the type VII collagen chains
result in decreased anchoring fibrils, but the pathway
leading to this reduction is unknown. It may be that
type VII collagen chains that are newly synthesized
but decorated with EBA autoantibodies cannot form
triple-helical structures and stable anchoring fibrils.
Healed burn wounds that have been covered with cultured keratinocyte sheets also have decreased numbers
of anchoring fibrils within the first year after transplantation, and this is associated with spontaneous blister
formation, shortened suction blistering times, and skin
fragility.8 These observations provide indirect evidence
that anchoring fibrils play a role in maintaining adherence between the epidermis and dermis.
The type VII collagen chain has a molecular mass
between 250 and 320 kDa, and the collagen consists of
a homotrimer of three identical chains (see Chapter
53). Each chain consists of a large globular noncollagenous amino terminus called the noncollagenous 1
(NC-1) domain that is approximately one-half the entire
mass of the chain. Next, there is a helical domain with
typical glycine-X-Y repeats. At the carboxyl terminus is
a second globular noncollagenous domain, NC-2, that
is much smaller than NC-1.9 Most EBA autoantibodies
recognize four predominant antigenic epitopes within
the NC-1 domain and do not recognize the helical or
NC-2 domains.10,11 There may be something intrinsically antigenic about the NC-1 domain because the
available monoclonal antibodies that have been generated against type VII collagen specifically recognize
only NC-1 subdomains.
A reduction in the number of anchoring fibrils is
seen in lesional and perilesional skin of EBA patients,
but the pathway leading to this reduction is unknown.
Several independent lines of evidence have implicated autoimmune responses as a key element in the
pathogenesis of EBA. First, the pathogenic role of EBA
antibodies is suggested by the observation that when
patients with SLE develop autoantibodies to the EBA
CLINICAL FINDINGS
(Fig. 60-1)
If a patient presents with bullae on the skin with
no reasonable explanation despite a thorough history and physical examination, three tests should be
done: (1) a skin biopsy for routine hematoxylin and
eosin histology, (2) a second biopsy juxtaposed to a
635
Approach to patient with epidermolysis bullosa acquisita (EBA)
Lesional biopsy
Sub-epidermal bulla
Perilesional DIF
Intraepidermal bulla
Section 8
Positive for IgE
::
Consider EBA and anti-L5

CP Chan disease
Ghohestani disease
Salt-split DIF
Dermal floor
staining
Epidermal roof
staining
Negative
IIF
If available:
ELISA
Western Blot
EM
Immuno-EM
Consider other DX
(e.g., pemphigus)
Consider other DX
Negative
Consider bullous
pemphigoid
EBA still possible
Positive for circulating

anti-BMZ antibodies
Salt-split skin IIF
Dermal floor staining
Figure 60-1 Approach to the patient with epidermolysis bullosa acquisita (EBA). BMZ = basement membrane zone;
DIF = direct immunofluorescence; DX = diagnosis; ELISA = enzyme-linked immunosorbent assay; IgG = immunoglobulin G;
IIF = indirect immunofluorescence.
lesion but on normal-appearing skin for DIF, and (3)
a blood draw to test for antibodies against the BMZ
and/or type VII collagen by indirect immunofluorescence (IIF) or enzyme-linked immunosorbent assay
(ELISA).
CLASSIC PRESENTATION. The classic presentation (Figs. 60-2 and 60-3A) is of a noninflammatory
bullous disease with an acral distribution that heals
HISTORY
636
CUTANEOUS LESIONS. The cutaneous lesions of

EBA can be quite varied and can mimic other types of
acquired autoimmune bullous diseases. The common
denominator for patients with EBA is autoimmunity to
type VII (anchoring fibril) collagen. Although the clinical spectrum of EBA is still being defined, there are at
least five clinical presentations: (1) a classic presentation, (2) a bullous pemphigoid (BP)-like presentation,
(3) a cicatricial pemphigoid (CP)-like presentation,
(4) a presentation reminiscent of BrunstingPerry pemphigoid with scarring lesions and a predominant head
and neck distribution, and (5) a presentation reminiscent of linear IgA bullous dermatosis or chronic bullous disease of childhood.
Figure 60-2 Patient with epidermolysis bullosa acquisita

who has severe blistering, erosions, scarring, and milia
formation on trauma-prone areas of her skin. This is the
classic presentation.
Chapter 60
::
with scarring and milia formation. This presentation is

reminiscent of porphyria cutanea tarda (PCT; see Chapter 132) when it is mild and of the hereditary form of
recessive dystrophic EB when it is severe (see Chapter
62). The classic form of EBA is thus a mechanobullous
disease marked by skin fragility. These patients have
erosions, tense blisters within noninflamed skin, and
scars over trauma-prone surfaces such as the backs of
the hands, knuckles, elbows, knees, sacral area, and
toes (see Figs. 60-2, 60-3A, and 60-4). Some blisters may
be hemorrhagic or develop scales, crusts, or erosions.
The lesions heal with scarring and frequently with the
formation of pearl-like milia cysts within the scarred
areas (see Fig. 60-3A). Although this presentation may
be reminiscent of PCT, these patients do not have other
hallmarks of PCT, such as hirsutism, a photodistribution of the eruption, or scleroderma-like changes, and
their urinary porphyrins are within normal limits. A
Figure 60-3 A. Classic presentation of epidermolysis

bullosa acquisita with scarring and milia over traumaprone areas of skin. B. Bullous pemphigoid-like presentation of epidermolysis bullosa acquisita with a widespread
inflammatory vesiculobullous dermatosis. C. Cicatricial
pemphigoid-like presentation of epidermolysis bullosa
acquisita with a mucosa-centered bullous scarring eruption. D. BrunstingPerry pemphigoid-like presentation of
epidermolysis bullosa acquisita with bullous and scarring
lesions predominantly on the head and neck.
scarring alopecia and some degree of nail dystrophy

may be seen.
Although the disease is usually not as severe as that
of patients with hereditary forms of recessive dystrophic EB, EBA patients with the classic form of the
disease may have many of the same sequelae, such as
scarring, loss of scalp hair, loss of nails, fibrosis of the
hands and fingers, and esophageal stenosis.19
BULLOUS PEMPHIGOID-LIKE
PRESENTATION
(See Chapter 56)
A second clinical presentation of EBA is of a widespread, inflammatory vesiculobullous eruption involving the trunk, central body, and skin folds in addition
to the extremities.20 The bullous lesions are tense and
637
mucosal involvement. However, the antigenic target

for the IgG autoantibodies has not been defined. Nevertheless, a patient reported with this constellation of
findings had IgG autoantibodies directed to anchoring
fibrils below the lamina densa.22 We have seen three
additional patients with the features of Brunsting
Perry pemphigoid and autoantibodies directed to type
VII collagen (unpublished observations). Therefore, it
appears that EBA patients may present with a clinical
phenotype of BrunstingPerry pemphigoid (see Fig.
60-3D).
Section 8
IMMUNOGLOBULIN A BULLOUS
DERMATOSIS-LIKE PRESENTATION
::
Figure 60-4 An epidermolysis bullosa acquisita patient

with involvement of the leg. Note bullae, erosions, and
crusts.
surrounded by inflamed or even urticarial skin. Large
areas of inflamed skin may be seen without any blisters and only erythema or urticarial plaques. These
patients often complain of pruritus and do not demonstrate prominent skin fragility, scarring, or milia formation. This clinical constellation is more reminiscent
of BP (see Figs. 60-3B and 60-4) than a mechanobullous
disorder. Similar to BP, the distribution of the lesions
may show an accentuation within flexural areas and
skin folds.
CICATRICIAL PEMPHIGOID-LIKE
PRESENTATION
(See Chapter 57)
Both the classic and BP-like forms of EBA may have
involvement of mucosal surfaces. However, EBA also
may present with such predominant mucosal involvement that the clinical appearance is reminiscent of CP
(see Fig. 60-3C).24 These patients usually have erosions
and scars on the mucosal surfaces of the mouth, upper
esophagus, conjunctiva, anus, or vagina with or without similar lesions on the glabrous skin.
BRUNSTINGPERRY PEMPHIGOIDLIKE PRESENTATION
638
(See Chapter 57)

BrunstingPerry cicatricial BP is a chronic, recurrent
vesiculobullous eruption localized to the head and
neck and characterized by residual scars, subepidermal bullae, IgG deposits at the DEJ, and minimal or no
(See Chapter 58)

IgA bullous dermatosis-like presentation of EBA
is manifested by a subepidermal bullous eruption, a
neutrophilic infiltrate, and linear IgA deposits at the
BMZ when viewed by DIF. It may resemble linear IgA
bullous dermatosis (LABD), dermatitis herpetiformis,
or chronic bullous disease of childhood and may feature tense vesicles arranged in an annular fashion and
involvement of mucous membranes.23 The autoantibodies are usually IgA, IgG, or both.
The diagnosis of these subepidermal blistering cases
with IgA antitype VII collagen antibodies showing
linear IgA deposition at the BMZ is disputable. Some
clinicians regard the patients as having purely LABD,
whereas others regard them as having a subset of EBA.
Further, the majority of EBA patients have low titer
IgA antibodies in their blood directed against type VII
collagen.
Childhood EBA is a rare disease. It has a variable
presentation, including an LABD-like disease, a BPlike disease, and the classic mechanobullous EBA presentation. Although mucosal involvement is frequent
and severe in childhood EBA, the overall prognosis is
more favorable than in adult EBA.
INCIDENCE OF THE CLINICAL

PRESENTATIONS OF EPIDERMOLYSIS
BULLOSA ACQUISITA
According to the authors experience, approximately
25% of patients with EBA may present with a BPlike clinical appearance. The disease of some of these
patients eventually smolders into a more noninflammatory mechanobullous form. However, both the classic and BP-like forms of the disease may coexist in the
same patient (Fig. 60-5). The clinical phenotype of EBA
that is reminiscent of pure CP occurs in fewer than 10%
of all EBA cases.

EBA patients may have many physical findings similar
to patients with hereditary dystrophic EB due to gene
defects in the type VII collagen gene. These include
oral erosions, esophageal strictures, hypo- and hyper-
HISTOPATHOLOGY
Routine histologic examination of lesional skin obtained
from EBA patients shows a subepidermal blister and a
clean separation between the epidermis and dermis.
The degree of inflammatory infiltrate within the dermis usually reflects the degree of inflammation of the
lesion observed by the clinician. Lesions that are reminiscent of recessive dystrophic EB or PCT usually have
a notable scarcity of inflammatory cells within the dermis. Lesions that are clinically reminiscent of BP usually
have significantly more inflammatory cells within the
dermis, and these cells may be a mixture of lymphocytes, monocytes, neutrophils, and eosinophils. The
histology of EBA skin specimens obtained from BP-like
lesions may be difficult to distinguish from BP itself.
IMMUNOFLUORESCENCE
Patients with EBA have IgG deposits within the DEJ of
their skin.3,19 This is best detected by DIF of a biopsy
specimen obtained from a perilesional site (Fig. 60-6).

IgG is the predominant immunoglobulin class, but
deposits of complement, IgA, IgM, factor B, and properdin also may be detected. The DIF staining demonstrates an intense linear fluorescent band at the DEJ.
Yaoita et al2 have suggested that a positive DIF and IgG
deposits within the sublamina densa zone are necessary criteria for the diagnosis of EBA.
Patients with PCT, which may mimic EBA clinically, frequently have IgG and complement deposits at
the DEJ similar to those of EBA patients (see Chapter
132). However, the DIF feature that distinguishes PCT
from EBA is that PCT skin also demonstrates immune
deposits around the dermal blood vessels.
Patients with EBA may have autoantibodies in their
blood directed against the DEJ.3 These antibodies can
be detected by IIF of the patients serum on a substrate
of monkey or rabbit esophagus or human skin and
stain the DEJ in a linear fashion that may be indistinguishable from BP sera.15
LABORATORY TESTS
::
pigmentation skin mottling, nail loss, milia formation,

scarring, and a degree of fibrosis of the hands.
A number of published reports suggest that EBA
may be associated with various systemic diseases24
such as inflammatory bowel disease, SLE, amyloidosis, thyroiditis, multiple endocrinopathy syndrome,
rheumatoid arthritis, pulmonary fibrosis, chronic
lymphocytic leukemia, thymoma, diabetes, multiple
myeloma, and other diseases in which an autoimmune
pathogenesis has been implicated. At the University of
North Carolina, University of Stanford, University of
Northwestern, and University of Southern California,
with a combined experience of following over 62 EBA
patients, it appears that inflammatory bowel disease is
the systemic disease most frequently associated with
EBA.
Figure 60-6 Direct immunofluorescence staining for immunoglobulin G deposits in perilesional skin of an epidermolysis bullosa acquisita patient. Note the dense deposits
within the dermalepidermal junction (the epidermis is on
top in this section).
Chapter 60
Figure 60-5 An epidermolysis bullosa acquisita patient

demonstrating two presentations of the disease: the
classic mechanobullous presentation with erosions, scarring, and milia over the elbows and the more inflammatory bullous pemphigoid-like lesions on her trunk.
IMMUNOELECTRON MICROSCOPY
The localization of the immune deposits within the
DEJ of the skin of EBA patients by immunoelectron
microscopy is the gold standard for the diagnosis.
As demonstrated by Nieboer et al25 and Yaoita et al,2
patients with EBA have immune deposits within the
sublamina densa zone of the cutaneous BMZ. This
localization is clearly distinct from the deposits in BP,
which are higher up in the hemidesmosome area or
lamina lucida area of the basement membrane. It is
also distinct from CP, which has antigenic targets confined to the lamina lucida (see Chapters 56 and 57).
INDIRECT SALT-SPLIT SKIN

IMMUNOFLUORESCENCE
When human skin is incubated in 1 M NaCl, the DEJ
fractures cleanly through the lamina lucida zone. This
639
fracture places the BP antigen on the epidermal side of

the split and all other basement membrane structures
on the dermal side of the separation. Salt-split skin
substrate can be used to distinguish EBA and BP sera.3
If the serum antibody is IgG and labels the epidermal
roof, the patient does not have EBA and BP should be
considered. If, on the other hand, the antibody labels
the dermal side of the separation, the patient usually
has either EBA or bullous SLE. The latter can be ruled
out by other serology and by clinical criteria.
DIRECT SALT-SPLIT SKIN

IMMUNOFLUORESCENCE
Section 8
::
Perilesional skin incubated in cold 1 M NaCl is fractured through the DEJ, which effectively places the BP
antigen (and any associated immune deposits) on the
epidermal roof and the EBA antigen (and any associated immune deposits) on the dermal floor of the
separation.19 If the patient has EBA, immune deposits
are detected on the dermal side of the separation by a
routine DIF method using fluorescein-conjugated antihuman IgG.
WESTERN IMMUNOBLOTTING
Antibodies in EBA sera bind to a 290-kDa band in Western blots of human skin basement membrane proteins
containing type VII collagen, whereas sera from all
other primary blistering diseases do not.3 This band is
the chain of type VII collagen. Often, a second band
of 145 kDa is labeled with EBA antibodies. This band is
the amino-terminal globular NC-1 domain of the type
VII collagen chain, which is rich in carbohydrate and
contains the antigenic epitopes of EBA autoantibodies,
bullous SLE autoantibodies, and monoclonal antibodies against type VII collagen.10
ENZYME-LINKED
IMMUNOSORBENT ASSAY
Chen et al26 have produced milligram quantities of
recombinant, purified, posttranslationally modified
NC-1 in stably transfected human cells and have used
this NC-1 to develop an ELISA for autoantibody detection in EBA patients and in patients with bullous SLE.
This new ELISA is more sensitive than immunofluorescence and Western blotting, and yet it is very specific for antibodies to type VII collagen.

Most Likely
Pseudoporphyria cutanea tarda
Bullous pemphigoid
Consider
Linear immunoglobulin A bullous disease
BrunstingPerry pemphigoid
Bullous systemic lupus erythematosus
and can be ruled out by a urine or plasma test for uroporphyrins. Pseudo-PCT, usually caused by drugs
such as nonsteroidal anti-inflammatory agents, can
look similar to EBA with skin fragility, erosions, and
blisters over trauma-prone areas, scarring, and milia
formation. Nevertheless, the DIF appears different in
that pseudo-PCT, like PCT, shows IgG deposits at both
the BMZ at the DEJ and around dermal blood vessels
(which are not stained in EBA).
The BP-like EBA can be eliminated by several methods listed above, but the first-line test would be indirect and direct salt-split immunofluorescence.
DIAGNOSIS
The diagnostic criteria developed by Yaoita et al2 for the
diagnosis of EBA still stand. These criteria, with slightly
updated modifications, are shown in Table 60-1.
Alternatives for the last item are indirect or direct
salt-split skin immunofluorescence, Western blotting,
and ELISA.
COMPLICATIONS
The complications caused by EBA include secondary skin infections, usually due to Staphylococcus or
TABLE 60-1
Diagnostic Criteria for Epidermolysis

Bullosa Acquisita
A bullous disorder within the clinical spectrum outlined
640
(Box 60-1)
Because EBA has been described in infants and children, it is worth considering that a patient thought to
have genetic dystrophic EB just might be a rare childhood patient with EBA. This can be ruled out by the
antibody tests outlined in Section Laboratory Tests.
PCT can look clinically very much like classic EBA
earlier (see Section Clinical Findings).
No family history of a bullous disorder.

Histology showing a subepidermal blister.
Deposition of immunoglobulin G deposits within
the dermalepidermal junction (i.e., a positive direct
immunofluorescence of perilesional skin).
Immunoglobulin G deposits localized to the lower lamina
densa and/or sublamina densa zone of the dermal
epidermal junction when perilesional skin is examined by
direct immunoelectron microscopy.
Streptococcus, because the blisters and erosions compromise the skins barrier. Scarring and milia formation
are naturally occurring complications or sequelae of
the deep blistering process. Severe EBA patients may
develop significant fibrosis of the hands with decreased
range of motion of the palm and digits. Because of
wounds and fibrosis of the soles of the feet and toes,
some EBA patients have difficulty walking. Many
patients with EBA lose their fingernails. EBA patients
with significant mucosal involvement may develop
esophageal strictures and even laryngeal scarring.
TREATMENT
Medication
a
Colchicine
Cyclosporine A
Dapsoneb
Cytoxan
Prednisonec
Intravenous
immunoglobulind
Infliximab
Dose Range
0.63.0 mg/day
6 mg/kg/day
100300 mg/day
50200 mg/day
1.01.5 mg/kg
3 g/kg divided over 5 days
5 mg/kg at 0, 2, 4, and 6 week
EBA patients plasma is useful for gaining control of

EBA patients similar to pemphigus patients. Given
that the autoantibodies are pathogenic, this is not surprising, but when plasmapheresis is performed it is
necessary to have the patient also treated with a chemotherapy agent (such as azathiaprine, cyclophosphamide, mycotile mofelate, methotrexate).
Intravenous Ig has been used in dermatomyositis,
an entity in which autoimmunity may play a role.
Intravenous Ig has been reported to be effective in
some patients with EBA.30 The mechanism by which
globulin may invoke a positive response in EBA is
unknown.
The anti-TNF- biologics (such as infliximab; see
Chapter 234) and anti-CD antibodies against B cells
have been tried in EBA with some success in limited
open trials. Box 60-2 outlines treatment options in EBA
that have some support in the medical literature.
Recently, anecdotal reports have also shown that,
riuximab, a monoclonal antibody to the CD20 receptor on B lymphocytes is effective in treating recalcitrant
patients with EBA.
::
Must start with 0.40.6 mg/day and each 12 week double this
dose as tolerated. When patient develops diarrhea, back off 1
tablet (0.40.6 mg).
b
Begin at 25 mg/day and double each week after the complete
blood count and liver function tests. Most patients need between 100250 mg/day. Increasing the dose slowly helps the
patient tolerate the anemia that develops (i.e., less orthostatic
light-headedness, etc.). Expect a 1- to 2-g drop in the patients
hemoglobin on therapeutic doses.
c
Usually does not help the classic, mechanobullous type of EBA
with minimal inflammation. However, it may be somewhat helpful in the bullous pemphigoid-like type of EBA.
d
Intravenous immunoglobulin is given over 45 days every
month for 5 or 6 months to give it an adequate trial.
Chapter 60
EBA usually responds poorly to treatment. Supportive therapy is warranted in all patients with EBA. This
includes instruction in open wound care and strategies
for avoiding trauma. Patients should be warned not to
over wash or overuse hot water or harsh soaps and to
avoid prolonged or vigorous rubbing of their skin with
a washcloth or towel. In some patients, it appears that
prolonged sun exposure may aggravate or promote new
lesions on the dorsal hands and knuckles. Thus, avoidance of prolonged sun exposure and the use of sunscreens are helpful. The patient should be educated to
recognize localized skin infections and to seek medical
care and antibiotic therapy promptly when they occur.
EBA patients are often refractory to high doses of
systemic glucocorticoids, azathioprine, methotrexate,
and cyclophosphamide, especially when they have
the classic mechanobullous form of the disease. These
agents may be somewhat helpful in controlling EBA
when it appears as an inflammatory BP-like disease.
Some EBA patients improve on dapsone, especially
when neutrophils are present in their dermal infiltrate.
Cyclosporine has been shown to be beneficial in
EBA.27 However, the long-term toxicity of this drug
limits its use.
There are also independent reports of EBA patients
responding to high doses of colchicine.28 This is often
used as a first-line drug because its side effects are
relatively benign compared with other therapeutic
choices. However, diarrhea is a common side effect of
colchicine, which makes it difficult for many patients
to achieve a high enough dose to control the disease.
Moreover, because of this side effect, we are hesitant to
use colchicine in EBA patients who also have inflammatory bowel disease. In addition, there are patients
who do not respond to colchicine. Colchicine is a wellknown microtubule inhibitor, but it also appears to
have properties that have the potential to inhibit antigen presentation to T cells, which could downregulate
autoimmunity.
Photopheresis has been used in Szary syndrome,
mycosis fungoides, and a variety of autoimmune
bullous diseases (see Chapter 238). Photopheresis
improves the clinical features of EBA and remarkably
lengthens the suction blistering times of the patients,
suggesting an improvement in their epidermal
dermal adherence.29
In addition to photopheresis, plasmapheresis and
removal of the antibodies to type VII collagen in an
Box 60-2 Treatments

for Epidermolysis Bullosa
Acquisita (EBA)
KEY REFERENCES
2. Yaoita H et al: Epidermolysis bullosa acquisita: Ultrastructural and immunological studies. J Invest Dermatol
76:288, 1981
641
Section 8
3. Woodley DT et al: Identification of the skin basement

membrane autoantigen in epidermolysis bullosa acquisita. N Engl J Med 310:1007, 1984
12. Gammon WR et al: Evidence that antibasement membrane zone antibodies in bullous eruption of systemic
lupus erythematosus recognize epidermolysis bullosa
acquisita autoantigens. J Invest Dermatol 84:472, 1985
13. Woodley DT et al: Evidence that anti-type VII collagen
antibodies are pathogenic and responsible for the clinical, histological, and immunological features of epidermolysis bullosa acquisita. J Invest Dermatol 124:958, 2005
14. Sitaru C et al: Induction of dermal-epidermal separation
in mice by passive transfer of antibodies specific to type
VII collagen. J Clin Invest 115:870, 2005
15. Woodley DT et al: Induction of epidermolysis bullosa
acquisita in mice by passive transfer of autoantibodies
from patients. J Invest Dermatol 126:1324, 2006
16. Sitaru C et al: Induction of complement fixing autoantibodies against type VII collagen results in subepidermal
blistering in mice. J Immunol 177:3461-3468, 2006
17. Mihai S et al: The alternative pathway of complement
activation is critical for blister induction in experimental epidermolysis bullosa acquisita. J Immunol 178:65146521, 2007
18. Chiriac MT et al: NADPH oxidase is required for neutrophil-dependent autoantibody-induced tissue damage. J
Pathol 212:56-65, 2007
20. Gammon WR et al: Epidermolysis bullosa acquisita: A
pemphigoid-like disease. J Am Acad Dermatol 11:820,
1984
25. Nieboer C et al: Epidermolysis bullosa acquisita: Immunofluorescence, electron microscopic and immunoelectron microscopic studies in four patients. Br J Dermatol
102:383, 1980
::
Chapter 61 :: Dermatitis Herpetiformis

:: Arash Ronaghy, Stephen I. Katz, &
Russell P. Hall III
DERMATITIS HERPETIFORMIS
AT A GLANCE
Intensely itchy, chronic papulovesicular
eruption distributed symmetrically on
extensor surfaces.
Characterized histologically by dermal
papillary collections of neutrophils
(microabscesses).
Granular immunoglobulin (Ig) A deposits
in normal-appearing skin are diagnostic for
dermatitis herpetiformis.
Most, if not all, dermatitis herpetiformis
patients have an associated gluten-sensitive
enteropathy.
The rash responds rapidly to dapsone
therapy and, in many patients, to strict
adherence to a gluten-free diet.
EPIDEMIOLOGY
642
Dermatitis herpetiformis (DH) is characterized by an

intensely itchy, chronic papulovesicular eruption that
usually is distributed symmetrically on extensor surfaces. The disease can be clearly distinguished from
other subepidermal blistering eruptions by histologic,
immunologic, and gastrointestinal criteria. The prevalence of DH in various Caucasian populations varies
between 10/100,000 and 39/100,000 persons.13 Some
reports suggests a 1.5:1 male to female ratio of DH
patients. It may start at any age, including childhood;
however, the second, third, and fourth decades are the
most common. After presentation, DH persists indefinitely in most patients, although with varying severity. Two long-term studies of immunologically verified
patients have suggested that the disease in approximately 1012% of DH patients eventually remits.4,5
Patients with DH have an associated glutensensitive enteropathy (GSE) that is usually asymptomatic.

In 1884, Louis Duhring first described the clinical features and natural history of a polymorphous pruritic
disorder that he called dermatitis herpetiformis; however, the critical elements in the pathogenesis of DH
remained unknown until the 1960s.6 In 1966, Marks et
al first noted a gastrointestinal abnormality in patients
with DH.7 Shortly thereafter, it was shown that the
lesion was reversible by avoidance of the dietary protein gluten.8,9 Initially, the intestinal abnormality was
thought to be present in 60%75% of DH patients.
However, this view has been modified in two ways.
First, the diagnostic criteria for DH have been delineated more precisely, and second, it can be shown
that certain patients without apparent gastrointestinal
pathology can be induced to develop gastrointestinal
lesions by subjecting them to a large gluten intake; such
patients have been said to have latent celiac sprue.10
::
Dermatitis Herpetiformis
antibodies against tissue Tgase are not significantly

different between children and adults with celiac disease.24 This observation has led to the hypothesis that
epitope spread over time results in the development
of IgA antiepidermal Tgases and that this late onset of
IgA antiepidermal Tgase antibodies may play a role in
the typical development of DH in the second to third
decade of life.24
The mechanism whereby the IgA antiepidermal
Tgases bind to skin in patients with DH is not fully
understood. One long-standing hypothesis has been
that IgA-containing circulating immune complexes
are responsible for the IgA deposits in DH skin. The
recent discovery of IgA antiepidermal Tgase antibodies has led to the suggestion that IgAepidermal
Tgase immune complexes may be depositing in the
skin of DH patients. However, only a minority of DH
patients have been found to have IgA and epidermal
tissue Tgase deposits colocalized in a perivascular pattern.22,25 In addition, perivascular neutrophil deposits
that are typically found with the perivascular deposition of immune complexes rarely occur in patients
with DH.26 These findings suggest an alternative
hypothesis that IgA antiepidermal Tgase may directly
bind in the skin to epidermal tissue Tgase. Direct
antigenantibody binding of IgA antiepidermal Tgases
to skin also appears unlikely to represent the complete
mechanism, since IgA deposits in DH skin cannot be
removed using typical techniques for eluting antibody bound directly to antigen. It is possible that the
IgA antiepidermal Tgases bind initially via antigen
antibody interactions and that ability of Tgases to
cross-link proteins results in the IgA cross-linking to
dermal proteins resulting in the stable, long-lasting
IgA deposits seen in the skin of patients with DH. This
hypothesis awaits confirmation.
Whether the IgA skin deposits play a role in the
pathophysiology of blister formation is not known.
The finding of IgA and complement in almost all skin
sites, not only in lesional skin, makes one postulate
that if IgA (either alone or as a part of an immune
complex) does play a role, additional factors are still
needed to explain the initiation of lesions. Takeuchi
et al have demonstrated that minor trauma to skin
results in increased expression of IL-8 and E-selectin,
both of which may predispose to a neutrophilic inflammatory infiltrate.27 These findings, coupled with the
typical appearance of DH lesions on extensor surfaces
at sites of trauma, suggest local cytokine/chemokine
production after trauma may be one of the inciting factors of DH skin lesions. It may be that after the initial
neutrophilic infiltrate binds to the cutaneous IgA, factors such as cytokines, chemokines, and proteases are
released that both directly result in blister formation
and induce basal keratinocytes to produce collagenases or stromelysin-1 that further contributes to the
formation of blisters.28,29 Other studies have suggested
that T cells may play a role in the pathogenesis of the
skin lesions; however, no specific T-cell responses to
gluten have been detected.30,31
It has been known for some time that iodides, administered orally, can exacerbate or elicit eruptions of DH,
and this has, in former times, been used for diagnostic
Chapter 61
Thus, most patients with DH have a gastrointestinal

abnormality similar (if not identical) to celiac disease,
however minimal that may be when the patient is
ingesting a normal gluten load. These studies have all
confirmed that gluten, a protein found in wheat, barley, and rye, plays a critical role in the pathogenesis
of DH. Oats, long thought to contain gluten and play
a role in inducing DH lesions, have been shown to be
devoid of toxicity in patients with DH.11,12 As in celiac
disease, there is an increased density of small bowel
intraepithelial T cells with a / T-cell receptor in the
jejunum of patients with DH.13 The finding that T-cell
lines from patients with DH produce significantly
more interleukin 4 (IL-4) than those from patients with
GSE and that gut biopsies from symptomatic patients
with isolated GSE showed increased expression of
interferon- suggests that different cytokine patterns
may play a role in the varied clinical manifestations
of these two diseases.14,15 Systemic evidence of the
gut mucosal immune response has also been found in
the serum and the skin of patients with DH. Patients
with DH on regular gluten-containing diets have been
found to have increased serum IL-2 receptor levels and
serum IL-8 levels, increased endothelial cell E-selectin
expression in skin, and an increased expression of
CD11b on circulating neutrophils.1618 These systemic
manifestations of the gut mucosal immune response
may play a role in creating the proinflammatory environment in the skin necessary for the development of
skin lesions. The GSE seen in DH patients probably
relates to the immunoglobulin (Ig) A deposits that are
found in the skin of these patients, although a direct
relationship has not been demonstrated. Patients with
a clinical picture consistent with DH and partial IgA
deficiency have been reported.19
In 1999, Dieterich et al identified antibodies to tissue transglutaminases (Tgases) in the sera from DH
patients.20 Distinguishing various types of Tgases
enabled Sardy et al in 2002 to demonstrate that epidermal Tgase is the dominant autoantigen in DH.21 This
was confirmed by a study of nine DH patients by Donaldson et al demonstrating that the dermal deposits of
epidermal Tgase colocalized with cutaneous deposits of IgA, in the papillary tips.22 Because epidermal
Tgases were strongly expressed in the upper epidermis, the authors suggested that in regions of trauma
they may diffuse through the basement membrane
after release from epidermal keratinocytes. Epidermal
Tgases were also found in uninvolved skin at least 5
cm away from the lesion suggesting additional factors
involved in the production of DH lesions.22
It is also known that patients with both GSE and
DH have circulating IgA antibodies directed against
Tgases.20,23 There appears to be a predilection for these
circulating IgA autoantibodies to bind to epidermal
Tgase in DH, whereas the predilection is for autoantibodies to bind tissue Tgase in patients with isolated
GSE.21 The precise role of the circulating IgA antiepidermal Tgase in the development of skin lesions in
patients with DH is not known. However, children
with celiac disease have lower levels of circulating
IgA antiepidermal Tgase when compared to adults
with celiac disease, whereas levels of circulating IgA
643
Section 8
purposes. The availability of immunopathologic techniques for the detection of IgA deposits in skin has
made such provocation tests obsolete.
The absence of animal models of DH, either naturally occurring or developed in the laboratory, has
limited advances in our understanding of the pathogenesis of DH. Recently, Marietta and coworkers
reported a new mouse model for DH. They reported
an HLA-DQ8 transgenic nonobese diabetic mouse that
when immunized with gluten developed neutrophilic
skin lesions along with cutaneous deposits of IgA.
In addition, withdrawal of dietary gluten resulted in
resolution of the skin lesions.32 Further investigation of
this mouse model may provide important information
regarding the pathogenesis of DH. Finally, there are a
few case reports describing the onset of DH with such
medication use as interferon, ribavirin, and gonadotropin-releasing hormone analog.33,34
::
644
CLINICAL FINDINGS
The primary lesion of DH is an erythematous papule,
an urticaria-like plaque, or, most commonly, a vesicle
(Figs. 61-161-3). Large bullae occur infrequently.
Vesicles, especially if they occur on the palms, may
be hemorrhagic. The continual appearance and disappearance of lesions may result in hyperpigmentation
and hypopigmentation. Patients may present with
only crusted lesions, and a thorough search may not
reveal a primary lesion. The herpetiform (herpes-like)
grouping of lesions is often present in some areas (see
Figure 61-1 Dermatitis herpetiformis. Extensive eruption

with grouped papules, vesicles, and crusts on the back.
Figure 61-2 Dermatitis herpetiformis. Papules, vesicles,

and crusts on knees.
Figs. 61-1 and 61-3), but patients also may have many
individual nongrouped lesions.
Symptoms vary considerably from the usually
severe burning and itching in most patients to the
almost complete lack of symptoms in a rare patient.
Most patients usually can predict the eruption of a
lesion as much as 812 hours before its appearance
because of localized stinging, burning, or itching.
The usual symmetric distribution of lesions on
elbows, knees, buttocks, shoulders, and sacral areas
is seen in most patients at one time or another (see
Figs. 61-161-4). Although these regions are affected
most commonly, most patients have scalp lesions
Figure 61-3 Dermatitis herpetiformis. This patient has

many firm-topped vesicles and bullae, some erosions,
and residual hyperpigmentation. Some of the vesicles are
arranged in an annular pattern.
Chapter 61
::
Figure 61-5 Dermatitis herpetiformis. Direct immunofluorescence showing granular dermal papillary deposits
of immunoglobulin A.
appearing skin near active lesions.43 In DH, other Igs

sometimes are bound to the skin in the same areas as
the IgA.40 IgA deposits also may be seen in the skin of
patients with bullous pemphigoid, scarring pemphigoid, HenochSchnlein purpura, and alcoholic liver
disease, although in different patterns of distribution
than those seen in DH.
Because of the IgA skin deposits and the association between DH and GSE (celiac disease), several
groups have studied the IgA subclasses in DH. IgA1 is
the predominant (or exclusive) subclass that has been
identified in the skin of DH patients.44,45 Most IgA1 is
produced in the bone marrow, whereas most IgA2 is
produced at mucosal sites. This does not negate the
possibility that the IgA1 in skin may still be of mucosal
origin because IgA1 is the predominant IgA subclass
of IgA antibodies directed against dietary proteins
produced in gut secretions in patients with DH. 46,47
Recently, Kantele et al reported a DH association with
an increase in circulating IgA1-plasmoblasts with skinhoming receptors (CLA) as compared to those with
IgA2.48
The third component of complement (C3) is frequently found in the same location as IgA. The presence of C3 in both perilesional and normal-appearing
skin is not affected by treatment with dapsone (diaminodiphenyl sulfone), but C3 may not be detectable
after treatment with a gluten-free diet.42,49,50 C5 and
components of the alternative complement pathway
also may be seen in areas corresponding to the IgA
deposits. The C5C9 membrane attack complex, which
645
Figure 61-4 Dermatitis herpetiformis. Pattern of distribution.

and/or lesions in the posterior nuchal area. Another
commonly affected area is the face and facial hairline.
Mucous membrane lesions are uncommon, as are
lesions on the palms and soles.
LABORATORY TESTS
IN VIVOBOUND IMMUNOGLOBULIN
A AND COMPLEMENT
After Cormane demonstrated that both perilesional
and uninvolved skin of patients with DH contained
granular Ig deposits located in dermal papillary tips,
van der Meer found that the most regularly detected
Ig class in DH skin was IgA (Fig. 61-5).35,36 Although
most patients have granular IgA deposits in their skin,
recent studies have suggested that a distinct fibrillar
pattern of IgA deposits can be found in some patients
with DH.37 The potential clinical significance of this
difference is not known. For the most part IgA deposits
have not been seen in the skin of patients with isolated
GSE (celiac disease).38 Recently, however, Cannistraci
and coworkers have used confocal microscopy and
reported faint colocalization of IgA and epidermal
Tgases in the papillary dermis and in a perivascular
distribution in the skin of patients with isolated GSE.39
The significance of these findings in the pathogenesis
of DH is not known.
Finding granular IgA deposits in normal-appearing
skin is the most reliable criterion for the diagnosis of
DH.26,40 These IgA deposits are unaffected by treatment
with drugs, but may decrease in intensity or disappear
after long-term adherence to a gluten-free diet.41,42 The
IgA deposits are not uniformly intense throughout
the skin and may be detected more easily in normal-
Section 8
is formed as the terminal event in complement activation, is also seen in normal-appearing and perilesional
skin of patients.51
The exact site of the IgA deposits in DH skin has
been studied by immunoelectron microscopy. Early
studies indicated that IgA is preferentially associated
with bundles of microfibrils and with anchoring fibrils
of the papillary dermis immediately below the basal
lamina.52,53 More recent studies, however, have indicated that some or almost all of the IgA deposits are
related to nonfibrillar components of skin and other
connective tissues.5355 There is also no agreement as
to whether the IgA deposits in DH colocalize to fibrillin, a major component of the elastic microfibrillar
bundles.55,56
SERUM STUDIES
::
Antireticulin antibodies of the IgA and IgG classes

have been detected in the sera of 17%93% of patients
with DH and in higher percentages of patients with
other diseases, especially celiac disease.57 Thyroid
microsomal antibodies and antinuclear antibodies
also have been detected in increased frequency in the
sera of patients with DH.58,59 Putative immune complexes have been detected in the sera of 25%40% of
patients.60,61
Chorzelski et al have described an IgA antibody that
binds to an intermyofibril substance (endomysium) of
smooth muscle.62 The nature of this antigen has been
identified recently by the studies of Sardy et al, who
showed that these IgA autoantibodies have specificity
for Tgases, particularly epidermis-specific Tgases.21
Although a majority of DH patients on gluten-containing diets have circulating antiepidermal Tgase
antibodies, a significant number of patients do not.24,63
Therefore, the presence of circulating antiepidermal
Tgase antibodies should probably not be considered as
a diagnostic test.
IMMUNOGENETIC FINDINGS
There is a marked increase in the incidence of certain
major histocompatibility complex antigens in patients
646
with DH. Worldwide studies have found that 77%

87% of DH patients have HLA-B8 (compared with
20%30% of unaffected individuals).6466 In addition,
the class II major histocompatibility complex antigens
HLA-DR and -DQ are associated with DH even more
frequently than is HLA-B8.67,68 Park et al reported that
more than 90% of patients expressed Te24, which was
later shown to be similar to HLA-DQw2, and this finding has been confirmed by others.69 Molecular studies indicate that susceptibility to DH is not associated
with a unique HLA-DQw2 molecule.70,71 Virtually all
patients with DH have genes that encode the HLADQ (1*0501, 1*02) or the HLA-DQ (1*03, 1*0302)
heterodimers, a pattern identical to that seen in celiac
disease.70,72 This strong association between susceptibility genes and DH and GSE is important clinically
and pathophysiologically in that there is a strong concordance of these two diseases in monozygotic twins.71
Furthermore, first-degree relatives of both DH and
GSE patients are often (4%5%) affected with one or
the other of these diseases.73
Nonmajor histocompatibility complex susceptibility
genes have been recently associated with DH. The *2
allele of the DNase-hypersensitivity region 1,2 of the
Ig heavy chain regulatory region has been found with
higher frequency in patients with DH.74
HISTOPATHOLOGY
The histology of an early skin lesion (clinically nonvesicular) is characterized by dermal papillary collections of neutrophils (microabscesses), neutrophilic
fragments, varying numbers of eosinophils, fibrin,
and, at times, separation of the papillary tips from the
overlying epidermis (Fig. 61-6). In addition, in such
early lesions, the upper and middle dermal blood
vessels are surrounded by a lymphohistiocytic infiltrate as well as some neutrophils and an occasional
eosinophil.75,76 At times, early lesions may be difficult or impossible to differentiate from those of linear
IgA disease (see Chapter 58), the bullous eruption of
lupus erythematosus (see Chapter 155), bullous pemphigoid (see Chapter 56), or the neutrophil-rich form
of epidermolysis bullosa acquisita (see Chapter 60).
The histology of older lesions shows subepidermal
Figure 61-6 Dermatitis herpetiformis. Biopsy of an early lesion showing dermal papillary collections of neutrophils and
eosinophils and subepidermal vesiculation at low (A) and high (B) magnification.
vesicles that may be impossible to differentiate from

other subepidermal bullous eruptions, such as bullous pemphigoid, erythema multiforme, bullous drug
eruption, and pemphigoid gestationis. Immunofluorescent localization and ultrastructural studies of the
site of blister formation in DH have demonstrated that
the blister forms above the lamina densawithin the
lamina lucida. This is thought to occur because the
lamina lucida is the most vulnerable component of
the dermalepidermal junction.77,78
ASSOCIATED PROBLEMS
Leonard et al have reported an increased frequency of

malignancies, especially gastrointestinal lymphomas,
and Collin et al have reported a significant increase
in non-Hodgkin lymphomas in patients with DH.81,82
A combined retrospective study from both these
groups suggests a protective role for a gluten-free diet
against gastrointestinal lymphomas.83 Hervonen and
coworkers reported that 1% of 1,104 patients with DH
developed a lymphoma from 2 to 31 years after the
diagnosis of DH.84 Of interest, only two lymphomas
were of the enteropathy-associated type, whereas eight
were B-cell type lymphomas and one was unclassified.
The patients with DH that developed lymphoma had
In addition to celiac disease, atrophic gastritis, and

pernicious anemia (see Section Gastrointestinal Manifestations), DH patients have a higher incidence of
other autoimmune diseases such as thyroid disease,
insulin-dependent diabetes, lupus erythematosus,
Sjgren syndrome, and vitiligo.58,87,88 This predilection
for associated autoimmune diseases may be due to the
high frequency of the 8.1 ancestral haplotype in these
DH patients.89
Neurologic disease has been reported in patients
with isolated celiac disease, including epilepsy, ataxia,
opsoclonus-myoclonus, and dementia; however, confirmation of these findings awaits confirmation with
large epidemiologic studies.90 Some authors have proposed that patients with DH may be at higher risk for
these neurologic complications due to long-standing
ingestion of gluten; however, Wills and coworkers
found no evidence of immune-mediated neurologic
disease in their evaluation of patients with DH.91,92
Patients with untreated celiac disease have also
been found to have an increased frequency of bone
loss.93 Patients with DH frequently continue on glutencontaining diets with a long-standing, albeit low
grade, malabsorption. Di Stefano demonstrated a significantly reduced bone mineral density in patients
with DH on gluten-containing diets.94 However,
recently Abuzakouk et al in a study of 25 DH patients
did not find evidence of bone disease or any relation
with bone mineral density and the severity of enteropathy.95 The authors suggest that the discrepancy
between their report and that of Di Stefano may be due
to the fact that in the latter study the DH patients were
newly diagnosed. These findings suggest that for now
patients with DH should be followed closely and those
on gluten-containing diets be screened for potential
decrease in bone density. If decreased bone mineral
density is found, patients should be encouraged to
begin a gluten-free diet.
MALIGNANCY
OTHER DISEASES
::
It is now well accepted that most, if not all, DH patients

have an associated gastrointestinal abnormality that
is caused by gluten sensitivity.18,9 The pathology of
the GSE associated with DH and that in isolated GSE
(GSE unassociated with DH) is essentially the same,
although the lesion in the latter is usually much more
severe; this applies to the epithelial cell derangement as well as to the character of the lymphoplasmacytic infiltrate. In addition, the distribution of the
gastrointestinal lesion in the small intestine is, as a
general rule, more widespread in celiac disease. The
functional changes in the bowel and clinical sequelae
encountered in the GSE associated with DH and those
encountered in celiac disease are similar but again differ in degree, those in the latter being more severe.
Thus, in DH one observes steatorrhea (20%30% of
patients), abnormal d-xylose absorption (10%33%
of patients), and occasional anemia secondary to iron
or folate deficiency. In patients not taking dapsone
or related drugs, the latter is usually due to malabsorption. Studies using elemental diets (see Section
Elemental and Other Diet Therapy) in the treatment
of DH have questioned the critical role attributed to
gluten in the pathogenesis of this disease. In addition
to the small intestinal lesion, patients with DH have
an increased incidence of achlorhydria and atrophic
gastritis.79,80 Reports of pernicious anemia and antibodies to gastric parietal cells are thus likely to be due
to more than chance.
Chapter 61
GASTROINTESTINAL
MANIFESTATIONS
adhered to a gluten-free diet less strictly than patients

without lymphoma.84 Recently, Viljamaa and coworkers reported on the rate of malignancies and mortality
in patients with DH with a 30-year population-based
study.85 They reported no difference in overall malignancy rate in patients with DH from the general
population; however, there was an increase in nonHodgkin lymphomas. Of interest, the mortality rate
for patients with DH was lower than in the general
population. Lewis et al utilized the General Practice
Research Database in the United Kingdom to study a
cohort of 846 DH patients and 4,225 matched controls.
They report no increased risk of malignancy in the DH
patients. The authors suggest a population bias of hospitalized patients in previous smaller studies resulted
in either differences in the degree of intestinal inflammation or unrelated illnesses increasing frequencies
of malignancy in the DH patients86 These most recent
studies suggest that patients with DH may not have an
increased risk of malignancy although further studies
are needed.
647

of Dermatitis Herpetiformis
Consider
Eczema
Atopic dermatitis
Papular urticaria
Neurotic excoriations
Bullous pemphigoid
Pemphigoid gestationis
Linear immunoglobulin A dermatosis
Atopic dermatitis
Section 8
::
648
Rule Out
Scabies
DH may be confused with numerous other conditions
because of its pleomorphic manifestations and the
occasional lack of diagnostic lesions (Box 61-1). Neurotic excoriations, eczema, papular urticaria, transient
acantholytic dermatosis, pemphigoid, pemphigoid
gestationis, erythema multiforme, and various other
dermatoses can be differentiated easily on the basis
of histologic and immunologic criteria. Linear IgA
disease may be more difficult to differentiate clinically and histologically, but it is distinctive immunologically. A high index of suspicion is very helpful in
that even in the absence of primary lesions, DH can be
diagnosed based on the typical in vivobound granular IgA deposits in normal-appearing skin.
TREATMENT
SULFONES
Diaminodiphenyl sulfone (dapsone), sulfoxone
(diasonenot available in the United States), and
sulfapyridine provide prompt improvement in symptoms and signs of the disease. Symptoms may abate in
as few as 3 hours or as long as a few days after the first
pill is taken, and new lesions no longer erupt after 12
days of treatment. Exacerbations occur from hours to
days after cessation of treatment. This response to therapy was, for a long time, the most important element
in making a diagnosis. The preferred treatment for an
adult is dapsone at an initial dosage of 100150 mg/
day (this usually can be taken once a day). An occasional patient may require 300400 mg of dapsone for
initial improvement. Patients should be instructed to
take the minimal dose required to suppress signs and
symptoms. Not all patients require daily treatment; in
rare cases, 25 mg weekly is sufficient. Sulfapyridine,
in a dosage of 1.01.5 g daily, is particularly useful in
patients intolerant of dapsone, in elderly patients, and
in those with cardiopulmonary problems. The pharmacology, mechanism(s) of action, adverse effects, and
monitoring of dapsone are discussed in Chapter 225. It

is important to know that nonsteroidal anti-inflammatory drugs often exacerbate DH, even in patients taking dapsone.96
GLUTEN-FREE DIET
EFFECT ON THE SMALL INTESTINE. There
is no doubt that the intestinal lesion in DH responds
to dietary gluten withdrawal. The time course of the
response in adults with DH is the same as that in
adults with celiac disease.
EFFECT ON THE SKIN DISEASE. Strict adherence to a gluten-free diet will, after variable periods of
time (from 5 months to 1 year), reduce or completely
eliminate the requirement for medication in most, but
not all, patients. The most extensive early study by Fry
et al has been confirmed by several groups.97 However, it is only the very highly motivated patient who
can adhere to the diet, which requires counseling by a
dietitian who is very familiar with its use.
ELEMENTAL AND OTHER
DIET THERAPY
Studies in small numbers of DH patients have indicated that elemental diets (composed of free amino
acids, short-chain polysaccharides, and small amounts
of triglycerides) can be very beneficial in alleviating
the skin disease within a few weeks.98,99 The beneficial
effect on the skin disease may be achieved even if the
patient ingests large amounts of gluten.98 Unfortunately, elemental diets are difficult to tolerate for long
periods. Interestingly, complete resolution of the skin
lesions of DH has also been reported by adherence to
the high-protein, unlimited fat, low-carbohydrate diet
popularized as the Atkins Diet.100 Further studies are
needed to confirm this report.
KEY REFERENCES
6. Duhring LA. Dermatitis herpetiformis. JAMA 3:225, 1893
7. Marks J, Shuster S, Watson AJ: Small bowel changes in
dermatitis herpetiformis. Lancet 1280-1282, 1966
9. Fry L et al: Effect of gluten free-diet on dermatological, intestinal and haematological manifestations of dermatitis
herpetiformis. Lancet 1:557-561, 1968
20. Dieterich W et al: Antibodies to tissue transglutaminase
as serologic markers in patients with dermatitis herpetiformis. J Invest Dermatol 113:133-136, 1999
21. Sardy M et al: Epidermal transglutaminase (TGase 3) is
the autoantigen of dermatitis herpetiformis. J Exp Med
195:747-757, 2002
32. Marietta E FAU - et al: A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. J
Clin Invest 114:1090-1097, 2004
35. van der Meer JB: Granular deposits of immunoglobulins
in the skin of patients with dermatitis herpetiformis : An
immunofluorescent study. Br J Dermatol 81:493-503, 1969
41. Leonard J et.al: Gluten challenge in dermatitis herpetiformis. N Engl J Med 308:816-819, 1983
64. Katz SI et al: HL-A8: A genetic link between dermatitis
herpetiformis and gluten-sensitive enteropathy. J Clin Invest 51:2977, 1972
85. Viljamaa M et al: Malignancy and mortality in patients
with coeliac disease and dermatitis herpetiformis: 30-year
population based study. Digestive and Liver Disease 38:374380, 2006
86. Lewis, NR et al: No increase in risk of fracture, malignancy or mortality in dermatitis herpetiformis: A cohort
study. Aliment Pharmacol Ther 27(11):1140-1147, 2008
97. Fry L et al: Clearance of skin lesions in dermatitis herpetiformis after gluten withdrawal. Lancet 1:288-291, 1973
98. Kadunce DP et al: The effect of an elemental diet with and
without gluten on disease activity in dermatitis herpetiformis. J Invest Dermatol 97:175-182, 1991
Blistering level categories: simplex,

junctional, and dystrophic subtypes
Cutaneous involvement varies from
localized to widespread blistering,
depending on subtype
Extracutaneous involvement varies from
none to severely debilitating or lethal
Oropharynx, trachea, esophagus, eyes, teeth,
nails, hair can be involved, depending on
subtype
Diagnosis is made by immunofluorescent
and/or electron microscopy followed by
DNA analysis
INTRODUCTION
Inherited epidermolysis bullosa (EB), is a family of diseases, with the common feature of blistering in response
to mild trauma. Patients with EB can show blistering in
the form of small vesicles or larger bullae, which can
occur on both the cutaneous surfaces as well as on the
mucosal tissues. The fragility of the skin and mucosa
and the traumatic production of painful blisters are
what all EB cases share in common. However, the distribution of the involvement, the depth of blister formation, any associated extracutaneous involvement and
the severity of the blistering process vary with the different EB subtypes and depend on the underlying heritable molecular defect. Different EB subtypes also vary
in the way in which blistered areas heal. The wound
Inherited Epidermolysis Bullosa
Family of inherited genodermatoses

characterized by blistering in response to
minor trauma
repair responses are often abnormal and can eventuate

into chronic erosions, hypertrophic granulation tissue,
scarring, or even invasive carcinoma. While the milder
EB subtypes are associated with a normal lifespan and
little or no internal involvement, the most severe recessively inherited forms are mutilating, multiorgan disorders that threaten both the quality and length of life.
A number of early studies identified the major subtypes of EB. Studies of von Hebra13 were the first to
distinguish pemphigus from inherited blistering and
the term epidermolysis bullosa hereditaria was first
suggested by Koebner.4 Hallopeau was the first to distinguish between simplex (nonscarring) and dystrophic (scarring) forms of the disease5 while Weber6 and
Cockayne,7 Dowling and Meara8 and Koebner4 each
described unique forms of epidermolysis bullosa simplex. Hoffman,9 Cockayne,10 Touraine,11 Pasini,12 and
Bart13 provided much of the information about subtypes
of dystrophic epidermolysis bullosa. Herlitz described
epidermolysis bullosa letalis,14 which was later found to
be a part of the third major category of epidermolysis
bullosa: the junctional form. The application of electron
microscopy toward diagnosis of epidermolysis bullosa
led to the studies of Pearson15 and collaborators who
classified the patients not only on the basis of clinical
findings but also on the existence of ultrastructural
changes. A comprehensive classification of epidermolysis bullosa based on a combination of ultrastructural
and clinical findings was completed in an early landmark treatise by Gedde-Dahl.16 Recent major advances
have led to the identification of protein and genetic
abnormalities in most types of epidermolysis bullosa
patients. These studies have led to an improved understanding of the biological basis of epidermolysis bullosa
and, finally, a classification of epidermolysis bullosa
based on genetic/protein defects, which provides a
rational approach to specific molecular therapy.
::
AT A GLANCE
Chapter 62
Chapter 62 :: Inherited Epidermolysis Bullosa

:: M. Peter Marinkovich

OVERVIEW
Epidermolysis bullosa arises from defects of attachment of basal keratinocytes to the underlying dermis.
649
Section 8
::
These defects can arise from inside the keratinocyte

plasma membrane or extracellularly in the dermal
epidermal basement membrane zone (BMZ). Many tissues such as the skin and cornea, which are subjected
to external disruptive forces, contain a complex BMZ
composed of a group of specialized components that
combine together to form anchoring complexes (Fig.
62-1). At the most superior aspect of the BMZ, keratin-containing intermediate filaments of the basal cell
cytoskeleton insert upon electron dense condensations
of the basal cell plasma membrane termed hemidesmosomes. Anchoring filaments span the lamina lucida
connecting hemidesmosomes with the lamina densa
and anchoring filaments. At the most inferior aspect
of the BMZ, collagen VII-containing anchoring fibrils
extend from the lamina densa into the papillary dermis and combine with the lamina densa and anchoring
plaques, trapping interstitial collagen fibrils. Thus, the
cutaneous BMZ connects the extensive basal cell cytoskeletal network with the abundant network of interstitial collagen fibrils in the dermis.17,18
KERATIN FILAMENTS
Keratins are obligate heteropolymers that are composed of pairs of acidic and basic monomers. The
keratin pair 5 and 14 assembles together to form the
extensive intermediate filament network of the basal
cell cytoskeleton.19 Keratins contain a central -helical
rod with several nonhelical interruptions as well as
nonhelical carboxyl and amino-terminal regions. The

regions of highest conservation between the keratins
are located on the ends of the keratin rod in the helix
boundary motifs. Extensive mutagenesis studies suggest that helical regions near the ends of the central rod
are important in keratin filament elongation, whereas
the nonhelical domains may be important in forming
lateral associations.20
HEMIDESMOSOMES
Hemidesmosomes contain intracellular proteins,
including plectin and BP230. Plectin is a 500-kDa protein, which acts as an intermediate filament-binding
protein. It is possible that plectin also interacts with
microfilaments, as plectin contains a domain with
similarity to the actin-binding domain of spectrin.21,22
BP230, also known as BPAG1, is a 230-kDa protein
which has homology both to desmoplakin23 and to
plectin. Several splicing variants of BP230 are of vital
importance in the nervous system.2426 BP230 localizes to a region referred to as the inner plate on the
cytoplasmic surface of the hemidesmosome and like
plectin, functions in the connection between hemidesmosomes and intermediate filaments. BP230 negative
transgenic mice lack a hemidesmosomal inner plate
and the connection between hemidesmosomes and
intermediate filaments is severed, creating a cytoplasmic zone of mechanical fragility just above the
hemidesmosomes.
Components of the dermal-epidermal basement membrane
Hemidesmosome
Keratin 5/14
Plectin
Intermediate
filaments
BP230
64
integrin
Hemidesmosome
Cell membrane
Collagen
XVII
Laminin-332/
laminin-311
Anchoring
filaments
Lamina densa
Lamina
densa
Collagen VII
Anchoring
fibrils
Interstitial
collagen fibrils
650
Figure 62-1 Schematic of the components of the dermalepidermal basement membrane (left) compared with ultrastructural appearance of basement membrane morphological entities (right).
ANCHORING FILAMENTS
Collagen VII is the major constituent of anchoring

fibrils. Analysis of the deduced amino acid sequence
of collagen VII59 reveals the presence of a long central
collagenous region characterized by repeating GlyXY
sequences that contains a number of noncollagenous
interruptions, including a 39 amino acid noncollagenous segment in the center of the helix which corresponds to the hinge region predicted by biochemical
studies.60,61 These interruptions account for the flexibility of the collagen VII molecule, and explain its
ability to loop around and entrap dermal matrix molecules, thus stabilizing the basement membrane to the
underlying papillary dermis.62 A 50 KDa component
of anchoring fibrils has also been identified which
appears to localize to the insertion sites of anchoring
fibrils to the lamina densa.63
The 145-kDa Nterminal end of collagen VII contains
the largest noncollagenous domain, which inserts onto
the lamina densa and anchoring plaques. Collagen
IV, the most abundant component of these structures,
binds to the collagen VII NC-1 domain. A direct interaction between anchoring filaments and anchoring fibrils
exists from a specific interaction between the anchoring filament component laminin-332 and the collagen
VII NC-1 domain.64,65 Collagen VII binds the 3 chain
on laminin-332.64,6668 This appears to be a critical factor in the maintenance of dermalepidermal cohesion.
Like all collagens, collagen VII assembles into a triple
helix. Only one gene and one chain of collagen VII, the
1 chain, have been identified, and thus collagen VII
is a homotrimer. Collagen VII triple helices are joined
together at their processed NC2 globular domains
to form antiparallel dimers.62,69 Processing of the NC-2
domains takes place via the same family of C-proteinases
(bone morphogenic protein 1 and/or mammalian tolloid) that are known to process laminin-332, a closely
associated molecule. Anchoring fibrils may derive from
lateral associations of collagen VII antiparallel dimers.
::
ANCHORING FIBRILS
Chapter 62
Hemidesmosomes also contain the transmembrane

proteins collagen XVII (also termed BPAG2 and
BP180)27 and 64 integrin.28 The cytoplasmic portions
of these molecules make up part of the hemidesmosome dense plaque. The extracellular portions of these
molecules make up portions of the anchoring filament
that probably contribute to the structure known as the
subbasal dense plate, which underlies hemidesmosomes in the lamina lucida region. 4 integrin only
pairs with the 6 subunit, whereas the 6 subunit
can combine either with the 4 integrin or with the
1 integrin. Both the 61 or 64 integrin combinations have been shown to act as receptors for laminins,
but only 64 integrin acts as a specific receptor for
laminin-332. 64 integrin plays a central role in organization of the hemidesmosome. The 4 integrin contains an especially large cytoplasmic domain, which
functions in the interaction with other proteins of the
hemidesmosomal plaque, including collagen XVII and
plectin.29 Skin from transgenic mice lacking 4 integrin
is devoid of hemidesmosomes and shows severe deficits in cell adhesion.30 Interactions between plectin and
64 integrin appear to be critical both in the assembly
as well as the disassembly of hemidesmosomes.31
Collagen XVII (BPAG2, BP180) is a collagenous protein with a type II transmembrane orientation. Based
on electron microscopy and cross-linking studies, collagen XVII assembles into a triple-helical homotrimer
and contains three main regions: (1) an intracellular
amino-terminal globular head, (2) a central rod, and
(3) an extracellular flexible tail.32 Collagen XVII associates with laminin-332 and 64 integrin in adhesion
structures termed stable anchoring contacts. These
stable anchoring contacts are formed by keratinocytes
in vivo, and are thought to represent prehemidesmosomes.33 The autoantigen in linear immunoglobulin
(Ig) A bullous dermatosis, LAD-134,35 is a 120-kD protein which has been shown by peptide sequencing to
be the cleaved exodomain of collagen XVII.36 Collagen
XVII undergoes processing in keratinocyte cultures
and in skin through the action of sheddases, membrane-associated proteases that solubilize cell surface
receptors.3739
In addition to 64 integrin and collagen XVII,
anchoring filaments contain the molecules laminin-332
and laminin-311. Like all members of the family of
laminin proteins,4042 laminin-332 is a large heterotrimeric molecule, and contains 3, 3, and 2 chains.43,44
The first laminins to be described contained three short
arms and one long arm, forming a cross shape as shown
by rotary shadowing analysis. In contrast, laminin-332
contains truncations of each short arm.4547 Because of
these short arm truncations, laminin-332 cannot selfpolymerize with other laminins or bind to nidogen.
Instead, laminin-332 forms a disulfide-bonded attachment to laminin-311,48 the other known anchoring filament laminin49 which contains 3, 1, and 1 chains.
Laminin-332 also undergoes processing of its 2 and
3 chains.50 While the rat laminin 2 chain has been
previously been shown to be processed by metallopro-
teinase-251 and membrane type metalloproteinase type

1,52 the predominant site of cleavage by these enzymes
is not conserved in human laminin-332.53 Other studies have shown that processing of laminin 2 chain
takes place through a special class of proteins termed
C-proteinases which also process C-terminal domains
of procollagen molecules.54 While one member of this
class of proteins, bone morphogenic protein 1,55 is
capable of performing this action, a splice variant of
bone morphogenic protein 1 (mammalian tolloid) is
predominantly expressed in keratinocytes and fibroblasts and thus likely performs this function in the
skin.53 Mammalian tolloid also processes the laminin
3 chain,53 although other enzymes such as plasmin,56
matrix metalloproteinase 251 or membrane type matrix
metalloproteinase 152 are also capable of this function. The 2 chain short arm appears important in the
assembly of laminin-332 into basement membrane.57
The antigen recognized by mAb 19-DEJ-158 also localizes to anchoring filaments but its molecular identity
remains unknown.
651
Comparison levels of skin separation in EB with clinical findings
EBS
Section 8
EBS
JEB
::
F
JEB
DEB
H
Figure 62-2 Comparison of levels of skin separation in EB with clinical findings. A. Transmission electron micrograph
showing typical intraepidermal separation in EBS. B. Palmar hyperkeratosis and erosions in EB herpetiformis. C. Radiograph showing pyloric atresia associated with EB. D. Localized blister on heel in EBS WeberCockayne. E. Transmission
electron micrograph showing typical separation at level of hemidesmosome in EB with pyloric atresia, alternatively classified as EBS or JEB. F. Nonscarring diffuse alopecia and scalp erosions in generalized atrophic benign epidermolysis bullosa.
G. Localized dystrophic changes with milia in dominant DEB. H. Transmission electron microscopy showing typical intralamina lucida separation in JEB. I. Transmission electron microscopy showing typical sublamina densa separation in
DEB. J. Pseudosyndactly in recessive DEB. K. Generalized blistering in Herlitz JEB. EBS = epidermolysis bullosa simplex;
DEB = dystrophic epidermolysis bullosa; JEB = junctional epidermolysis bullosa.
652
CLINICAL FINDINGS
EPIDERMOLYSIS BULLOSA SIMPLEX
Consider
Chronic bullous dermatosis of childhood
(linear IgA disease)
Bullous pemphigoid
Bullous systemic lupus erythematosus
Pemphigus vulgaris
group of suprabasal EBS subtypes. EBS is not usually

associated with growth retardation or anemia.
DOWLINGMEARA EBS. This subtype presents

at birth, has a generalized distribution and is regarded
Always Rule Out

::
Epidermolysis bullosa simplex (EBS) is a disease

group characterized by intraepidermal blistering and
most often is associated with keratin gene mutations.
The disease phenotypes range from mild to severe
among different subgroups.72 The common EBS types
are dominantly inherited and include DowlingMeara
(Herpetiformis) EBS, generalized (Koebner) EBS, and
localized (WeberCockayne) EBS. There are several
uncommon varieties that include EBS Ogna, EBS with
muscular dystrophy, EBS with mottled pigmentation,
EBS associated with BP230/BPAG1 mutation, and a
Most Likely
Pompholyx
Insect bites
Friction blisters
Thermal burns
Bullous impetigo
Chapter 62
Epidermolysis bullosa has been traditionally classified

according to the level of BMZ separation on transmission electron microscopy into simplex, junctional and
dystrophic subtypes,70 (Fig. 62-2). Although this ultrastructural gold standard for diagnostic grouping of
EB has been electron microscopy, immunomapping of
basement membrane antigens as viewed by indirect
immunofluorescence can also be quite useful in distinguishing subtypes of EB as well as from other disorders
in the differential (see Box 62-1) and is considerably less
labor intensive. Within each of these groups there are
several distinct types of EB based on clinical, genetic,
histologic, and biochemical evaluation.71 These findings are summarized below (Table 60-1).

of Epidermolysis Bullosa
TABLE 62-1
Classification of Epidermolysis Bullosa

Level of Separation
Disease
Defect
Simplex
Generalized
KRT5/KRT14
Simplex
DowlingMeara
KRT5/KRT14
Simplex
Localized
KRT5/KRT14
Simplex
Ogna
KRT5/KRT14/PLEC1
Simplex
Mottled pigmentation
KRT5/KRT14
Simplex
EB with muscular dystrophy
PLEC1
Simplex
Superficialis
KRT5/KRT14
Simplex
Ectodermal dysplasia-skin fragility
PKP1
Junctional
EB with pyloric atresias
ITGB4/ITGA6/PLEC1
Junctional
Herlitz
LAMB3/LAMA3/LAM2
Junctional
Non-Herlitz
LAMB3/LAMA3/LAMG2/COL17A1
Junctional
Localized
COL17A1
Dystrophic
Generalized dominant
COL7A1
Dystrophic
Localized dominant
COL7A1
Dystrophic
Recessive
COL7A1
Variable
Kindler syndrome
KIND1
Alternatively classified as simplex.
653
Section 8
Figure 62-3 Characteristic blister formation on trunk and

arm in patient with DowlingMeara EBS.
::
as the most severe of the EBS subtypes (Fig. 62-3).

However, it differs from the Koebner variant in that
the oral mucosa is more often involved, occasionally
showing extensive erosions. Milium formation may
sometimes occur in infancy in patients with this subtype; however, this postwound phenomenon usually
resolves after infancy. The disease can often be associated with spontaneous appearance of grouped or
herpetiform blisters. These occur on the trunk and
proximal extremities and heal without scarring. It
should be noted that this herpetiform pattern may not
be seen when patients show a generalized blistering.
Therefore, its absence should not be used as a basis to
exclude this EB subtype. DowlingMeara EBS often
shows nail involvement, with shedding and regrowth
with dystrophy or long nails with subungual hyperkeratosis. Hyperkeratosis of the palms and soles often
develops beginning in early childhood and can progress to confluent keratoderma of the palms and soles.
These can be quite painful and, occasionally, interference with ambulation has led to flexural contractures.
Esophageal involvement in DowlingMeara has occasionally been reported, and ranges ranging from erosions to pyloric atresia.73 The upper respiratory tract
can also be affected, including the laryngeal mucosa.74
Natal teeth have been described.
Figure 62-4 Widespread blistering in an infant with generalized EBS.

of EB and often presents during infancy or childhood.
Occasionally, it presents in early adulthood, such as
when blisters are noted following marching during
military service. It is speculated that there are a number of undiagnosed cases of this form of EB, as it can be
mild enough to escape reporting or detection during
clinical visits. Hyperhidrosis of the palms and soles is a
common association. Blisters can occasionally become
secondarily infected. Postinflammatory pigmentary
abnormalities occur with this variant, but milia and
scarring as a rule are absent. Blistering activity usually
follows areas of trauma, with hands and feet being the
most common and the scalp being the least common.
Mild oral erosions are present only rarely and usually
GENERALIZED EBS. The other common form of

generalized EBS is also known as the Koebner EBS.
This subtype shows an onset of generalized blistering
at birth or at latest during early infancy. The hands,
feet, and extremities usually show the most involvement. Lesions often heal with postinflammatory
hyper- or hypopigmentation. Atrophy and milia can
occur, but are much less frequent than in Dowling
Meara EBS. Palmoplantar hyperkeratosis and erosions
may be present (Fig. 62-4). Thickening of the soles is
common, but often does not present until later childhood. The oral mucosa sometimes shows mild erosive
activity but these usually improve with increasing age.
654
LOCALIZED EBS. This is the mildest form of EB and

is often referred to as the WeberCockayne subtype of
EBS (Fig. 62-5). This disease is the most common form
Figure 62-5 Trauma-induced blistering from clothing in

patient with localized EBS.
resolve with increasing age. Nail involvement is rare

with this EB subtype.
ADDITIONAL VARIANTS OF EBS

EBS of Ogna. Onset in infancy is common
with
seasonal blistering (summer) on the acral areas. Small
hemorrhagic and serous blisters occur primarily on the
extremities. Healing occurs without scarring. This disease was originally reported in patients from Norway.
These patients also show a characteristic onychogryphosis of the great toenails.
uncommon form of EBS, named after the subcorneal

separation that produces the blisters in this disease.80
Erosions and crusts, rather than intact bullae, are usually seen in these patients, and heal with postinflammatory pigmentary changes. Despite the superficial
cleavage plane, nail involvement. Atrophic scarring
and milia have been observed in this disease.
Lethal acantholytic EBS81 is a rare recessively inherited and lethal disorder characterized by generalized
erosions at birth. As in the superficialis subtype, intact
blisters are not normally seen, due to the very superficial level of epidermal separation, which appears
sheet-like. Nails are dystrophic to absent. Complete
alopecia, neonatal teeth, oral erosions, and respiratory involvement distinguish this disorder from other
superficial EBS subtypes.
Ectodermal dysplasia skin fragility syndrome is another
inherited disorder of suprabasilar epidermal separation, characterized by generalized erosions and
sometimes superficial blisters at birth.82 Alopecia is
characteristic, as are palmoplantar keratoderma, painful fissures and nail dystrophy. Patients may sometimes
demonstrate failure to thrive, cheilitis, hypohidrosis,
and pruritus as well. Like the other superficial EBS
subtypes, this disorder is associated with dystrophic
nails.
Suprabasal EBS Subtypes. EBS superficialis is an
::
EBS with Mottled Pigmentation. This form

of EB, as its name implies, is characterized by mottled
hyperpigmentation of the trunk and proximal extremities. Blistering tends to be mild, and begins at birth or
early infancy. Pigmentary alterations appear reticulated and increase with advancing age, as blistering
may improve. Mild oral mucosal involvement may be
present in infancy. This progressive pigmentation is
distinct from the large melanocytic nevi, which can be
seen in all three EB types.79
Most of
the patients with EB simplex analyzed at the genetic
level have been found to be associated with mutations of the genes coding for keratins 5 and 14.20,72 The
level of separation of the skin in these patients is at the
midbasal cell, shown in Fig. 62-2A, associated with
variable intermediate filament clumping. Hemidesmosomes and other BMZ structures are normal by
electron microscopy. The majority of keratin gene
mutations associated with epidermolysis bullosa simplex are dominantly inherited due to abnormalities in
the multimeric assembly of keratin filaments. There is
a smaller subset of patients with recessively inherited
disease of varying severity.83,84
Mutations coding for the most highly conserved
regions of keratins 5 and 14, the helix boundary
domains,85 correlate with the most severe form of EBS,
the DowlingMeara subtype, which exhibits intermediate filament clumping seen by transmission electron
microscopy. On the other hand, milder types of disease, such as the WeberCockayne subtype, are associated with mutations coding for regions of keratins
5 and 14 that are less conserved. Mutations that code
for a specific region of the amino-terminus of keratin 5 are present in patients having EBS with mottled
pigmentation.86 Although significance of this type of
mutation and its association with pigmentary abnormalities remains unclear,87,88 it has been suggested that
the keratin 5 globular head domain is responsible for
keratin filament insertion onto melanosomes. Recent
studies have shown that some mutations of the keratin
5 gene may produce protein which is unstable under
increased temperatures.89 This could help to explain
the well-observed exacerbation of some subtypes of
EBS to warm temperatures.
The mutations associated with EBS with muscular
dystrophy produce premature termination codons,
splice site, or other mutations which result in lack
of expression or defective expression of plectin.90
Although the form of EB associated with plectin abnormalities is classified as simplex, it has an identical level
of skin separation to that seen in junctional epidermolysis bullosa (JEB) with pyloric atresia. Specifically
the separation is present just above the level of the
hemidesmosome in the intracellular part of the BMZ.
This separation of EBS with muscular dystrophy and
JEB with pyloric atresia, diseases with identical levels
of separation, into two distinct EB categories illustrates
the limitations of the current EB classification system.
Plectin defects, like 64 integrin defects, can also be
associated with pyloric atresia.90
Plectin is normally expressed in a wide range of
tissues, including muscle.21 While the mechanism of
muscular dystrophy in plectin-deficient patients is
unknown, it has been observed that disorganization of
muscle sarcomeres occurs in the absence of plectin. It is
possible that absence of plectins spectrin-like domain,
which may normally interact with actin filaments in
muscle, may be a key factor in the muscle pathology.91
Interestingly, a case report of autosomal recessive EBS
has been recently identified to be associated with both
muscular dystrophy and pyloric atresia.92 This case
Chapter 62
EBS with Muscular Dystrophy. This rare clinical entity is an autosomal recessive disorder which
consists of generalized blistering of the skin at birth or
shortly thereafter. This is accompanied by a progressive muscular dystrophy.75 It presents with generalized
blistering similar to EBS of Koebner clinically. These
patients have been shown to harbor mutations in the
gene coding for HD1/plectin.7678 Mutations in plectin
can also cause EB with pyloric atresia (see Junctional
EB with Pyloric Atresia) and be difficult to distinguish
clinically from disease resulting from integrin mutations.
MOLECULAR PATHOLOGY OF EBS.
655
Section 8
::
656
was associated with homozygous premature termination codon mutations in the plectin gene causing a significant loss of plectin expression in the skin.92
Recently, another unique case of recessive dominant
EBS has been identified, this one associated with null
mutations of the dystonin gene coding for BP230/
BPAG1.93 Inherited blistering/skin fragility described
with this defect was associated ultrastructurally by loss
of hemidesmosomal inner dense plate and a concomitant reduction of other hemidesmosomal proteins, presumably by loss of BP230 stabilization. This patients
blistering was also accompanied by a neuropathy,
which may be part of the inherited defect, since a splice
variant of this molecule has a neural distribution.
The underlying molecular defect of ectodermal dysplasia skin fragility syndrome has been shown to be
loss of function of the desmosomal protein plakophilin
1, encoded by PKP1.94,95100 Plakophilin is expressed
mainly in suprabasilar keratinocytes and outer root
sheath cells. Microscopic findings in this disease are
usually intraepidermal acantholysis, located in the
areas where plakophilin 1 is normally expressed.
JUNCTIONAL EB
All patients with JEB share the common histopathologic feature of blister formation within the lamina
lucida of the BMZ due to defects of anchoring filaments located in the lamina lucida and superior lamina
densa. This group of diseases is inherited in an autosomal recessive manner and there is considerable variation of the individual clinical phenotypes depending
on the molecular defect. Three principal forms of JEB
are most common. Herlitz disease, JEB gravis or lethal
JEB are each used to describe patients presenting with
the most severe and most common phenotype.14,101
HERLITZ JEB. Patients with Herlitz JEB, also known

as JEB letalis, is one of the most severe EB subtypes
and is lethal in most affected children during infancy
or early childhood.102 This disorder is characterized
by generalized and often extensive blistering at birth
(Fig. 62-6). Later during infancy, a distinctive periori-
Figure 62-6 Widespread blistering at birth in an infant

with Herlitz JEB.
ficial granulation tissue begins to manifest, primarily

around the mouth, eyes, and nares. The scalp, periauricular areas and, less frequently, locations outside of
the head and neck may also be affected. This hypertrophic granulation tissue much less commonly occurs in
nonlethal subtypes. Nails are usually severely affected
and often are lost during infancy. The presence of nail
involvement with periungual hypertrophic granulation tissue during the neonatal period can be a clue
to this diagnosis. When nails are still present, they are
usually dystrophic. Tooth enamel pitting is characteristic in both primary and secondary teeth, and can
progress after tooth eruption. Oropharyngeal mucosal erosions are usually present and may be widespread. Erosions of all stratified squamous epithelial
tissues, including nasal, conjunctival, esophageal,
tracheal, laryngeal, rectal, and urethral mucosa can be
affected. Associated systemic findings in severe cases
are important factors in the lethality of this disease.
Involvement of the large airways, including tracheolaryngeal stenosis or obstruction, is commonly associated with Herlitz JEB disease and hoarseness in early
infancy is an ominous sign. There is a characteristic
failure to thrive and growth retardation in this disease, often with a mixed anemia. Sepsis is a common
and often lethal complication.
NON-HERLITZ JEB. (Figs. 62-7 and 62-8). Sometimes patients initially presenting with a Herlitzlike phenotype will survive infancy and clinically
improve with age. These patients eventually prove
to have a severity of blistering and oral erosions less
than in the lethal form. In particular, a lack of significant hoarseness is regarded as a favorable prognostic
sign, indicative of less severe internal disease manifestations. Scalp and nail lesions, as well as periorificial nonhealing erosions with exuberant granulation
tissue are among the most common findings in these
patients during childhood. Despite the lack of lethality
in infancy, these patients nonetheless can have severe
epithelial adhesion abnormalities. Tracheostomies or
gastrostomy tubes may help in patient survival. The
Figure 62-7 Periorificial erosions and hypertrohic granulation tissue in a patient with non-Herlitz JEB.
patchy hair loss associated with atrophic scarring has

been described, often the alopecia is quite diffuse and
scarring is subtle or nonexistent.
LOCALIZED JEB. A very rare subtype of JEB is the

localized variant, also known as minimus JEB. These
patients generally show mild disease that can be
accentuated in localized areas, most often the hands,
feet and pretibial regions. Nails can sometimes be shed
or become dystrophic, and enamel pitting can occur.
Oral or nasal erosions can also occur; however, there
is absence of any internal involvement. These patients
generally have a favorable prognosis and a normal
lifespan.
MOLECULAR PATHOLOGY OF JEB. JEB can

be associated with mutations of the genes coding for
any of the 3, 3, or 2 subunits of laminin-332.110,111
Absence of any of the three chains results in a lack of
trimeric laminin-332 assembly and secretion, which
results in a similar blistering phenotype. Patients with
mutations of genes coding for the 3 or 2 laminin subunits will still show normal expression of laminin-311,
which contains 3, 1, and 1 chains.44 Therefore, positive linear BMZ staining of JEB skin for the 3 chain
on immunofluorescence mapping studies with absent
expression of the other chains is an indication of either
a 3 or 2 chain defect. Conversely, absence of 3
staining on immunofluorescence can be indicative of
a mutation of the a3 gene. About 80% of laminin-332
mutations can be traced to one of two recurrent nonsense mutations in the LAMB3 gene, making prenatal
testing for laminin-332 lesions easier than other EB
candidate genes.112 In the Herlitz patients, all of the
mutations so far detected have been those producing
::
nonlethal status of these patients distinguishes them

from the Herlitz group and the terms nonlethal JEB or
JEB mitis have been used in the past to describe these
patients. They are much less common than Herlitz EB
patients. There are other rare variants of nonlethal JEB
that present with localized junctional blistering of the
extremities or intertriginous areas.
Interestingly, the association of hypertrophic granulation tissue and laminin-332 defects has been noted in
another group of patients with mutations of the laminin
3 (LAMA3) gene leading to a small truncation of the
N-terminal IIIa domain of the laminin 3 chain. This
disease, termed laryngo-onycho-cutaneous syndrome,
is characterized by a triad of cutaneous erosions, nail
dystrophy, and exuberant mucocutaneous granulation
tissue, especially in the conjunctiva and larynx.103 An
experimental animal model of engineered laminin-332
deletions has been recently described which recapitulates this hypergranulation tissue phenotype.104
Generalized atrophic benign EB (GABEB) is a distinct subset of non-Herlitz JEB that also presents at
birth with generalized cutaneous involvement.105
Despite the widespread cutaneous blistering, there is
a relative paucity of oral erosions or other mucosal
disease. While enamel pitting is present, resulting in
extensive dental caries, and nail dystrophy can often
be severe, there is little other extracutaenous involvement noted in these patients. The blisters in these
patients, which heal with a characteristic atrophic scarring, are debilitating and can be widespread, but nonetheless these patients generally have a normal lifespan.
Blistering improves with age, growth is normal and
anemia is uncommon. Some patients with this disease
have undergone normal uncomplicated pregnancies
and deliveries. One peculiar characteristic of these
patients is a progressive alopecia of the scalp and terminal hairs elsewhere in the body. The hair loss starts
to become severe after the onset of puberty. While
Chapter 62
Figure 62-8 Loss of nails and skin atrophy a patient with

non-Herlitz JEB/generalized atrophic benign EB.
JEB WITH PYLORIC ATRESIA. These patients

exhibit extreme mucosal and cutaneous fragility
and may also have various urological abnormalities,
including hydronephrosis, and nephritis, and rudimentary ears. Mutations of the genes coding for the 4
and 6 integrin are associated with EB106 and in which
pyloric atresia. Plectin mutations can also be associated
with EB and pyloric atresia, although the the integrin
mutations are more reliably associated with pyloric
atresia. In these patients, hemidesmosomes are usually absent or rudimentary, and the level of separation
is intraepidermal at the level of the hemidesmosome
as seen in EBS with muscular dystrophy described
above. The skin ultrastructure in patients with 64
defects is remarkably similar to the 4 integrin knockout mice described above; however, the mice do not
show pyloric atresia. These studies illustrate well that
there are limitations in the utility of animal models to
study human epidermolysis bullosa. Most cases of this
disease are quite severe and lethal in infancy, due to
extensive extracutaneous epithelial sloughing, in addition to widespread blistering of the skin and mucosa.
Rare nonlethal cases of this disease have been characterized which appear to result from a partial loss of
function of 4 integrin.107 Interestingly, nonlethal JEB
can sometimes ameliorate itself through alterations in
mRNA splicing.108,109
657
Section 8
::
premature termination codons, resulting in absence of

expression of laminin-332. While Herlitz cases generally show a complete lack of expression of laminin-332,
non-Herlitz patients with abnormal granulation tissue and significant mucosal involvement often show
reduced expression of laminin-332. This is due to deletions or missense mutations that result in partial loss of
laminin-332 function.113115 In some cases, spontaneous
amelioration of blistering in severe junctional epidermolysis bullosa cases has taken place, leading to the
expression of laminin-332.109
In the GABEB variant of non-Herlitz JEB, blistering
occurs in the lamina lucida region and abnormalities
of hemidesmosomes/anchoring filaments are usually present (Fig. 62-3). While laminin-332 mutations
underlie a subset of GABEB patients, the majority of
these patients have abnormalities of the hemidesmosomal protein collagen XVII (also known as BP180 or
BPAG2). A number of mutations of the gene coding for
collagen XVII have been described in GABEB patients,
including premature termination codon mutations,
missense mutations, splice site mutations, truncations,
and a glycine substitution mutation.111,116 While intralamina lucida/junctional skin separation has been
shown in all patients with this disease, one patient was
described with a cytoplasmic deletion of collagen XVII
who showed intrabasal epidermal skin separation.117
Localized junctional EB has been shown to be associated with COL17A1 mutations.118
Of interest, mosaic GABEB patients have been identified who demonstrate well-defined areas of blistering
associated with absence of collagen XVII expression as
well as areas of nonblistering skin associated with normal collagen XVII expression. Careful analysis of these
patients keratinocytes revealed reversion of one of the
two alleles of the mutation, most likely due to a mitotic
gene conversion involving nonreciprocal exchange of
parental allele DNA.119,120 It is possible that this phenomenon of mutational rescue of genes affecting recessive cases of EB is more widespread that currently
reported and more careful examination of involved
and uninvolved regions of EB skin undoubtedly will
reveal more cases. Understanding how epidermolysis
bullosa can undergo spontaneous molecular correction
(revertant mosaicism) in these cases could help in the
design of future molecular therapeutic strategies.
DYSTROPHIC EB
Dystrophic EB (DEB) is characterized by blisters that
heal with scarring and milium formation. DEB can be
inherited either in an autosomal recessive (RDEB) or
dominant fashion (DDEB). One of the most important
reasons to distinguish between these two subtypes is the
increased prevalence of invasive squamous carcinoma
associated primarily with the recessive form. Regardless
of the mode of inheritance, DEB is derived from defects
of the ultrastructural entity known as the anchoring
fibril, which results in sublamina densa separation.
658
LOCALIZED DDEB. The localized subtype of dominant DDEB (sometimes called the CockayneTouraine
Figure 62-9 Localized trauma-induced blistering with

secondary milia in a patient with dominant DEB.
of DDEB) can present at birth, but occasionally it is not

appreciated until childhood. While generalized blistering can take place especially early in life, the blistering
usually becomes localized to repetitively traumatized
areas such as knees, sacrum, and acral surfaces (Fig.
62-9). These areas show a characteristic scarred, dystrophic appearance. Often the scarring is hypertrophic.
Milia are common accompanying features of the healing process in these patients. Nail dystrophy or nail loss
with atrophic scarring of the distal digits are common.
Occasionally, nail abnormalities can be the only presenting abnormality in DDEB. Oral lesions are not common and teeth are usually unaffected. These patients
have a good prognosis and a normal lifespan.
GENERALIZED DDEB. The generalized form of

DDEB (sometimes referred to as the Pasini subtype of
DDEB) presents at birth with a generally more severe
and widespread blistering phenotype compared to the
localized subtype. Blisters in generalized DDEB heal
with scarring plaques and milia, in a fashion similar to
other DEB subtypes. In addition, this disease is sometimes distinguished by the spontaneous appearance of
distinctive scar-like flesh colored papules on the trunk.
These albopapuloid lesions are not pathognomonic,
and can also be seen in other EB subtypes. As the
patients get older the generalized blistering may eventually localize to the extremities. Patients often show
dystrophic or absent nails. Oral erosions can often be
present, but usually are not extensive, and enamel
defects can be seen in some patients. A rare variant of
self-remitting generalized DDEB, termed bullous dermolysis of the newborn, consists of generalized blistering that gradually recedes after infancy.121
RECESSIVE DEB. Recessive DEB (RDEB) can be
quite variable in its severity. While the severe subtype
is the most common, a localized form can occasionally
be seen which has been termed RDEB mitis. Similar
to localized DDEB, localized RDEB is usually confined
to repetitively traumatized skin surfaces, most often in
an acral distribution. Scarring and milium formation
Figure 62-10 Widespread blistering with localized

absence of skin at birth in a patient with recessive DEB.
::
Figure 62-11 Oral erosions in a patient with dominant

DEB.
MOLECULAR PATHOLOGY OF DEB. Abnormalities of anchoring fibrils are present in DEB

patients, ranging from subtle changes in some patients
with dominant disease, to absence of anchoring fibrils
in patients with RDEB. A sublamina densa plane of
blister cleavage is present in all dystrophic blistering
(Fig. 62-3). These observations correlate with immunofluorescent microscopic analysis of DEB patients,
which demonstrates varying degrees of linear basement membrane staining in dominant patients and
total absence of staining in severe recessive patients.
In some patients, there is cytoplasmic retention of collagen VII in patient keratinocytes.122
Dystrophic EB has been shown to be associated in
all cases thus far with mutations of the gene coding for
collagen VII (COL7A1). In the recessive forms, mutations usually cause premature termination codons,
leading to lack of collagen VII in tissue. It is known
that mRNAs bearing premature stop codons show
accelerated turnover.123 In addition, truncated proteins
that are not secreted or not assembled into anchoring fibrils may also show accelerated turnover. Either
or both of these mechanisms can explain the lack of
detectable collagen VII in the tissue of individuals with
severe RDEB whose mutations lead to premature termination.62,124,125 Recently, a revertant mosaicism phenotype has also been reported in RDEB.126
Generally, COL7A1 mutations that do not cause
premature termination codons produce less severe
disease.110,116 In particular, mutations which produce
glycine substitutions of the triple helical region interfere with triple helical assembly of the collagen VII
molecule. These types of mutations are present in
many patients with milder dominant forms of this disease. In these patients, collagen VII molecules may not
be able to assume the proper conformation needed to
polymerize into anchoring fibrils. One subtype of DEB
Chapter 62
accompany the healing of blisters. Mucosal involvement in localized RDEB, if present, is mild.
Severe RDEB, also known by the eponym the
HallopeauSiemens, is a devastating disease (Fig.
62-10). This disease presents with generalized blistering at birth. Occasionally, there is extensive denudation
of an entire region of skin at birth, often involving one
of the limbs. This congenital absence of skin is sometimes termed Barts syndrome, and has been described
with all three major subtypes of EB. In RDEB, healing
and blistering cycles occurring during infancy can
lead to a progressive scarring which can become quite
extensive. Pseudosyndactyly, resulting from a closure
of the digits in a mitten of skin, is extremely common in this disease (Fig. 62-2J). Scarring can lead to
flexion contracture of the hands, as well as the limbs.
In contrast to the severe JEB patients, these patients do
not show significant periorificial involvement. Instead,
the scalp is the most commonly affected area on the
head and neck of these patients. Alopecia is progressive, often without significant associated blistering.
The oropharynx can be extensively involved in both
dominant and recessive DEB (Fig. 62-11) with generalized erosions evolving into a scarring which limits
the movement of the tongue and narrows the opening of the oral cavity. The teeth can show significant
enamel pitting, and caries can be extensive, leading to

loss of teeth. Involvement of the trachea or larynx can
lead to a narrowing of the airway, which can require
intervention with a tracheostomy. Mucosal erosions
of the esophagus can lead to stricture formation and
webbing. The combination of oral lesions, dental caries, esophageal strictures, and increased caloric needs
from extensive wound healing can lead these patients
toward malnutrition and growth retardation. These
patients usually have problems with anemia and may
show a deficiency of iron absorption.
In the past, most severe RDEB patients died in
infancy of sepsis and other complications of extensive blistering. With improved nutritional, infection,
and wound support, these patients now usually can
survive into their teens or into adulthood. However, after puberty, another devastating complication, squamous cell carcinoma, can, and often does,
appear. It is estimated that 50%80% of HS-RDEB
patients eventually develop these carcinomas and
many of these die of metastatic disease. RDEBassociated carcinomas are distinct from other cutaneous squamous cell carcinomas in that they are
extremely aggressive with strong tendencies for
invasion and metastasis.
659
associated with increased pruritus, EB pruriginosa,

has also been associated with glycine mutations.127
Other COL7A1 mutations have been associated with
impaired secretion of collagen VII, resulting in intracellular accumulation of this molecule. In one study,
DEB patient mutations that involve the area of the gene
coding for the collagen VII NC-2 domain were shown
to interfere with NC-2 processing and the assembly of
anchoring fibrils.128
KINDLER SYNDROME
Section 8
::
New advances in our understanding of the molecular pathology of the skin have brought to light the
underlying pathophysiology of a disease related to
EB, Kindler syndrome. Kindler syndrome was first
described by Theresa Kindler in 1954.129 It is characterized by EB-like trauma-induced blistering at birth and
during infancy, with atrophic changes during healing
reminiscent of junctional or dystrophic EB.130136 However, in later childhood, the blistering usually subsides,
and gives way to a progressive poikiloderma which
distributes to sun-exposed areas. The poikiloderma
may show areas of atrophy and hyperkeratosis, as well
as hypopigmentation, hyperpigmentation, and telangiectasias. These patients often show photosensitivity.
Nail changes and webbing of the toes and fingers are
also sometimes present. Internal complications include
oral inflammation, esophageal, or ureteral strictures
and ectropion. Ultrastructurally, these patients show
reduplication of the basement membrane, which is
the most consistent feature seen. While there is often
a sublamina densa split with anchoring fibril abnormalities, sometimes lamina lucida or intraepidermal
separation can be seen associated with the blistering
phenotype. Molecular investigation of this disease led
to the discovery of a new epidermal protein, kindlin-1,
which shows decreased expression by immunofluorescent microscopy in this disease. Kindlin-1 appears
to have some homology to signaling proteins such as
talin, which suggests a signaling function.137 A number
of mutations of the gene coding for kindlin-1, KIND1,
have been described.138140 These include nonsense,
frameshift, and splice site mutations which underlie the observed decrease in kindlin-1 expression in
affected skin. Why the disease evolves from a blistering to a poikilodermatous phenotype and the exact
function of kindlin-1 in epidermal homeostasis remain
to be fully elucidated.
DIAGNOSIS
660
The first step toward making the diagnosis of EB begins

with a thorough history and physical examination
(Fig. 62-12). Useful historical information includes the
age of onset of blistering and the presence of blistering
in other family members. A review of gastrointestinal,
respiratory, ocular, dental, bone, and genitourinary
systems is important as is evaluation of general growth
and development. Physical examination requires not
only a complete skin exam, but a thorough evaluation
of mucosal tissues, hair, nails, and teeth. Laboratory

measurements of importance in the initial visit include
evaluation for anemia, and for measures of nutrition,
such as serum albumin.
Skin biopsy is another important diagnostic step.
Routine histologic analysis cannot be used to diagnose
EB but can be useful for excluding other causes of blistering. The dermalepidermal BMZ is simply too small
to be visualized by light microscopy. To differentiate
levels of BMZ separation in skin biopsies, transmission
electron microscopy (TEM), and/or indirect immunofluorescent microscopy (IDIF) must be used. While
both TEM and IDIF will map the level of skin separation, each test can also provide additional unique diagnostic information, the utility of which depends on
the clinical circumstances. For example, in dominant
diseases such as EBS and DDEB, there is often not a
detectable loss of antigens by IDIF, but ultrastructural
abnormalities such as keratin filament clumping or
anchoring filament abnormalities can still be seen by
TEM. Conversely, in recessive disease, while TEM can
detect ultrastructural abnormalities such as rudimentary hemidesmosomes, it cannot distinguish the loss of
individual components of hemidesmosomes and other
BMZ structures, as IDIF can.
The interior of blisters rapidly reepithelializes,
which can obscure correct determination of blister
levels. For this reason, it is critical to biopsy a blister
that is as fresh as possible. One way to ensure a fresh
blister is for the clinician to induce it in the office. This
can be accomplished by gently rotating a pencil eraser
over an intact area of patients skin until separation of
the epidermis from the dermis can be observed. When
actually doing the biopsy, one should place the circular biopsy punch so that only 10% of the punch covers
the visible blister with 90% covering intact skin. This is
because it is helpful to have both intact and blistered
skin on the same biopsy and extension of the blister
is likely to occur either during the biopsy process or
during shipping.
TEM has been used for decades for determining the
level of blistering in EB subtypes. In addition to determining the level of blistering, ultrastructural entities
can also be analyzed by TEM for characteristic alterations. For example, clumping of keratin intermediate
filaments in basal keratinocyte cytoplasm is a pathognomonic finding for DowlingMeara EBS. Rudimentary hemidesmosomes can be an important clue to the
diagnosis of junctional EB. Absent or altered anchoring
fibrils often occur in DEB subtypes especially the recessive forms.
IDDF microscopy has proved increasingly useful in
recent years due to the availability of antibody panels
directed against all the known EB antigens. In this technique, a panel of antibodies against known BMZ antigens is applied to frozen sections of blistered patient
skin. The localization of the antigens to the epidermal
or dermal portion of the blister indicates the level of
skin separation in the BMZ. In EBS samples, for example, intracellular hemidesmosomal components such
as BP230 and a lamina densa protein such as type IV
collagen would each localize to the floor of the blister. In JEB cases, BP230 would localize to the roof of
Components of the dermal-epidermal basement membrane
Review of systems:
gastrointestinals, respiratory,
ocular, or growth abnormalities?
Personal history:
onset of trauma-induced
blisters at birth or childhood?
Biopsy (light microscopy):

cannot be used to Dx EB, but
can rule out other disorders
biopsy suspicious or non-healing
lesions in postpubertal RDEB
patients to rule out SCC
Physical exam:
scarring, atrophy, or milia?
nails, eyes, mucosa,
hair, teeth involved?
Family history:
siblings or
parents with disease?
Laboratory:
examine CBC, albumin, and
other laboratory values as
needed to evaluate
anemia and malnutrition
Biopsy (immunofluorescent microscopy)

can show cleavage plane and defective
expression of EB associated proteins
Chapter 62
Biopsy (electron microscopy)

can show cleavage plane, clumped
tonofilaments, abnormal hemidesmosomes
and anchoring filaments
::
Therapy:
support wound care and nutrition; instruct family
treat infection, anemia and extracutaneous
disease through multi-disciplinary approach
implementation of molecular therapies
in the future
DNA analysis and genetic counseling:

patient and family members DNA analyzed
can show specific DNA defect
useful for family planning prenatal diagnosis
and future molecular therapy
Figure 62-12 Approach to EB patients. A complete history, including family history and review of systems is essential.
Physical exam can provide important clues, and laboratory values can help identify associated anemia and malnutrition.
Electron microscopy and/or indirect immunofluorescent microscopy are required for diagnosis. DNA analysis is helpful for
determining prognosis and family planning. Therapy is mainly supportive. Teaching and working with nursing staff and
especially families is critical, as is interdisciplinary interactions with other specialties in the treatment of extracutaneous
complications.
the blister while type IV collagen would localize to the

floor. In DEB, collagen VII and BP230 would localize to
the roof of the blister. The specific absence or presence
of staining with a particular antibody in frozen sections of intact portions of patient skin gives important
clues to the specific molecular defect. Samples that lack
staining with antibodies specific to laminin-332 would
further support a JEB diagnosis while a lack of staining for collagen VII would support a DEB diagnosis.
Absence of staining for collagen XVII would support
a non-Herlitz JEB/generalized atrophic benign EB
diagnosis.
A complete panel of antibodies to support IDDFbased diagnosis of EB would include antibodies
against laminin-332 (Herlitz and non-Herlitz JEB),
as well as antibodies against BP230/BPAG1, BP180/
collagen XVII (non-Herlitz JEB/generalized atrophic
benign EB), collagen VII (RDEB), 6 and 4 integrins
(JEB with pyloric atresia), plectin (EBS with muscular dystrophy), and keratins 5 and 14 (recessive EBS).
Antibodies against the individual chains 3, 2, and 3

chains of laminin-332 are especially helpful.
Its known that laminin-311 (which shares the same
laminin 3 chain as laminin-332) is expressed in Herlitz JEB associated with null mutations of genes coding for 3 chain (LAMB3) and 2 chain (LAMC2), but
not in Herliz JEB associated with null mutations of the
3 chain gene (LAMA3).44 Therefore, if laminin 3 and
2 antibodies are negative and 3 antibody is positive, this could point the genetic analysis to examine
the LAMB3 and LAMC2. Conversely, if all three laminin-332 chains are absent by IDIF, this could point the
genetic investigation toward LAMA3, saving time and
effort in arriving at the final molecular diagnosis.
Gene mutation analysis has revolutionized our
understanding of the EB family of diseases and is
considered the ultimate final step in arriving at the
molecular diagnosis in EB. Concurrent advances in our
knowledge of the biochemical structure and supramolecular assembly of BMZ proteins have both facilitated
661
and complemented the molecular biology studies.

Thus, EB patient diagnosis requires both clinical and
molecular information. Blood samples or buccal swabs
are taken from the patient as well as the parents and
siblings for genetic analysis.
GENETIC COUNSELING
Section 8
::
DNA mutation analyses can be extremely helpful to

EB patients. The prognostic benefit to the patient can
often be highly significant. For example, milder recessive DEB cases may have equivalent blistering activity
compared to the more severe dominant cases, but their
risk of invasive SCC is much greater. Through DNA
diagnosis, these two groups can be distinguished,
thereby identifying patients potentially at risk for
invasive SCC.
Prenatal diagnosis of EB in affected families can be
an extremely accurate technique, especially if the original proband has previously had mutational analysis
or identification of the defective gene. Fetal skin biopsies and fetoscopy with their increased risk of pregnancy loss can now be avoided by analysis of either
chorionic villus sampling as early as 810 weeks141 or
amniocentesis in the second trimester.142 The development of highly informative intragenic and flanking
polymorphic DNA markers in EB candidate genes
together with rapid screening of genetic hotspots
makes genetic screening of at risk pregnancies a viable
option.112,143 Coupling of the technique of in vitro fertilization with EB prenatal diagnosis, preimplantation
diagnosis has now been successfully performed for EB
cases.144 Another promising area of prenatal diagnosis
with potential future applications to EB is the detection
and analysis of fetal cells in the maternal circulation.145
TREATMENT
Most therapy for epidermolysis bullosa is supportive.
The regimen is tailored to the severity and extent of
skin and systemic involvement and usually entails a
combination of wound management, infection control, surgical management as needed, and nutritional
support. Skin care and supportive care for other organ
systems in certain EB subtypes is most optimally coordinated through a multidisciplinary approach. Comprehensive topical therapy is a mainstay of treatment
in EB, with avoidance of trauma as a primary goal.
Wound healing is impaired by endogenous factors,
including foreign bodies, bacteria, nutritional deficiencies, anemia, and repeated trauma. Therefore, optimizing wound healing in EB patients involves control of
all of these factors.146
SUPPORTIVE SKIN CARE
662
Extensive areas of denuded skin can result in the loss

of the barrier provided by the stratum corneum. Subsequent microbial penetration can result in the accumulation of serum and moisture that further enhances
bacterial propagation. The above factors combined

with immunosuppressive therapy facilitate development of infections. Prevention of infection is obviously
the preferred strategy.
A modified Dakins solution (0.025% w/v sodium
hypochlorite) can be helpful in reducing the bacterial
load in patient skin. Soaking wounds in this solution
for 20 minutes prior to dressing changes also helps
to free adherent bandages that have dried onto the
wound bed. After soaking, wounds can be dressed
with mupirocin or other topical antibiotics, and covered with semiocclusive nonadhesive dressings. Tape
causes further blistering and peeling of the skin; thus,
it is essential to use self-adhering (clinging) gauze or
self-adherent tape to hold nonadherent dressings in
place.
For patients with generalized or localized subtypes
of EBS, controlling exposure to heat may prove helpful in controlling blister formation. Advising patients
to use soft, well-ventilated shoes is also recommended.
Herlitz JEB patients, lacking functional laminin-332, an
extracellular matrix protein shown to be involved in
keratinocyte adhesion and migration, may have especially difficult problems with wound healing. For DEB
patients, use of finger splinting or diligent hand wrapping and appropriate hand protection against trauma
are helpful, especially following hand surgery (see
below).
INFECTION
Management of skin infections is a critical part of EB
patient care. Large areas of denuded skin provide an
inadequate barrier to microbial penetration. Patients
with severe EB subtypes such as recessive DEB
may also have immunologic abnormalities including
decreased lymphocyte production due to poor nutritional status that lower patients resistance to infection.
Staphylococcus aureus and Streptococcus pyogenes are
common infectious agents. Gram-negative infections
with Pseudomonas aeruginosa can also occur. Sepsis is
a common cause of death in Herlitz JEB patients. Skin
cultures and the use of the appropriate systemic antibiotics are indicated for wound infection. To prevent
infections in chronic wounds, a regimen entailing regular whirlpool therapy followed by topical antibiotics
is the preferred strategy. Rotation of topical antibiotics
is also a helpful way to combat resistant bacteria.
SURGICAL TREATMENT
Among the EB patient population, those with the
severe recessive DEB (HallopeauSiemens) variant
are generally the most in need of surgical intervention.147 Mitten pseudosyndactyly in these patients can
be surgically released; however, this procedure may
have to be repeated periodically due to the strong
tendency of this condition to recur.148151 Splinting following surgery is essential to reducing recurrence of
hand deformities. Surgery may also be used to correct
limb, perioral, and perineal contracture deformities,
but a high rate of recurrence is common. Extra care

must be taken to minimize trauma to oral mucosa in
EB patients during intubation.
Application of allogeneic skin equivalents has
recently demonstrated some promise in wound healing and improvement of quality of life152 and thus
represents an area of future investigation. While longterm benefit or persistence of allografted cells has not
been demonstrated, this therapy nonetheless appears
to a helpful short-term therapy to help chronic EB
wounds to heal.
TUMORS
EYE LESIONS. EBS patients, particularly those with

the DowlingMeara subtype can experience recurrent inflammation of the eyelid, with bullous lesions
in the conjunctivae. Junctional EB patients and recessive DEB patients can experience corneal ulcerations
with scarring, obliteration of tear ducts, and eyelid
lesions.158 Cicatricial conjunctivitis can also occur in
recessive DEB patients. Corneal erosions are treated
critical in EB patients163 for several reasons. Extensive

cutaneous injury is associated with marked alterations in hemodynamic and metabolic responses, with
increased caloric and protein requirements. Nutritional problems such as low selenium, iron overload,
and chronic anemia in the setting of severe blistering
may predispose the patient to severe internal complications. Congestive heart failure and cardiomyopathy
are prime example of this. This uncommon but nonetheless severe and potentially fatal complication can
occur both patients with RDEB or non-Herlitz JEB,
becoming more frequent as patients get older.164
Oropharyngeal as well as gastrointestinal lesions
provide the greatest overall threat to nutritional
well-being. These include oral blistering, abnormal
esophageal motility, strictures, dysphagia, diarrhea,
malabsorption, and dental problems. Nutritional
assessment must take into account the above factors
in order to develop a supplemental regimen to replenish nutritional deficiencies. Patients are often unable
to increase their food intake to balance this increased
caloric need. For example, hypoplastic enamel formation in certain subtypes of EB such as GABEB
may lead to tooth decay, mucosal blistering, and oral
candidiasis. All of these potential complications may
compromise patients ability to eat. Extensive internal
mucosal disadhesion in the gastrointestinal tract may
cause abnormal GI motility, strictures, and diarrhea
complications that may lead to malabsorption of iron
and other nutrients. Anemia of chronic disease can
certainly affect all severe EB subtypes. Recessive DEB
patients often show a particularly severe defect of iron
absorption from the GI tract. In these patients, an iron
deficient anemia can develop, which is not responsive
to oral supplementation. For these patients, parenteral
GI MANAGEMENT. Esophageal lesions are often

the most disabling complication found in recessive
DEB and JEB of both the Herlitz and non-Herlitz varieties. Esophageal strictures usually respond to dilatation; however, recurrence of strictures after dilation is
common.156 Colonic interposition has proven effective
in advanced cases. Gastrostomy tube insertion has
been effective in providing nutrition to individuals
with esophageal strictures.157 Increased fluid and fiber
intake and stool softeners may also be of value in EB
patients who suffer from constipation.
NUTRITION AND ANEMIA COMPLICATIONS. Nutritional assessment and support can be
::
CARE FOR EXTRACUTANEOUS

INVOLVEMENT
OROPHARYNGEAL LESIONS. Good dental

hygiene is essential for EB patients, and regular visits to
the dentist are especially important. Enamel defects in
JEB and DEB patients often lead to dental carries.160,161
The softest brush available should be used for regular
cleansing. Oral mucosal blistering may also accompany forms of JEB and DEB. Normal saline rinses are
effective for gentle cleaning of the mucosal surfaces.
Mouthwashes containing alcohol or other harsh agents
should be avoided. Erosions and scarring involving
the trachea and larynx with resultant narrowing of the
airway. In patients with airway involvement, there is
danger of pulmonary aspiration.162
Chapter 62
Squamous cell carcinoma often arises after puberty in

patients with recessive DEB. SCC may arise in multiple primary sites, especially in nonhealing areas.
Careful surveillance of nonhealing areas is of utmost
importance since patients often die from metastatic
disease, and the average survival rate after diagnosis
of an RDEB-associated squamous cell carcinoma is
5 years. Surgical excision using either Mohs or nonMohs approaches is an important first-line modality
with radiation therapy limited by poor tumor response
and impaired site healing.153 Amputation is often used
to control local spread of carcinomas detected on the
limbs. Isotretinoin has been used for RDEB patients for
chemoprevention of SCC. While it appears well tolerated, it is not clear whether in can increase the overall survival rate of these patients.154 The epidermal
growth factor receptor antagonist cetuximab has also
been reported used in RDEB associated with advanced
metastatic disease.155 While the short-term results were
positive in the one patient tested, published reports of
long-term results and experience with wider groups of
RDEB cancer patients are currently lacking.
supportively with application of antibiotic ointments

and use of cycloplegic agents to reduce ciliary spasms
and provide comfort. Moisture chambers and ocular
lubricants are also commonly used. Severely affected
upper eyelids may be surgically managed with fullthickness skin grafting. Complete correction of any eye
disorder in EB patients is difficult to achieve. Proper
management of eye lesions in EB patients must include
the assistance of an ophthalmologist to prevent serious
visual compromise.159
663
iron can be helpful. Furthermore, if a lack of a reticulocyte response to iron supplementation is seen in iron
deficient patients, it is helpful to assess the erythropoietin level and to treat with recombinant erythropoietin if necessary.165 Transfusion is also useful in the
treatment of anemia in EB, especially when symptoms
require a rapid correction. Deficiencies of other trace
minerals and other vitamins such as vitamin D, zinc
have also been noted in severe RDEB patients.166 Osteoporosis and fractures are also a frequent complication
of RDEB patients, and bone scans, vitamin D and calcium supplementation may be helpful. Bisphosphonates can be useful in combating this problem.167
Section 8
PSYCHOLOGICAL ASPECTS OF EPIDERMOLYSIS BULLOSA. Patients with EB, especially
::
the severe subtypes, can be plagued with chronic pain

and debilitation.168170 While many, despite extremely
adverse conditions, seem to find a way to maintain a
surprisingly positive outlook on life, others lapse into
depression.171,172 Severe epidermolysis bullosa patients
can also create stress for their families and loved
ones.173 Thus, it is important to identify the warning
signs of depression when they arise and to work in
a mutidisciplinary approach with psychiatrists and
clinical psychologists as needed. Supportive psychotherapy and patient support group meetings can help
patients and their families in this regard. An additional
source of support for patients and families include several important patient-based organizations that assist
with education and support including Dystrophic Epidermolysis Bullosa Research Association and Epidermolysis Bullosa Medical Research Foundation.
SYSTEMIC THERAPIES
Systemic therapies are not effective in ameliorating the
fundamental blistering tendencies in EB patients. Tetracycline and phenytoin have been used in the past for
EB but are not currently indicated treatment.174 Corticosteroids, either topical or systemic, have no beneficial long-term use in inherited EB.
MOLECULAR THERAPY FOR

664
A number of preclinical models have facilitated the

study and development of therapy for epidermolysis
bullosa. Some of these models utilize mouse genetic
approaches to produce entirely murine tissue models.175 These include transgenic mouse models with
skin targeted expression of trans-dominant molecules
including inducible disease phenotype models.176
These include dominant-negative basal keratins in
models of epidermolysis bullosa simplex. Murine
knockout models have also been used, including
knockout of basal keratin genes in a model of the same
disorder and of the 6 and 4 integrins, laminin-332,
and types XVII and VII collagens.177181 These targeted
gene disruptions in mice have accurately recapitulated
the blistering phenotype of the corresponding human
disorders. These murine genetic models have been

of great utility in clarifying our understanding of the
pathogenesis of this group of disorders and in providing disease models for development of potential future
therapies. Other animal models have also been shown
to have the potential to study epidermolysis bullosa
pathophysiology and therapy in a preclinical setting.
Canine, murine, equine, and feline forms of a number
of subtypes of epidermolysis bullosa show promise as
preclinical models of molecular therapy.
In addition to such pure animal models, human skin/
mouse chimeras have been generated in an attempt to
produce true human tissue models of epidermolysis
bullosa. These chimeras have either used full thickness
grafting of EB patient skin or epidermis regenerated
on skin composites and sheets from EB keratinocytes
grown in culture.182 Immune deficient SCID and nude
mice readily accept such xenografts and the grafted EB
skin retains the clinical and molecular characteristics of
the patient donor. This immunodeficient mouse models can be extended to study injections of human cells
or proteins as well. This approach has been reported for
recessive dystrophic EB due to mutations in collagen VII
and for benign junctional EB due to mutations in collagen XVII. Because human epidermis differs dramatically
from mouse in tissue architecture, these in vivo models
of human tissue in EB may be of special utility in development of models for gene therapy of these disorders.
Potential therapies for EB include protein and gene
therapy. In the former case, the missing or defective protein is produced by recombinant methods and applied
or injected directly to intact or blistered skin or given
intravenously. Recent preclinical studies of collagen VII
protein transfer into RDEB-derived skin equivalents
have shown successful incorporation of this molecule
into anchoring fibrils combined with clinical improvement of skin separation.183 Collagen VII has a longer
in vivo half-life than most molecules. This suggests
that protein application or injection could take place
at extended intervals, perhaps greater than 3 months,
as persistence of exogenous collagen VII protein was
detected in animal models at least this long.
In the case of gene therapy, delivery of genes targeted
to restore normal protein expression is the goal.184,185
Successful corrective gene delivery has recently been
achieved in human EB tissue in the immune deficient
model system described below for both laminin-332
and collagen XVII.186,187 More recently both viral and
nonviral methods of gene transfer have demonstrated
successful expression of collagen VII in RDEB skin
equivalents on immunodeficient mice183,188190 as well
as in a canine animal model.191
The approach of retroviral ex vivo gene therapy using
autologous keratinocytes was recently performed for
one patient with junctional epidermolysis bullosa.192 In
this study, a patient with a missense mutation of laminin-332 was grafted with genetically corrected keratinocyte monolayers expressing wild type laminin-332.
After over 1 year of post grafting follow up, grafts still
showed positive expression of laminin-332 and resistance to blistering. Observations from this study suggested that proper selection of patient skin stem cells
were an important part of the success of this study.

16. Gedde-Dahl T: Epidermolysis Bullosa: A Clinical, Genetic
and Epidemiologic Study. Baltimore, The John Hopkins
Press, 1971, pp. 1-180
17. LeBleu VS, Macdonald B, Kalluri R: Structure and function of basement membranes. Exp Biol Med (Maywood)
232:1121-1129, 2007
20. Coulombe PA, Kerns ML, Fuchs E: Epidermolysis bullosa simplex: A paradigm for disorders of tissue fragility.
J Clin Invest 119:1784-1793, 2009
70. Smith LT: Ultrastructural findings in epidermolysis bullosa. Arch Dermatol 129:1578-1584, 1993
::
KEY REFERENCES
71. Fine JD et al: The classification of inherited epidermolysis bullosa (EB): Report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J
Am Acad Dermatol 58:931-50, 2008
92. Natsuga K et al: Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex. Hum Mutat 31(10):E1687-E1698, 2010
93. Groves RW et al: A homozygous nonsense mutation
within the dystonin gene coding for the coiled-coil
domain of the epithelial isoform of BPAG1 underlies a
new subtype of autosomal recessive epidermolysis bullosa simplex. J Invest Dermatol 130:1551-1557, 2010
103. McLean WH et al: An unusual N-terminal deletion of the
laminin alpha3a isoform leads to the chronic granulation
tissue disorder laryngo-onycho-cutaneous syndrome.
Hum Mol Genet 12:2395-2409, 2003
104. Sakai N et al: Observations of skin grafts derived from
keratinocytes expressing selectively engineered mutant
laminin-332 molecules. J Invest Dermatol 130:2147-2150,
2010
110. Pfendner EG et al: Basic science of epidermolysis bullosa
and diagnostic and molecular characterization: Proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile, 2005. Int J Dermatol
46:781-794, 2007
155. Arnold AW et al: Cetuximab therapy of metastasizing
cutaneous squamous cell carcinoma in a patient with
severe recessive dystrophic epidermolysis bullosa. Dermatology 219(1):80-83, 2009
164. Lara-Corrales I, Pope E: Dilated cardiomyopathy in epidermolysis bullosa. Dermatol Clin 28(2):347-351, 2010
166. Ingen-Housz-Oro S et al: Vitamin and trace metal levels
in recessive dystrophic epidermolysis bullosa. J Eur Acad
Dermatol Venereol 18(6):649-653, 2004
167. Martinez AE, Mellerio JE: Osteopenia and osteoporosis
in epidermolysis bullosa. Dermatol Clin 28(2):353-355,
2010
170. Tabolli S et al: Quality of life in patients with epidermolysis bullosa. Br J Dermatol 161:869-877, 2009
177. Bruckner-Tuderman L et al: Animal models of epidermolysis bullosa: update 2010. J Invest Dermatol 130:14851488, 2010
201. Wagner JE et al: Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med
363(7):629-639, 2010
Chapter 62
This latter study was the first to demonstrate that gene

therapy for epidermolysis bullosa can be successfully
performed in humans, and opens the door for many
new clinical studies in other EB subtypes.
Dermal fibroblasts have long been appreciated as
contributors of collagen VII to the dermalepidermal
basement membrane.193 The technique of injecting collagen VII expressing fibroblasts have proven successful in restoring collagen VII expression and reversing
the blistering phenotype in RDEB skin equivalents
on immunodeficient mice189,194 and in a mouse model
of RDEB.195 In addition, allogenic fibroblast-based
approaches to the treatment of dystrophic EB have
recently found their way into clinical trials, showing
some success at delivering collagen VII to deficient
RDEB patient skin.196,197 Although profound immunosupression against a background of extensive skin erosions is not without significant risks, including sepsis
and death, new advances in bone marrow transplantation of collagen VII expressing stem cells represents
another novel and potentially effective route of cellbased molecular therapy for RDEB.198201
665
Disorders of the Dermal

Connective Tissue
Chapter 63 :: C
ollagens, Elastic Fibers,
and Other Extracellular Matrix
Proteins of the Dermis

:: Thomas Krieg, Monique Aumailley,
Manuel Koch, Mon-Li Chu, & Jouni Uitto
COLLAGENs, ELASTIC FIBERS
AND OTHER EXTRACELLULAR
MATRIX PROTEINS OF THE DERMIS
AT A GLANCE
The extracellular matrix (ECM) is a complex
network composed of a large number of
components, which determines tissue
stiffness, compliance, and resilience.
ECM proteins (i.e., collagens, proteoglycans,
glycoproteins) consist of structural domains
with different biological functions.
ECM signals control cell differentiation,
polarity, migration, survival, and expression
of specific genes.
There are many ECM-associated heritable
diseases. The molecular mechanisms
responsible for the resulting phenotypes are
often complex and involve several different
cellular pathways.
The dynamic balance between ECM
synthesis and degradation is critical for
many acquired disease processes, i.e.,
tumor invasion and metastasis, fibrosis, and
inflammatory pathologies.
INTRODUCTION
The extracellular matrix (ECM) is a complex network
of different components, responsible for determining
and maintaining tissue architecture, and for mediating
a number of important biological events. It is composed of a large number of diverse protein families,
each constituted by many different individual members. These include the collagens, encoded by 42 different genes, elastin and associated microfibrillar proteins,
fibronectin, proteoglycans, and many more molecules.
(See Table 63-1.)
Although all of these proteins are genetically, structurally, and biologically diverse, a common denominator is that most of them have a modular structure, and
they are composed of one, a few, or several copies of a
limited set of individual structural modules, also called
domains.1 These can be combined in multiple ways
giving rise to proteins as diverse as fibrillin and laminin (Fig. 63-1). Specific functions have been unraveled
for some of these domains, for instance, interaction
with other ECM proteins, cell adhesion-promoting
activity, cytokine trapping, and regulation. Therefore,
the ECM has a critical role for many cellular functions,
including proliferation, survival, polarity, differentiation, expression of specific genes, and migration.24 All
different cell types, such as mesenchymal, epithelial,
and endothelial cells, and also inflammatory and
tumor cells, participate in the production of distinct
ECM macromolecules, and are all influenced by interactions with these compounds. It is well established
that the ECM determines the biophysical properties of
connective tissues. More recently it became clear that,
conversely, stiffness and compliance of connective tissues are important factors for the regulation of cellular
functions.58
Collagens
The proteins of the collagens family are the main structural components of the connective tissues and the
major extracellular proteins of the human body. In
human skin, collagens comprises approximately 80%
of the dry weight of the dermis. The classical and first
recognized physiologic role of collagens in the skin is
to provide tensile properties that allow the skin to
serve as a protective organ against external trauma. In
addition, it is clear that collagens displays important
TABLE 63-1
Major Genes and Proteins of the Extracellular Matrix

Proteins
Number of Genes
Number and Name of Proteins
Collagens
42
28; collagens type I to XXVIII
Elastin
Several splice variants
Fibronectin
1; 20 splice variants
7; Fibulin 17
3; Fibrillin 13
Laminins
11
15; LM-111, LM-332, LM-511, etc.
Matrilins
4; Matrilins 14
Nidogens
2; Nidogen 1 and 2
Tenascins
4; Tenascin-C, -X, -R, and -W
Thrombospondins
5; Thrombospondin 15
Vitronectin
Laminin-332
3
3
Fibrillin-1
KEY
biological properties regulating multiple cellular and

tissue activities.
THE Collagens TRIPLE HELIX

The bulk of collagens in dermis is deposited as large
bundles of regularly oriented fibers composed of
fibrils that are aligned in a parallel manner, which
results in a pattern of cross-striations that can be visualized by electron microscopy (Fig. 63-2). The most
prominent cross-striations appear as repeating bands
spaced approximately 70 nm apart. The major component of these fibrils is type I collagens, the first
identified member of the collagens family and the
most abundant collagens in the dermis and most
Coiled-coil heterotrimerisation domain

Laminin-type epidermal growth
factor-like domain
Fibrillin-type epidermal growth
factor-like domain
Calcium-binding, fibrillin-type epidermal
growth factor-like domain
Glycosylation
Collagens, Elastic Fibers, and Other Extracellular Matrix Proteins
Modular structure of extracellular matrix proteins
::
Fibrillins
Chapter 63
Fibulins
Unique domains
Transforming growth factor -binding
protein-like (T) motif
Laminin N terminal (LN) domain
Laminin globular (Lg) domain
Figure 63-1 Modular structure of extracellular matrix

(ECM) proteins. ECM proteins are composed by a few individual structural modules, such as fibrillin- and laminintype epidermal-growth factor-like modules, von Willebrand factor A domain, follistatin-like and EF-hand Ca2+binding motif or coiled-coil oligomerization domains.
These modules can be combined in multiple ways giving
rise to proteins as diverse as fibrillin or laminin displayed
here as examples. In addition, ECM proteins can be formed
of a single polypeptide chain, as fibrillin, or of several
polypeptide chains. For instance, laminin 332 is formed
by three polypeptide chains, the a3, b3 and g2 chains.
Figure 63-2 Electron micrograph of collagens fibers demonstrating the regular banding pattern at approximately
70-nm intervals (45,000).
667
is largely explainable by the unusual amino acid composition of the chains. Specifically, each chain of
type I collagens has approximately 1,000 amino acids,
and glycine (Gly), the smallest amino acid, accounts for
approximately one-third of the total number of amino
acids, evenly distributed along the polypeptide. Consequently, the polypeptide chains of type I collagens can
be described as repeating triplets represented as (GlyX-Y)333. Although the X and Y positions of the triplets
can be occupied by any amino acid, they are often occupied by proline and hydroxyproline, respectively. These
two amino acids account for approximately 22% of the
total amino acid composition of type I collagens. The
relatively high content of these amino acids and the
characteristic distribution of glycine in every third position are necessary for the triple-helical conformation of
the collagens molecule, and hydroxyproline plays a
critical role in stabilizing the triple helix at body temperature. The triple-helical conformation defines the
so-called collagenous domain, and it gives type I collagens many of its unique properties.12 In particular, it is
essential for assembly into fibrils. Mutations that affect
the formation of the stable triple helix prevent collagens from forming fibers, which results in serious
defects of connective tissue function and a spectrum of
clinical phenotypes.1315
Type I collagen structure
II
III
300 nm
Section 9
= 1/4 of
molecule
IV
1
::
Disorders of the Dermal Connective Tissue
668
Glycine
V
Y
4-hydroxyproline
HO
X
Proline
0.95
Figure 63-3 Schematic representation of the structure of

type I collagens. The collagens fibers (I), which on electron
microscopy demonstrate a repeating periodicity (see Fig.
63-2), are composed of individual collagens molecules
aligned in a quarter-stagger arrangement (II). Each type
I collagens molecule is an approximately 300-nm-long
rod-like structure (III) consisting of three individual polypeptides, known as chains, which are twisted around
each other in a right-handed triple helix (IV). Each chain is
composed of amino acids in a repeating Gly-X-Y sequence
(V); as indicated, the X position is frequently occupied by
a prolyl residue and the Y position is frequently occupied
by a 4-hydroxyprolyl residue. The individual chains have
a left-handed helical secondary structure with a pitch of
0.95 nm. (From Uitto J et al: Collagens structure, function, and pathology. In: Progress in Diseases of the Skin, vol.
1, edited by R Fleischmajer. New York, Grune & Stratton,
1981, p. 103, with permission.)
other connective tissues.911 The characteristic structural features of collagens were deduced from the
study of type I collagens, which is therefore considered as the prototype of the collagens family.
The type I collagens molecule has an approximate
molecular mass of 290 kDa and is composed of three
polypeptide chains, each approximately 94 kDa. These
three polypeptides, known as the chains, are coiled
around each other much like strands of rope, so that the
collagens monomer has a triple-helical structure. This
conformation gives the molecule a rigid, rod-like shape
with approximate dimensions of 1.5 300 nm (see Fig.
63-3). The special structure of the collagens triple helix
GENETIC HETEROGENEITY
OF Collagens
Collagens comprises a family of closely related yet
genetically distinct proteins. In the human genome,
there are as many as 42 different genes encoding
chains with variable amino acid sequences. These
chains correspond to at least 28 different types of collagens, which have been assigned Roman numerals I
to XXVIII (Table 63-2). These are subdivided into several subfamilies, mainly according to the length and
number of collagenous and noncollagenous domains.
In addition to well-characterized collagens, short triple-helical collagenous segments are present in other
proteins, including acetyl cholinesterase, the C1q component of the complement system, gliomedin, pulmonary surfactant proteins, macrophage scavenger
receptors, emilins (elastin microfibril interface-located
glycoproteins), and ectodysplasin A, a product of the
gene mutated in X-linked anhidrotic ectodermal dysplasia.16 However, these proteins are not included in
the collagens family because the collagenous domains
are not a predominant part of the molecules, and the
proteins do not function primarily as structural components of the ECM of connective tissue.
The genetically distinct collagens are distributed
into several classes, mainly according to the length and
number of triple-helical collagenous segments and
noncollagenous domains present in the molecule,
and on the basis of the architecture of their assembly in
tissues (see Table 63-2). A classification and an overview of the major collagens types contributing to skin
physiology and pathology are presented in the following paragraphs. Some collagens types are not discussed in detail because they do not appear to be
TABLE 63-2
Genetic Heterogeneity of Collagens

Chromosome Localization
a Chains
Comments
COL1A1
COL1A2
17q21.31q22
7q22.1
a1(I)
a2(I)
Fibrillar
II
COL2A1
12q13.11q13.2
a1(II)
Fibrillar
III
COL3A1
2q31
a1(III)
Fibrillar
IV
COL4A1
COL4A2
COL4A3
COL4A4
COL4A5
COL4A6
13q34
13q34
2q36 q37
2q36 q37
Xq22.3
Xp22.3
a1(IV)
a2(IV)
a3(IV)
a4(IV)
a5(IV)
a6(IV)
Network
COL5A1
COL5A2
COL5A3
9q34.2 q34.3
2q31
19p13.2
a1(V)
a2(V)
a3(V)
Fibrillar
VI
COL6A1
COL6A2
COL6A3
COL6A5
COL6A6
21q22.3
21q22.3
2q37
3q21
3q21
a1(VI)
a2(VI)
a3(VI)
a5(VI)
a6(VI)
Microfibril
VII
COL7A1
3p21.3
a1(VII)
Anchoring fibril
VIII
COL8A1
COL8A2
3q12 q13.1
1p34.3 p32.3
a1(VIII)
a2(VIII)
Network
IX
COL9A1
COL9A2
COL9A3
6q13
1p33 p32.2
20q13.3
a1(IX)
a2(IX)
a3(IX)
FACIT
COL10A1
6q21 q22.3
a1(X)
Network
XI
COL11A1
COL11A2
1p21
6p21.3
a1(XI)
a2(XI)
Fibrillar
XII
COL12A1
6q12 q13
a1(XII)
FACIT
XIII
COL13A1
10q22
a1(XIII)
Transmembrane
XIV
COL14A1
8q23
a1(XIV)
FACIT
XV
COL15A1
9q21 q22
a1(XV)
Multiplexin
XVI
COL16A1
1p34
a1(XVI)
FACIT
XVII
COL17A1
10q24.3
a1(XVII)
Transmembrane
XVIII
COL18A1
21q22.3
a1(XVIII)
Multiplexin
XIX
COL19A1
6q12 q14
a1(XIX)
FACIT
XX
COL20A1
20q13.3
a1(XX)
FACIT
XXI
COL21A1
6p12.3 p11.2
a1(XXI)
FACIT
XXII
COL22A1
8q24.2
a1(XXII)
FACIT
XXIII
COL23A1
5q35
a1(XXIII)
Transmembrane
XXIV
COL24A1
1p22.3
a1(XXIV)
Fibrillar
XXV
COL25A1
4q25
a1(XXV)
Transmembrane
XXVI
COL26A1
16p11.2
a1(XXVI)
FACIT
XXVII
COL27A1
9q32
a1(XXVII)
Fibrillar
XXVIII
COL28A1
7p21.3
a1(XXVIII)
FACIT = fibril-associated collagens with interrupted triple helices.

Red: The polypeptide is expressed in the dermis.
Green: The polypeptide is present at the dermalepidermal junction (basement membrane).
::
Gene
Chapter 63
Collagens Type
669
present in the skin in significant quantities, or they do

not seem to contribute to the physiologic properties of
dermis, or because information is still lacking.
The first class groups the fibril-forming collagens
types I, II, III, V, XI, XXIV, and XXVII. Except for collagens II, XXIV, and XXVII that were not detected in
skin, all other fibril-forming collagens types are
expressed in the dermis. These collagens types consist of a single 300-nm long collagenous domain, with
very short nontriple-helical extensions (Fig. 63-4),
Major collagen species of the skin
Section 9
Fibril-forming collagens type I, III and V
Microfibrillar collagen type VI
::
Monomer
Dimer
Tetramer
Microfibril
Network-forming collagen type IV
Anchoring fibril collagen type VII
FACIT type XII and XIV
Transmembrane collagen type XVII
Cell membrane
670
Figure 63-4 The major collagens species of the skin. According to several features, including length and number
of collagenous and noncollagenous domains and supramolecular assemblies, the collagens molecules are
grouped in different families. Type I, III, and V collagens
have the characteristic rod-like structure and form the
large collagens fibrils of the dermis. Type VI collagens
molecules are arranged following a unique microfibrillar
pattern of thin and long aggregates in the dermis. Also
present in the dermal extracellular matrix are two FACITs
(fibril-associated collagens with interrupted triple helices),
type XII and XIV collagens associated to the large collagens fibrils formed by type I, III, and V collagens. Type IV
collagens is ubiquitous of basement membranes where
it forms large hexagonal networks. Two further collagens,
type VII and type XVII, are specific of the dermalepidermal junction, where type VII collagens is a component of
the anchoring fibrils, while the ectodomain of transmembrane type XVII collagens is located in the anchoring filaments anchoring basal keratinocytes of the epidermis to
the underlying basement membrane.
and they assemble into relatively large fibrils.11,12,17

Type I collagens, the most widely distributed and the
most extensively characterized form of collagens,
accounts for approximately 80% of the total collagens
of adult human dermis. It is formed by two identical
chains, designated 1(I), and a third chain, called
2(I), that is clearly different in its amino acid composition. Thus, the chain composition of type I collagens
is [1(I)]22(I). Type III collagens represents approximately 10% of the total collagens in the adult human
dermis.18 It is composed of three identical 1(III)
chains, distinguished from the chains of type I collagens by a relatively high content of hydroxyproline
and glycine and the presence of one cysteine residue.
Collagens types I and III form the relatively broad
extracellular fibers that are primarily responsible for
the tensile strength of the human dermis. Mutations
in the type I and III collagens genes can result in connective tissue abnormalities in the skin and joints,
among other tissues, in different forms of Ehlers
Danlos syndrome and fragility of bones in osteogenesis imperfecta.1315 Type V collagens forms a
subfamily of similar interrelated collagens resulting
from various assemblies of three different types of
chains, 1(V), 2(V), and 3(V). The predominant
form in the skin is [1(V)]22(V), where it represents
less than 5% of the total collagens. In dermis, type V
collagens is associated with major collagens fibers
consisting of type I and III collagens, and type V collagens has been postulated to regulate the fiber diameter during fibrillogenesis. The importance of type V
collagens has been demonstrated by the discovery of
mutations in type V collagens genes in patients with
classical autosomal dominant forms (types I and II) of
EhlersDanlos syndrome.19 It is of interest that a clinically similar, classical type of EhlersDanlos syndrome can be based on the absence of tenascin-X
expression, which leads to an autosomal recessive
form of the disease.20 Tenascin-X is developmentally
associated with collagens fibrillogenesis, and its
absence could explain the presence of defective collagens fibers similar to those found in patients with
mutations in type V collagens genes.
Another class comprises the network-forming
collagens types IV, VIII, and X, which are, however,
very different structurally (Fig. 63-4). Type IV collagens is a typical component of basement membranes, where it forms a lattice rather than the fibers
characteristic of dermal collagens. Six different
(IV) chains exist, 1(IV) to 6(IV), and participate in
the assembly of heterotrimers. In human skin, 1(IV)
to 4(IV) chains are present in the basement membrane at the dermalepidermal junction, with
[1(IV)]22(IV) being the predominant heterotrimer.17,21 Type IV collagens chains contain imperfect
Gly-X-Y triplets, a feature that confers flexibility to
the triple-helical domain of the molecule. A noncollagenous globular domain at the amino-terminal
part of the molecule mediates dimer formation,
while a short segment at the carboxyl-terminal
region of the molecule allows for tetramer assembly,
altogether resulting in the so-called chicken-wire
assembly network for collagens type IV.17 Although
::
mutations in the type VII collagens gene, COL7A1,

have been demonstrated in more than 500 families
with different forms of DEB, and none of the families
with DEB studied so far has revealed mutations in
genes other than that encoding the 1(VII) polypeptide of type VII collagens.2931 Furthermore, type VII
collagens serves as the autoantigen in the acquired
form of epidermolysis bullosa, an autoimmune disorder with circulating antitype VII collagens antibodies
(see Chapter 60).
A further class groups the Fibril-Associated
Collagens with Interrupted Triple helices, in short
FACITs, including types IX, XII, XIV, XVI, XIX, XX,
XXI, XXII, and XXVI.11,32 An association with collagens fibers has been demonstrated for several of
these collagens, hence the concept that they serve as
important molecular bridges for the organization
and stability of extracellular matrices. These collagens types form homotrimers with a relatively short
triple-helical domain, and 24 noncollagenous
domains (Fig. 63-4). In the skin, type XII and type
XIV collagens associate with the large collagens
fibrils of the dermis.
Type XV collagens and Type XVIII collagens are
basement membrane-associated collagens. They have
been called multiplexins because they contain multiple noncollagenous domains in their collagenous
sequences.33 Interest in these collagens stems from the
fact that proteolysis liberates fragments endowed with
functions different from those of the original intact
molecules.33,34
Type XIII, XVII, XXIII, and XXV collagens are
transmembrane proteins.35 Their supramolecular
assemblies remain unknown, and, except for types XIII
and XVII, their presence in skin has not been established. Type XVII collagens (Fig. 63-4) is particularly
important for skin physiology and pathology. It is a
transmembrane protein anchored in the membrane of
basal keratinocytes, with an intracellular domain and a
large extracellular domain, or ectodomain, which is a
component of the basement membrane at the dermal
epidermal junction. Immunoelectron microscopy has
localized type XVII collagens to hemidesmosomes of
basal keratinocytes and to the thin anchoring filaments
originating from the hemidesmosomes and spanning
the lamina lucida toward the lamina densa of the basement membrane.36 The ectodomain of type XVII collagens consists of 15 collagenous domains with the
characteristic repeating Gly-X-Y sequences that form
triple helices. These collagenous domains are separated by noncollagenous segments of variable sizes,
and consequently type XVII collagens is a protein characterized by alternating collagenous and noncollagenous segments.37 The ectodomain colocalizes and
interacts with laminin 332, also a component of anchoring filaments36,38 (see also Chapter 53). Type XVII collagens was initially identified as the 180-kDa bullous
pemphigoid antigen (BPAG2), which was recognized
by circulating autoantibodies in the sera of patients
with bullous pemphigoid or herpes gestationis.39
The importance of the type XVII collagens was also
shown by mutations in the corresponding gene
(COL17A1) that underlie a nonlethal variant of junctional
Chapter 63
skin disorders associated with genetic mutations in

type IV collagens have not been described, mutation
in the COL4A1 gene has been identified in a family
with autosomal dominant porencephaly and infantile hemiparesis,22 and mutations in the COL4A5
gene result in Alport syndrome,23 an X-linked renal
disease. Furthermore, autoantibodies recognizing
the collagens 3(IV) chain underlie Goodpasture
syndrome,23 and autoantibodies targeting the collagens 5(IV) chain are associated with a novel autoimmune disease characterized by subepidermal
blisters and renal insufficiency.24
Two further collagens, type VI collagens and type
VII collagens, are unique and each has its own distinct
molecular structure and supramolecular assembly.
Type VI collagens forms specific microfibrils in the dermis, while type VII collagens forms the anchoring
fibrils of the dermalepidermal junction. The microfibril-forming type VI collagens is relatively abundant in
a variety of tissues, including skin. In humans, five distinct chains1(VI), 2(VI), 3(VI), 5(VI), and
6(VI)11have been identified (Table 63-2). The 1(VI),
2(VI), and 3(VI) chains fold into a triple-helical
domain of approximately 100 nm in length, with globular domains at both ends (Fig. 63-4). The supramolecular assembly involves the formation of antiparallel
dimers, then tetramers, which in turn align in rows,
leading to relatively thin microfibrils, independently
of the broad collagens fibers.25,26 The microfibrils of
type VI collagens may perform an anchoring function
by stabilizing the assembly of the broad collagens
fibers as well as basement membranes. Studies have
now demonstrated that mutations in each of the three
type VI collagens genes can lead to different forms of
congenital muscular dystrophy, with multiple joint
contractures, laxity of distal joints, and characteristic
skin involvement.27
Type VII collagens, the major, if not the exclusive,
component of the anchoring fibrils at the dermalepidermal junction, has an unusually long triple-helical
region of approximately 450 nm.28 It has only one type
of chain, 1(VII), and the triple-helical collagenous
domain is flanked by a large, nonhelical (noncollagenous) domain, NC-1, at the amino terminus and a
shorter carboxyl-terminal nonhelical domain, NC-2
(Fig. 63-4). Type VII collagens molecules become organized into anchoring fibrils, which extend from the
lower part of the lamina densa to the papillary dermis,
through the formation of antiparallel dimers linked
through their carboxyl-terminal ends. The large
amino-terminal, noncollagenous domains of type VII
collagens interact with type IV collagens and laminin
332 components of the dermalepidermal basement
membrane, and it has been suggested that most
anchoring fibrils form U-shaped loops that entrap
broad dermal collagens fibers consisting of type I and
III collagens. Thus, alterations in the expression, structure, or molecular interactions of type VII with other
basement membrane components could result in skin
fragility. Such a situation is exemplified by dystrophic
epidermolysis bullosa (DEB), a group of mechanobullous diseases characterized by blistering of the skin
after minor trauma (see Chapter 62). In fact, distinct
671
epidermolysis bullosa, generalized atrophic benign

epidermolysis bullosa (see Chapter 62). These patients
have protracted, lifelong blistering of the skin, atrophic
scarring, alopecia, and nail dystrophy.37,40
FROM Collagens GENES TO

SUPRAMOLECULAR ASSEMBLIES
Section 9
::
672
The collagens genes, like most eukaryotic genes, are

large, multiexon genes interrupted at several points by
noncoding DNA sequences called introns.41 For expression, the entire gene is transcribed into a high-molecular-weight precursor messenger RNA (mRNA), which
undergoes posttranscriptional modifications, such as
capping, polyadenylation, and intron splicing to yield
a linear, uninterrupted coding sequence with 5 and 3
untranslated flanking regions. The mature mRNA is
then transported into the cytoplasm and translated to
the corresponding polypeptide. Thus, the eukaryotic
gene coding for a protein is much larger than would be
predicted from the amino acid sequences of the final
protein.
With few exceptions, the collagens genes are widely
scattered throughout the human genome (see Table
63-2). Knowledge of the precise chromosomal location
of the genes coding for collagens in human skin has
allowed identification of polymorphic markers within
the genes and in the flanking DNA for use in genetic
linkage studies. In addition, sophisticated mutation
detection strategies, based on scanning of the genes,
have led to identification of a large number of mutations in different collagens genes with characteristic
phenotypic consequences.
Under physiologic conditions, fibril-forming collagens molecules spontaneously assemble into insoluble
fibers.17 This observation presented a logistic problem,
because it was difficult to visualize how a collagens
molecule could be synthesized inside the cell and then
secreted into the extracellular space without premature assembly of the molecules into insoluble fibers.
The solution to this problem was found in the demonstration that fibril-forming collagens, and some other
collagens, is initially synthesized as a larger precursor
molecule, procollagen, which is soluble under physiologic conditions.
The precursor polypeptides of procollagen, so-called
pre-proa chains, are synthesized on the ribosomes of the
rough endoplasmic reticulum in fibroblasts and related
cells (Fig. 63-5). This initial translation product contains an amino-terminal signal (or leader) sequence
rich in hydrophobic amino acids. This sequence serves
as a signal for attachment of the ribosomes to the membranes of the rough endoplasmic reticulum and vectorial release of the nascent polypeptides into the
cisternae of the rough endoplasmic reticulum. During
the transmembrane transport of the polypeptides, the
signal sequence is enzymatically removed in a reaction
catalyzed by signal peptidase, and the polypeptides,
termed proa chains, are released inside the lumen of the
rough endoplasmic reticulum. For some collagens
types, in particular the fibril-forming collagens, proa
chains are larger than collagens chains because they
contain additional peptide sequences at both ends of

the molecule.
POSTTRANSLATIONAL
MODIFICATIONS OF
POLYPEPTIDE CHAINS
After the assembly of amino acids into pre-pro chains
on the ribosomes, the polypeptides undergo several
modifications before the completed collagens molecules are deposited into extracellular fibers (Fig. 63-5).
Most of these posttranslational modifications are catalyzed by specific enzymes (Table 63-3), and include
(1) synthesis of hydroxyproline by hydroxylation of
selected prolyl residues; (2) synthesis of hydroxylysine
by hydroxylation of selected lysyl residues; (3) attachment of carbohydrates, galactose, or glucosylgalactose,
onto certain hydroxylysyl residues; (4) chain association, disulfide bonding, and triple-helix formation;
(5) proteolytic conversion of procollagens to collagens;
and (6) fiber formation and cross-linking. Current evidence indicates that modification reactions (1)
(4) are intracellular events, whereas proteolytic conversion, fiber formation, and cross-linking probably
take place extracellularly (see Fig. 63-5).
SYNTHESIS OF HYDROXYPROLINE, HYDRO

XYLYSINE, AND ATTACHMENT OF CARBOHYDRATES. A characteristic feature of collagens is the
presence of hydroxyproline and hydroxylysine residues.9 Free hydroxyproline and hydroxylysine are not
incorporated into nascent polypeptide chains, but result
from the hydroxylation of prolyl and lysyl residues,
respectively (Fig. 63-6). The hydroxylation reactions are
catalyzed by enzymes belonging to the prolyl and lysyl
hydroxylase families.9,4145 These enzymes require
molecular oxygen, ferrous iron, -ketoglutarate, and a
reducing agent, such as ascorbate as cosubstrates or
cofactors for the reactions (Fig. 63-6 and Table 63-3).
Hydroxylation begins while the pro chains are growing on the ribosomes, and it is completed soon after the
release of full-length polypeptide chains from the ribosomes (Fig. 63-7). The hydroxyproline in collagens is
found in two isomeric forms, trans-3-hydroxy-l-proline,
and the most abundant trans-4-hydroxy-l-proline. A
critical amount of trans-4-hydroxy-l-proline is a prerequisite for the folding of chains into the triple helix, the
conformation required for secretion of procollagens
molecules out of the cells. Because triple-helix formation takes place in the cisternae of the rough endoplasmic reticulum, and because prolyl hydroxylases do not
hydroxylate prolyl residues if the collagens substrate is
in a triple-helical conformation, hydroxyproline formation must be completed before the procollagens molecules leave this cellular compartment. Thus, in the
absence of hydroxyproline, the critical triple-helical
structure of collagens would not form under physiologic conditions, and no functional collagens fibers
would appear in the extracellular space. Also, because
prolyl hydroxylase requires a reducing agent, such as
ascorbate, for its activity, ascorbic acid deficiency leads
to a decreased formation of collagens fibers. This
Biosynthesis of procollagen and the assembly of collagen molecules into the extracellular fibers
A
O
Gal
Glc
Glc
Gal
O
OH
O
Gal
HO
O Gal Glc
OH
HO
O Gal
OH
OH
O Gal
Glc
OH
Gal O
HO
Gal
O
Gal
Glc
OH
O
Gal
IC
HO
O
Gal
B
Secretion of procollagen
EC
Plasma
membrane
Glc
Gal
O
OH
OH
OH
OH
Glc
Gal
O
OH
OH
OH
OH
OH
Glc
Gal
O
OH
OH
Glc
Gal
O
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Glc
Gal
O
OH
Glc
Gal
O
OH
Glc
Gal
O
OH
OH
OH
OH
Extracellular modifications:
1. Cleavage of peptide extensions by
specific proteases
OH
OH
Glc
Gal
O
OH
OH
OH
OH
Glc
Gal
O
OH
OH
OH
2. Fibril formation
OH
OH
OH
OH
OH
~ 1/4 of molecule
OH
OH
3. Cross-linking of collagen fibrils by

deamination of hydroxylysine and lysine
residues to give alhehydes, followed by
cross-link formation by reaction of either
(a) 2 aldehydes or (b) 1 aldehydes and
1 -amino group on adjacent molecules
HO
OH
::
Glc
Gal
O
OH
Chapter 63
O
Gal
Intracellular steps:
1. Translation of pre-pro chains on
the ribosomes of the rough endoplasmic
reticulum
2. Cleavage of the signal sequence
3. Hydroxylation of selected prolyl and lysyl
residues
4. Glycosylation of some hydroxylysyl residues
5. Formation of interchain disulfide bonds
6. Formation of triple helices
Figure 63-5 Biosynthesis of procollagens and the assembly of collagens molecules into the extracellular fibers.
EC = extracellular; Glc-Gal = glucosylgalactose attached to a hydroxylysyl residue; IC = intracellular; mRNA = messenger
RNA; OH = hydroxyl group of hydroxyproline or hydroxylysine; RER = rough endoplasmic reticulum.
explains some of the clinical manifestations in scurvy,

such as poor wound healing and decreased tensile
strength of the connective tissues.46 An analogous situation may exist in tissues with hypoxia, because molecular oxygen is a specific requirement for the formation of
hydroxyl groups in hydroxyproline. Studies in animal

models demonstrate that wound healing is relatively
poor under hypobaric conditions, and in such situations
the low oxygen levels may limit the synthesis of
hydroxyproline.47 This observation may also explain the
673
TABLE 63-3
Characteristics of Enzymes Participating in the Biosynthesis of Collagens
Section 9
Product
Co-Factors and
Co-Substrates
Nascent pre-pro chains
Pro chains
None known
Prolyl residue in X-Pro-Gly

sequence in pro chainsb
4-Hydroxyproline
O2, Fe2+, -ketoglutarate,

ascorbic acid
Prolyl-3-hydroxylase
Prolyl residue in Pro-Hyp-Gly

sequence in pro chainsb
3-Hydroxyproline

ascorbic acid
Lysyl hydroxylase
Lysyl residue in Lys-Gly, LysSer, or Lys-Ala sequence in

pro chainsb
Hydroxylysine

ascorbic acid
Collagens galactosyl transferase
Hydroxylysine in pro chainsb
Gal-O-hydroxylysine
Mn2+, UDP-galactose
Collagens glucosyl transferase
Galactosyl-O-hydroxylysine in
pro chainsb
Glc-Gal-O-hydroxylysine
Mn2+, UDP-glucose
Protein disulfide isomerasec
Cysteine residues in the

extensions of pro chains
SS bonds stabilizing the

correct protein conformation
Thiols
Procollagen N-proteinase
(ADAMTS-2)
Procollagen or pn-collagens
Pc-collagens or collagensd
Ca2+
Procollagen C-proteinase
Procollagen pc-collagens
Pn-collagens or collagensd
Ca2+
Lysyl oxidases
Lysyl or hydroxylysyl residue in

fibrillar collagens
Aldehyde derivatives of lysine

or hydroxylysine
Cu2+, O2
Enzymea
Substrate
Signal peptidase
Prolyl-4-hydroxylase
::
ADAMTS = a disintegrin and metalloprotease with thrombospondin motifs; Ala = alanine; Gal = galactose; Glc = glucosyl; Gly = glycine; Hyp =
hydroxyproline; Lys = lysine; pc-collagens = collagens molecule with the C-terminal propeptide still attached whereas the N-propeptide has been
removed; pn-collagens= collagens molecule with the N-terminal propeptide still attached whereas the C-propeptide is cleaved off; Pro = proline;
Ser = serine; UDP = uridine diphosphate.
a
The action of these enzymes (with the exception of signal peptidase) is relatively specific to collagens; the complete sequences of procollagen
synthesis and collagens degradation involve additional, less specific enzymes, such as those of transcription and translation.
b
These reactions are terminated when the pro chains fold into the triple-helical conformation.
c
It has not been established whether the formation of interchain disulfides in procollagen involves enzymatic catalysis, as occurs in some other
proteins, or whether their synthesis takes place spontaneously.
d
If intact procollagen is used as a substrate, partially modified products are formed; however, if the partially cleaved proteins (pn-collagens,
pc-collagens) serve as substrates, collagens is produced.
Structures of proline and hydroxyproline
COOH
OH
COOH
N
I
H
N
I
H
L-proline
trans-4-hydroxyl-L-proline
Gly Pro Y Gly X Pro Gly X Y

Prolyl hydroxylase
O2, Fe2+, -KG, Ac.
Gly Pro Y Gly X Hypro Gly X Y
674
Figure 63-6 Structures of proline (Pro) and hydroxyproline (Hypro), and schematic representation of the enzymatic hydroxylation of prolyl residues in the Y position of
the repeating Gly-X-Y sequence of collagens polypeptides.
Ac = ascorbic acid; Gly = glycine; -KG = -ketoglutarate.
(From Uitto J, Prockop DJ: Inhibition of collagens accumulation by proline analogs: The mechanism of their action.
In: Collagens Metabolism in the Liver, edited by H Popper,
K Becker. New York, Stratton Intercontinental, 1975, p. 139,
with permission.)
Synthesis and secretion of procollagen

by a fibroblast
Extracellular
milieu
Golgi vesicles
OH
O
OHOH Glc
OH
OH
Gal
OH
O
Gal
II
OH
OH
Figure 63-7 Representation of the synthesis and secretion of procollagen by a fibroblast. The enlarged area demonstrates events taking place in the rough endoplasmic
reticulum of the cells during the synthesis of procollagen.
In the first stage (I), the polypeptide chains of procollagen
are synthesized on the membrane-bound ribosomes, and
the nascent chains are fed into the cisternae of the rough
endoplasmic reticulum. Hydroxylation of prolyl and lysyl
residues and glycosylation of hydroxylysyl residues are
initiated on the growing polypeptide chains, and these
reactions are completed soon after the release of full-size
chains from ribosomes (II). Three pro chains are linked together by the formation of interchain disulfide bonds, and
the collagenous portions of the polypeptides assume a
triple-helical conformation (III). The procollagen molecules
are then transferred from the rough endoplasmic reticulum to Golgi vesicles and are secreted from these vesicles
into the extracellular milieu. OH = hydroxyl groups of hydroxyproline and hydroxylysine; Gal = galactosyl residue
attached to hydroxylysine; Gal-Glc = glucosylgalactosyl
residue attached to hydroxylysine in O-glycosidic linkage;
the cloverleaf-like structures signify the hydroxylating and
glycosylating enzymes. (After Prockop DJ et al: Intracellular steps in the biosynthesis of collagens. In: Biochemistry of Collagens, edited by GN Ramachandran, AH Reddi.
New York, Plenum, 1976, p. 163, with permission.)
decreased healing tendency of wounds and ulcers in
peripheral tissues that are anoxic due to relatively poor
blood supply. It may also relate to the recent appreciation that prolyl hydroxylases are genuine oxygen sensors. In addition to the prolyl-4-hydroxylase playing a
critical role in the hydroxylation of prolyl residues on
nascent collagens polypeptide chains, there are additional prolyl-4-hydroxylase isoforms that are responsi-
CHAIN ASSOCIATION, DISULFIDE

BONDING, AND TRIPLE-HELIX
FORMATION
A critical step in the intracellular biosynthesis of procollagens is the association of three pro chains and
subsequent folding of the collagens portion of the
polypeptides into a triple helix (see Fig. 63-7). The
noncollagenous peptide extensions on the individual
pro chains assume globular conformations soon
after their translation, and this conformation contains
the specific information that directs the correct association of the three pro chains. Such a mechanism
might explain the association of pro1 and pro2
chains in a proper 2:1 ratio during the synthesis of
type I procollagen. It would also explain the rapid and
efficient association of the pro chains and folding of
the molecule into the triple helix. The association of
the extensions at the carboxyl-terminal ends of the
polypeptide chains appears to facilitate folding of the
molecules into the triple helix, perhaps by providing a
nucleation site from which the formation of the triple
helix is propagated throughout the collagenous portion of the molecule.
Glc
O Gal
OH
OH
::
III
OH OH
Chapter 63
Gal O OH
OH
ble for the hydroxylation of two proline residues that

earmarks the subunit of the hypoxia-inducible transcription factor (the master regulator of hypoxia-inducible genes) for proteasomal degradation.44,48,49
Lysyl hydroxylation is of critical importance because
hydroxylysyl residues serve either as an attachment
site for galactosyl and glucosylgalactosyl residues during the intracellular synthesis of procollagen, or to the
formation of cross-links that stabilize the collagens
matrix in the extracellular space.9,45,50 The intracellular
modification of lysyl residues is a sequential event,
with first hydroxylation of lysyl residues, followed by
the attachment of galactosyl residue to the hydroxyl
group of hydroxylysine with an O-glycosidic bond and
then a glucose moiety is attached to some of the galactosyl residues (see Figs. 63-5 and 63-7). Therefore, the
synthesis of hydroxylysine is a prerequisite for the glycosylation of collagens (see Table 63-3). Three lysyl
hydroxylase isoforms exist, and one of them, the lysyl3-hydroxylase (LH3), displays three activities: (1) lysyl
hydroxylase, (2) galactosyltransferase, and (3) glucosyltransfrase activities.45 The glycosylation reactions use
uridine diphosphate sugars as a source of the carbohydrate and require Mn2+ as a cofactor. In addition to the
glycosylation of hydroxylysyl residues in the triplehelical portion of the molecule, the nonhelical extensions contain complex carbohydrates, consisting
mainly of mannose. Deficiency of lysyl hydroxylase has
been identified in patients with the scoliotic form (type
VI) of EhlersDanlos syndrome, characterized by
hyperextensible skin, loose-jointedness, severe kyphoscoliosis, and ocular fragility. A connective tissue disorder caused by mutations of the lysyl hydroxylase 3
gene has been recently identified in humans. The disorder is associated with abnormalities in several organs,
including skin, and the phenotype has features that
overlap with a number of known collagens disorders.51
675
CONVERSION OF PROCollagenss
TO COLLAGENs
Section 9
::
After secretion into the extracellular space, procollagens molecules are converted to collagens by limited
proteolysis, which removes the extension peptides on
the molecule.52 The conversion of type I procollagens
to collagens is catalyzed by two specific enzymes, (1)
procollagens N-proteinase and (2) procollagens C-proteinase, that separately remove the amino-terminal
and carboxyl-terminal extensions, respectively (see
Table 63-3). Furthermore, the N-proteinase catalyzing
the conversion of type III procollagens to collagens is a
separate, specific enzyme.
The N-proteinase capable of cleaving type I procollagens belongs to the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family of
extracellular proteases, and is called ADAMTS-2.53 The
activity of this enzyme is dependent on the native conformation of the amino-terminal propeptides in procollagen,
because it does not catalyze the removal of the extension
peptides from isolated pro chains. Furthermore, partially purified N-proteinase is inhibited by metal chelators, which suggests a requirement for divalent cations.
C-proteinase is required for the removal of the carboxyl-terminal extension from type I, II, III, and V procollagen, which allows the fully processed molecules to
form functional fibers.52 Cloning of type I procollagens
C-proteinase revealed that it is identical to bone morphogenic protein-1, a metalloprotease implicated in
pattern formation during development of diverse
organisms and also capable of inducing ectopic bone
formation.54 The activity of C-proteinase/bone morphogenic protein-1 is stimulated by procollagens C-proteinase enhancers, glycoproteins that bind to the C-terminal
propeptide of type I procollagen.55 Thus, the conversion
of procollagens to collagens is a complex, carefully controlled process, and lack of removal of either the aminoor the carboxyl-terminal extensions results in impaired
tensile strength of collagens fibers in the skin. Specifically, deficiency in the removal of the amino-terminal
propeptide of type I collagens in vivo causes dermatosparaxis, a disease of fragile skin, originally recognized
in various animal species, and more recently recognized
in humans.56 Specifically, the human counterpart is the
dermatosparaxis type of EhlersDanlos syndrome (type
VIIc), caused by deficiency in N-proteinase activity. It
should be noted that a disease with similar phenotype,
the arthrochalasia type of EhlersDanlos syndrome
(types VIIa and VIIb), can be caused by mutations in the
type I collagens genes (COL1A1 and COL1A2, respectively) at the cleavage site for the N-proteinase.57
Collagens ASSEMBLY AND

CROSS-LINKING
676
Collagens assembly is best defined for fibrillar collagens. After removal of the extension peptides in the
extracellular space, the collagens molecules spontaneously align to form fibers. However, these fibers do not
attain the necessary tensile strength until the molecules
are linked together by specific covalent bonds known
as cross-links.58 The most common forms of cross-links

in collagens are derived from lysine or hydroxylysine.
The first step in the cross-linking of collagens is the
enzymatic conversion of some of the lysyl and hydroxylysyl residues to the corresponding aldehyde derivatives by removal of the -amino groups (see Figs. 63-5
and 63-7). The aldehydes then form cross-links by two
kinds of reactions. One reaction involves condensation
of an aldehyde with an -amino group still present in
another unmodified lysine or hydroxylysine to form a
Schiff base-type of covalent cross-link. The second type
of reaction is an aldol condensation between two aldehydes. In addition to these cross-links, collagens contains several more complex cross-links that also
involve lysyl or hydroxylysyl residues. The lysine- and
hydroxylysine-derived cross-links can be either intramolecular, occurring between two adjacent chains in
the same collagens molecule, or intermolecular, stabilizing the alignment of neighboring collagens molecules along microfibril structures.
The first step in collagens cross-linking, the oxidative
deamination of certain lysyl and hydroxylysyl residues,
is catalyzed by lysyl oxidase. This enzyme requires copper as a cofactor, and its activity is readily inhibited by
nitriles, such as -aminopropionitrile, which produce
lathyrism in animals. Because the cross-links of collagens provide the tensile strength required in certain tissues, a defect in the formation of these covalent bonds
can lead to a disturbance in connective tissue function.
An example is occipital horn syndrome (previously
known as EhlersDanlos syndrome type IX), which results
from reduced lysyl oxidase activity (see Chapter 137).
The primary defect resides in perturbed copper metabolism caused by mutations in a copper transport enzyme
protein, an adenosine triphosphatase encoded by the
gene MNK-1 that is also involved in Menkes syndrome.59
As a result, serum copper levels are reduced, which
leads to reduced lysyl oxidase activity.
CONTROL OF Collagens
AND EXTRACELLULAR MATRIX
PRODUCTION
A major question in ECM biology concerns the mechanisms that control the deposition of collagens and
other ECM proteins in tissues. Such control must exist
in vivo, because the consequences of uncontrolled
ECM accumulation are demonstrated by diseases such
as progressive systemic sclerosis (see Chapter 157) and
various other fibrotic conditions.60,61
The accumulation of ECM in tissues can be controlled at several different levels of biosynthesis and
degradation. Several observations suggest that an
important control mechanism acts at the level of
mRNA formation through regulation of the transcriptional activity of gene expression.62,63 The transcriptional regulation of gene expression involves both
cis-acting elements and trans-acting factors. The cisacting elements are nucleotide sequences in the promoter region of the gene that serve as binding sites for
trans-acting cellular proteins, which can upregulate or
downregulate the transcriptional promoter activity.
Some of the trans-acting factors are nuclear receptors,
Subfamily domain structures

Collagenases
Stromelysins
Metalloelastase
Matrilysin
Gelatinases
Gelatinase A
Gelatinase B
Membrane-type MMPs
Zn
Zn
Zn
Zn
Zn
Component domains
Propeptide
Hinge region
Catalytic domain
Hemopexin
domain
Fibronectin collagenbinding domain

Active site zinc
Transmembrane
region
Type V collagen
domain
Figure 63-8 Domain structure of matrix metalloproteinases (MMPs).

cal enzyme. Like the other MMPs, MMP-1 contains
intrinsic zinc in the active site and requires calcium for
its activity and thermostabilization.
MMP-1 degrades some of the collagens present in
skin, such as types I, III, and VII, but not others like
types IV and V.74 At physiologic pH and temperature,
the enzyme catalyzes a single cleavage three-quarter of
the distance from the amino terminus in each of the
three chains comprising the triple-helical, native collagens monomer. Specifically, MMP-1 cleaves the 1(I)
chain at a Gly-Ile (glycine-isoleucine) bond (residues
775 and 776) and the 2(I) chain at a Gly-Leu (glycineleucine) bond in the homologous region. Ten other GlyIle or Gly-Leu bonds within the triple-helical domain of
interstitial collagens are not cleaved, which suggests
that the local conformation of the collagenase cleavage
site is a major factor in determining substrate specificity.
Indeed, MMP-1 catalyzes multiple cleavages in the
denatured chains of all collagens types at Gly-Ile and
Gly-Leu bonds. Thus, it appears that the triple-helical
conformation of native collagens can drastically alter
MMP-1 ability to catalyze cleavages that would be permissible from primary sequence consideration alone.
Human neutrophil interstitial collagenase (MMP-8)
attacks collagens at the same site, as does human
MMP-1, to produce the characteristic three-quarter/
one-quarter collagens fragments. Human MMP-8 is
highly homologous to MMP-1, but has a higher degree
of glycosylation. It is not immediately secreted but is
stored in neutrophil granules and released on stimulation. Although both fibroblast (MMP-1) and neutrophil
(MMP-8) collagenases have similar affinities for type I
and III collagens, fibroblast collagenase degrades soluble
In the extracellular space, most collagens form polymers described above, which in turn interact with
other proteins of the ECM through multiple protein
protein interactions. It gives rise to large multimolecular assemblies and to the organization of the ECM
proteins into specific networks.17 In addition, many
growth factors and cytokines specifically interact with
ECM proteins, and they are therefore stored in the networks. There is a continuous remodeling of the multimolecular assemblies, at a rate that can be significantly
enhanced during development, wound healing or in
certain disease processes. This remodeling results in
the release of a large variety of biologically active peptides, including growth factors.34
The remodeling of the ECM is a cooperative multistep process involving a variety of molecular pathways and mechanisms. The initial step depends on the
presence of proteinases capable of initiating the degradation of the ECM proteins. These enzymes comprise
the matrix metalloproteinase (MMP) family,6771 which
includes collagenases, gelatinases, stromelysins, matrilysins, metalloelastase, enamelysin, and the membrane-type MMPs (Fig. 63-8 and Table 63-4). Interstitial
collagenase (MMP-1) was the first enzyme of the MMP
family to be discovered and was defined by its ability
to break down triple-helical collagens that is resistant
to most proteases.72 Human skin collagenase was initially isolated in active form from the culture medium
of skin explants and subsequently as a proenzyme
from monolayer fibroblast cultures.73 Other cell types
present in skin, including keratinocytes, endothelial
cells, monocytes, and macrophages, express an identi-
::
DEGRADATION AND TURNOVER
Domain structure of matrix metalloproteinases
Chapter 63
such as the retinoic acid receptors (RAR and RXR)49

that form a complex with the ligand (a retinoid) and
then bind to the retinoic acid-responsive elements
(RARE) in the target gene. Retinoids, such as all-transretinoic acid, modulate type I collagens gene expression both in vitro and in vivo.64 In particular, quiescent
nonproliferating cells can be stimulated by retinoic
acid to activate collagens gene expression. This may
have relevance to the elevated collagens synthesis
observed in photodamaged dermis after topical application of all-trans-retinoic acid (see Chapter 109).
Diverse growth factors, cytokines, and chemokines
are released into the extracellular space from different
types of cells, such as fibroblasts, keratinocytes, and
endothelial and inflammatory cells. By both paracrine
and autocrine mechanisms these factors elicit intracellular signaling pathways acting on the transcriptional
and/or translational levels. One of the most powerful
regulators of collagens and ECM production is transforming growth factor (TGF-), a member of a family
of growth factors involved in many physiological and
pathological conditions.65 Interestingly, TGF- can
induce the expression of other growth factors, in particular the expression of connective tissue growth factor in fibroblasts. Also, cytokines such as platelet-derived
growth factor, interleukin-1 and -4, and chemokines,
such as monocyte chemotactic protein-1 and -3, are
thought to induce collagens production.66
677
TABLE 63-4
Matrix Metalloproteinases (MMPs)
Section 9
MMP Number
Alternate Name
Interstitial collagenase
MMP-1
Type I collagenase
52,000
Collagens I, II, III, VII, VIII, X, entactin,

tenascin, aggrecan, denatured collagens,
interleukin-1, myelin basic protein,
L-selectin
Neutrophil collagenase
MMP-8
75,000
Collagens I, II, III, V, VII, VIII, X, gelatin,

aggrecan, fibronectin
Collagenase-3
MMP-13
52,000
Collagens I, II, IV, IX, X, XIV, aggrecan
Gelatinase A
MMP-2
72-kDa type IV
collagenase
72,000
Denatured collagens, collagens IV, V, VII,

X, XI, XIV; collagens I, species dependent;
elastin; fibronectin; laminin; aggrecan;
myelin basic protein
Gelatinase B
MMP-9
92-kDa type IV
collagenase
92,000
Denatured collagens, collagens IV, V,

VII, X, XIV, elastin, entactin, aggrecan,
fibronectin, osteonectin, interleukin-1,
plasminogen, myelin basic protein
Stromelysin-1
MMP-3
Proteoglycanase
57,000
Proteoglycan core protein, laminin,

fibronectin, collagens I, IV, V, IX, X, XI,
gelatin, elastin, tenascin, aggrecan,
myelin basic protein, entactin, decorin,
osteonectin
Stromelysin-2
MMP-10
Transin-2
55,000
Proteoglycan core protein, collagens III, IV,

V, laminin, fibronectin, elastin, aggrecan
Stromelysin-3
MMP-11
61,000
1-proteinase inhibitor
Matrilysin
MMP-7
PUMP, matrilysin-1
28,000
Collagens IV, denatured collagens,

laminin, fibronectin, elastin, aggrecan,
tenascin, myelin basic protein
Matrilysin-2
MMP-26
Endometase
28,000
Gelatin, 1-proteinase inhibitor
Membrane-type MMP-1
MMP-14
MTI-MMP
63,000
Progelatinase A, denatured collagens,

fibronectin, laminin, vitronectin, entactin,
proteoglycans
Membrane-type MMP-2
MMP-15
MT2-MMP
72,000
Progelatinase A
Membrane-type MMP-3
MMP-16
MT3-MMP
64,000
Progelatinase A
Membrane-type MMP-4
MMP-17
MT4-MMP
70,000
Unknown
Membrane-type MMP-5
MMP-24
MT5-MMP
73,000
Progelatinase A
Membrane-type MMP-6
MMP-25
MT6-MMP
63,000
Unknown
Metalloelastase
MMP-12
54,000
Elastin, collagens IV, vitronectin,

plasminogen, laminin, entactin,
fibrinogen, fibrin, fibronectin
Enamelysin
MMP-20
54,000
Amelogenin, aggrecan
MMP-19
MMP-19
RASI-1
57,000
Gelatin, aggrecan, fibronectin
MMP-21
MMP-21
Unknown
Unknown
MMP-22
MMP-22
Unknown
Unknown
MMP-23
MMP-23
44,000
Unknown
Epilysin
MMP-28
56,000
Unknown
::
Enzyme
Proenzyme
Molecular
Weight
PUMP = punctuated metalloproteinase.
678
Known Matrix Substrates
Elastic fibers form a network responsible for connective tissue elasticity and resilience specific of various
organs.76,77 The relative concentration of elastic fibers is
highest in the aorta and arterial blood vessels and in
the lungs, while in the skin they are only a minor component. Specifically, in sun-protected adult human
skin, the elastin content is 1%2% of the total dry
weight of dermis.78 In the papillary dermis, elastic
fibers are present either as bundles of microfibrils
(oxytalan fibers) or with small amounts of cross-linked
elastin (elaunin fibers). In the reticular dermis, the elastic fibers consist primarily of elastin, and they are ori-
ented horizontally in a network with vertical extensions

to the papillary dermis in the form of oxytalan fibers.
Examination of connective tissues by transmission
electron microscopy has demonstrated that mature
elastic fibers consist of two distinct components (Fig.
63-9). An amorphous, electron-lucent core consists primarily of elastin, surrounded by distinct electrondense microfibrillar structures that have a regular
diameter of 1012 nm, and which is composed of a
variety of microfibrillar proteins such as fibrillins and
fibulins.
Elastin and the microfibrillar proteins exist in close
association in various connective tissues; however, the
relative proportions of these components vary during
embryonic development. Elastic fibers that form during the first trimester of fetal development consist of
bundles of microfibrils, which are thought to form a
scaffold into which the elastin molecules will align
while fetal age is increasing. Analysis of mature, fully
developed elastic fibers suggests that elastin represents
well over 90% of the total content of such fibers (see Fig.
63-9). However, it should be noted that skin as well as
other tissues contain microfibrils devoid of elastin.
BIOLOGY OF THE ELASTIC FIBERS

Characterization of elastin was hindered for a long
time by its extreme insolubility in mature animal tissues. However, it was discovered that this insolubility is attributable to the presence of complex covalent
cross-links, known as desmosines (see Section Fibrillogenesis and Cross-Linking of Elastin), whose formation can be prevented by maintaining the animals
on a copper-deficient diet or by feeding them lathyrogens, such as -aminopropionitrile, which inhibit
elastin and collagens cross-linking. Once the formation of the cross-links is prevented, a large fraction of
newly synthesized elastin can be extracted from the
tissues.79
Cloning of cDNAs corresponding to the human elastin mRNA, approximately 3.5 kilobases (kb) in size, has
allowed elucidation of the entire primary sequence of
tropoelastin8084 (Fig. 63-10). The basic molecular unit of
elastin is a linear polypeptide, known as tropoelastin,
that consists of approximately 800 amino acids with a
molecular mass of around 70 kDa. Similar to collagens
STRUCTURE AND DEVELOPMENT

OF THE ELASTIC FIBERS
Figure 63-9 Transmission electron microscopy of human

skin demonstrating a fibroblast (F) surrounded by elastic
structures (E) and collagens fibers (C).
::
ELASTIN AND ASSOCIATED

MICROFIBRILLAR PROTEINS
Chapter 63
type III collagens with a higher turnover rate, whereas

neutrophil collagenase degrades soluble type I collagens more rapidly. For both enzymes, the differences
in specificity against monomeric collagens are largely
abolished when the substrates are reconstituted into
the insoluble fibrillar forms found in tissues.75
Important mechanistic information on collagens
degradation has recently emerged, and specifically, it
has been shown75 that activated collagenase (MMP-1)
moves processively on collagens fibrils in which the
mechanism of movement is a biased diffusion with
the biased component of the motion depending on the
proteolysis of collagens and not on ATP hydrolysis.
Most importantly, the closely related MMPs, MMP-2
(gelatinase) MMP-9, and the extracellular portion of
the membrane-associated metalloproteinase MT1
MMP, can also diffuse on collagens fibrils. These studies also show that a collagenolytic MT1MMP complex
exists at the cell surface. The MT1MMP complex
anchored at the cell surface has profound implications
concerning the generation of the forces required for
cell locomotion, not only in the normal physiologic
processes of tissue remodeling but also in pathologic
processes, such as tumor invasion.
Collagenase-3 (MMP-13), first cloned from breast carcinoma, is homologous to rodent collagenase.69 The purified recombinant enzyme cleaves triple-helical collagens,
giving the characteristic three-quarter/one-quarter fragments. However, unlike interstitial and neutrophil collagenases, collagenase-3 acts five to ten times more
rapidly on soluble type II collagens, a cartilage-specific
collagens, than on types I and III. At physiologic temperature, the collagens cleavage products (i.e., the threequarter/one-quarter fragments), which are initially
triple helical, become soluble, are thermally unstable,
and denature spontaneously, forming gelatin (denatured
collagens). These denatured gelatin polypeptides are
then susceptible to attack by other proteinases. Thus, the
interstitial collagenases stand at a key point in connective tissue metabolism: they initiate the proteolytic
events that result in the degradation of collagens and
overall turnover of the extracellular matrices.
679
Representation of the human elastin gene and the corresponding complementary DNA
A
S S B B B BSE B S B E
Exon#
S SHSH SB SB
2 3 4
ESB
H BB
E SBB
B BSaB S H SS HE B
5 6 9 1011 13
7
12 14
8
15
16 18 19 20 23
17
21
22
20
30
10
2427 28
25
29
26
30
26a
H S
HS BB
31
32
33
36
40
Nuceotides, kb
Section 9
::
680
Human elastin complementary DNA
poly A poly A
1 3 5 7 9 11 13 15 17
19
21 23 25 26a 28 30 32 36
Exon# 2 4 6 8 10 12 14 16 18
20 22 24 26 27 29 31 33
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Figure 63-10 Representation of the human elastin gene (A) and the corresponding complementary DNA (cDNA) (B). A.
The exons have been numbered starting from the 5 end of the gene and correspond to those shown in the cDNA (see
B). The presence of restriction endonuclease cleavage sites: BamHI (B), EcoRI (E), HindIII (H), and Sacl (S) are noted on top.
B. The cDNA, approximately 3.5 kilobases (kb) in size, is divided into separate exons that are numbered from 1 to 36 and
drawn to scale. Note that the human elastin gene contains only 34 exons; however, to maintain a consistent numbering
system between the bovine and human elastin genes, the last exon is designated as number 36; thus, the human gene is
missing the counterparts of bovine exons 34 and 35. The arrows indicate the exons that have been shown to be subject
to alternative splicing. The arrows with poly A indicate the polyadenylation sites. (From Uitto et al: Elastic fibers of the
connective tissue. In: Biochemistry and Physiology of Skin, 2nd edition, edited by L Goldsmith. New York, Oxford University
Press, 1991, with permission.)
type I, glycine accounts for about one-third of the

amino acid residues in elastin; however, it is not evenly
distributed as it is in a typical collagens sequence.
Instead, the glycine residues are grouped in valineand proline-rich regions, which are interspersed with
alanine-rich sequences. Elastin also contains some
hydroxyproline, but the relative content of this amino
acid is considerably lower than that in collagens, and
the values for hydroxyproline are variable. Elastin does
not contain hydroxylysine or carbohydrate moieties
covalently linked to the polypeptide chain.
A characteristic feature of elastic fibers is the presence of cross-links that covalently bind elastin polypeptide chains into a fiber network. The deduced amino
acid sequence depicts alternating segments of crosslink domains, characterized by the presence of lysyl
residues separated by two or three alanine residues,
and hydrophobic domains. The two major cross-link
compounds, desmosine and its isomer, isodesmosine,
are structures that appear to be unique to elastin.79 The
content of desmosines in various elastin preparations
has been shown to be fairly constant, approximately 1.5
residues per 1,000 amino acids. Consequently, assay of
desmosine and isodesmosine can provide a quantitative measure of the elastin content in tissues.79
CONSTITUTIVE AND ALTERNATIVE SPLICING OF ELASTIN. The human elastin gene consists
of 34 separate exons spanning a total of 45 kb of

genomic DNA (see Fig. 63-10). The information stored
in the DNA sequence is transcribed in the nucleus of
the cells to a large mRNA precursor, which undergoes
several posttranscriptional modifications, including
splicing and polyadenylation. The processed molecules are then transported to the cytoplasm, where the
functional mRNAs serve as templates for the synthesis
of elastin polypeptides during translation. Several
lines of evidence suggest that the rate of elastin biosynthesis is largely regulated by the abundance of the
functional mRNA, and consequently, assay of elastin
mRNA levels allows measurements of the rate of elastin biosynthesis in tissues and cells.
An early observation during the isolation of human
elastin cDNAs was that several overlapping clones
were identical, with the exception of short sequences
that were absent in some clones but present in others.81,83,84 Comparison of these sequences in the cDNAs
with the corresponding genomic DNA segments indicated that the differences were due to alternative splicing of certain exons during posttranscriptional
processing of the elastin pre-mRNA. In fact, at least six
exons in the human gene have been reported to be subject to alternative splicing, and several of the variant
mRNAs are translated into protein. This mechanism
can provide significant variation in the amino acid
composition of individual elastin polypeptides and
presumably in the function of the elastic fibers in different tissues. However, the developmental significance and tissue specificity of alternative splicing have
not been elucidated in detail.
REGULATION OF ELASTIN GENE EXPRESSION. The elastin promoter contains a remarkable
extracellular space, and the first step is the oxidative

deamination of lysyl residues to corresponding aldehydes, known as allysines. This conversion is catalyzed
by copper-requiring enzymes, lysyl oxidases.94,95 The
desmosines are formed by the fusion of three allysines
and a fourth unmodified lysyl residue in two adjacent
tropoelastin chains. Thus, the desmosines link the individual elastin polypeptides into an insoluble network.
Lysyl oxidases, a group of closely related enzymes,
require copper and molecular oxygen as cofactors. It
has been shown that the activity of lysyl oxidases is
reduced with copper deficiency and that it is associated with a disorder of connective tissue.96,97 In particular, the individual tropoelastin polypeptides remain
soluble and the elastin-rich tissues are fragile.
ple cis-acting elements in the elastin promoter region

suggests that elastin gene expression is subject to modulation at the transcriptional level by trans-acting factors. For example, previous studies have indicated that
tumor necrosis factor- decreases elastin mRNA abundance primarily by suppressing promoter activity.88 In
other studies, TGF- has been shown to upregulate the
abundance of human elastin mRNA by up to approximately 30-fold,89 but evidence from transient transfection assays suggests that this upregulation is, at least in
part, posttranscriptional. In fact, assay of elastin
mRNA half-life suggests that TGF- stabilizes the elastin mRNA, which leads to elevated steady-state levels.
These observations collectively suggest that mediators
FIBRILLOGENESIS AND CROSS-LINKING OF

ELASTIN. The formation of desmosines occurs in the
::
CYTOKINE AND HORMONAL REGULATION

OF ELASTIN SYNTHESIS. The presence of multi-
ELASTIN BIOSYNTHESIS. Elastin biosynthesis

involves several specific steps necessary for the assembly of elastic fibers. Several studies show that smooth
muscle cells in culture synthesize relatively large quantities of elastin, which suggests that they may be the
major source of elastin in tissues rich in elastic fibers,
such as vascular connective tissue.92,93 The amount of
elastin synthesized by cultured human skin fibroblasts
is relatively small; nonetheless, fibroblasts may be the
primary source of elastin in the dermis. After the completion of translation, newly synthesized polypeptides
are translocated into the cisternae of the rough endoplasmic reticulum, and then transferred from the
rough endoplasmic reticulum into the extracellular
space. Several observations suggest that the secretion
of elastin polypeptides is a process that involves the
microtubules of the cells and that the molecules may
be transferred out of the cells packaged in Golgi vacuoles or related vesicles.
Chapter 63
constellation of potential binding sites for transcriptional regulatory factors indicative of complex transcriptional regulation. These include multiple Sp1
and AP2 binding sites, putative glucocorticoidresponsive elements, and phorbol ester tumor promoter,
12-O-tetradecanoylphorbol
and
cyclic
adenosine monophosphate-responsive elements. The
absence of a TATA box in the promoter region suggests that there may be multiple sites of transcriptional initiation, and various molecular tests support
this notion.82 Functional analyses of the human elastin promoter segment have been carried out by constructing a panel of promoter-reporter gene (such as
chloramphenicol acetyl transferase) constructs.85 Use
of these constructs in transient transfection of a variety of cultured cells, including human skin fibroblasts, indicated that the core promoter necessary for
basal expression of the gene is contained within the
region 128 to 1 (in reference to translation initiation
site 1, +1), and the upstream sequences contain several upregulatory and downregulatory elements.
Development of transgenic mice expressing the
human elastin promoter has revealed that 5.2 kb of
DNA flanking the human elastin gene contains the
elements necessary for tissue-specific expression.86 In
addition to the 5 upstream sequences, the first introns
of both the bovine and human elastin genes contain
regions of extremely strong sequence homology.
Because it has been demonstrated that the first intron
of three different collagens genes contains segments
that act as enhancer elements of the promoter activity,87 the strong conservation within intron 1 of the
elastin gene suggests the possible presence of an
enhancer in this gene as well.
released from inflammatory cells can modulate elastin

gene expression, and such modulation may play a role
in diseases characterized by altered accumulation of
elastic fibers in tissues.
Vitamin D3 also modulates elastin gene expression.
Specifically, incubation of fibroblasts with vitamin D3
results in an 80%90% decrease in total accumulation
of tropoelastin, accompanied by a parallel decrease in
steady-state levels of the corresponding mRNA.90 At
the same time, insulin-like growth factor-1 enhances
elastin gene expression at the transcriptional level.91
Although there is preliminary evidence for modulation of elastin gene expression by selective growth factors and hormone-like substances, the precise details
are largely unknown.
DEGRADATION AND REMODELING OF

ELASTIN. Although the metabolic turnover of elastin
is very slow compared with that of proteins in general,

a portion of the bodys elastin is continuously degraded
and may partly be replaced by newly synthesized
fibers.98 In addition, degradation of elastin is markedly
increased in a variety of pathologic conditions.99 Thus,
the tissues containing elastin must contain proteolytic
enzymes that are capable of degrading elastic fibers.
681
TABLE 63-5
Microfibrillar Component Proteins

Microfibrillar Protein
Characteristic Features
Human Chromosomal Locus
Fibrillins (FBNs)
FBN1
FBN2
350 kDa
Mutations in Marfan syndrome
Mutations in congenital contractural
arachnodactyly
15q15-q21
5q23-q31
FBN3
19p13.313.2
Section 9
::
Latent TGF--binding proteins (LTBPs)

LTBP1
LTBP2
LTBP3
LTBP4
125310 kDa
Fibulins (FBLNs)
FBLN1
FBLN2
FBLN3
FBLN4
FBLN5
60240 kDa
Microfibril-associated glycoproteins (MAGPs)

MAGP1
MAGP2
Microfibril-associated proteins (MFAPs)
MFAP1
MFAP2
MFAP3
MFAP4
2p2224
14q22-q33
11q12
19q13.113.2
Mutations in cutis laxa

Mutations in cutis laxa
22q13.3
3p24-p25
2p16
11q13
14q32.1
31 kDa; widely distributed in microfibrils

25 kDa
1p36.1-p35
12p12.3-p13.1
Very acidic
15q15-q21
1p36.1-p35
5q32-q33.2
17p11.2
Frequently deleted in SmithMagenis

syndrome
ig-h3
Lysyl oxidases (LOXs)
LOX
LOXL1
LOXL2
LOXL3
LOXL4
5q31
Probably not structural components
Emilins
Emilin1 (gp115)
Emilin2
5q23-q31
15q24-q25
8p21.3-p21.2
2p13
10q24
2p23
18p11.3
EGF = epidermal growth factor; TGF- = transforming growth factor-; ig-h3 = TGF--inducible gene h3.
682
Evidence for elastase, a specific elastolytic enzyme,

was first obtained from study of the pancreas, and since
then elastolytic enzymes have been detected in several
other tissues, as well as in a variety of cell types, including polymorphonuclear leukocytes, monocytes/macrophages, and platelets.100 However, elastases from
different sources (pancreas vs. polymorphonuclear leukocytes) have different cleavage specificities, as shown
by peptide mapping of degradation products.101
The classic elastases are serine proteases that
degrade insoluble elastic fibers at neutral or slightly
alkaline pH. The activity of these enzymes is inhibited
by serum factors, such as 1-antitrypsin and 2macroglobulin. In addition to the classic elastases,
which are serine proteases, others were shown to be
metalloenzymes requiring calcium for their activity.
One such enzyme is secreted by macrophages isolated
from human alveolar macrophage exudates.102
MICROFIBRILLAR PROTEINS
At the electron microscopic level, the microfibrils of
the dermis appear in cross section as an outer electrondense shell surrounding an inner lucid core, and in
longitudinal section as a beaded chain, which suggests
that they may be composed of more than one protein.
Moreover, there is no immunoreactive elastin associated with microfibrils located close to the dermalepidermal junction, but as microfibrils traverse the
dermis, they are associated with an increasing amount
of amorphous elastin. Because of their insolubility and
apparent complexity, chemical characterization of the
microfibrils has progressed slowly until recently. These
structural proteins can now be divided into several
groups based on their molecular characteristics. Table
63-5 lists these proteins and provides some distinguishing features, including their human chromosomal
localizations. These groups include several gene families that share common structural motifs.
THE FIBULINS. The fibulins are a family of ECM

glycoproteins that contain tandem EGF-like repeats
similar to fibrillins and LTBPs, and a common carboxyl-terminal globular domain (see Fig. 63-11).
LTBP-1
Fibrillin-1
KEY
Proline-rich domain
Anaphylatoxin-like motif
Hybrid domain
Eight cysteine domain
EGF-like domain
EGF-like domain-calcium binding
Four cysteine domain
Figure 63-11 Modular domain structure of major elastinassociated microfibrillar proteins, including fibrillin (FBN),
latent transforming growth factor--binding protein
(LTBP), and fibulin (FBLN). The first member of each gene
family is represented. The FBN, LTBP, and FBLN families
are related because they share common protein motifs.
(Adapted from Rosenbloom J, Abrams WR: Elastin and the
microfibrillar apparatus. In: Connective Tissue and Its Heritable Disorders, 2nd edition, edited by RM Royce, B Steinmann. New York, Wiley-Liss, 2002.)
Regulation of TGF- activity

LAP
(latency associatied protein)
that LTBPs contain EGF-like motifs similar to those

found in fibrillins (Fig. 63-11 provides a comparison of
the structures of fibrillins and LTBPs). TGF- is always
secreted as a latent complex with Latency-Associated
Peptide (LAP) and this complex is bound to an LTBP
(Fig. 63-12). To date, four distinct genes (LTBP1 to
LTBP4) have been identified, coding for LTBPs ranging
in size from 125 to 310 kDa.108,109 Although LTBPs may
facilitate the secretion of TGF- or association of the
inactive complex to the cell surface where activation
takes place, they are also found as free proteins associated with components of the ECM. Development of an
LTBP3 knockout mouse revealed craniofacial malformations, perturbed ossification, and development of
osteosclerosis and osteoarthritis in the deficient animals. These observations were interpreted to mean
that LTBP3 is important for the control of TGF- action
and, specifically, that LTBPs may modulate TGF- bioavailability. Immunohistologic studies have localized
LTBP1 to microfibrils in elastic fibers, which strongly
suggests that one or more of the LTBPs may be a component of these fibrils. Furthermore, levels of LTBP1
are altered in a number of pathologic conditions,
including solar elastosis.110
Fibulin-1
::
THE LATENT TRANSFORMING GROWTH

FACTOR--BINDING PROTEINS. It is of interest
Chapter 63
THE FIBRILLINS. The largest, and perhaps the most

important microfibrillar proteins for biology and
pathology of the dermis, are the fibrillins, 350-kDa glycoproteins that form an integral part of the microfibril
structure.103,104 Electron microscopic images of human
monomeric fibrillin synthesized by cultured fibroblasts show an extended flexible molecule, approximately 148-nm long and 2.2-nm wide. Multiple fibrillin
molecules align in a parallel head-to-tail fashion to
form microfibrils. Molecular cloning studies have so
far identified three distinct homologous human genes,
(1) FBN1, (2) FBN2, and (3) FBN3, encoding fibrillin-1,
-2, and 3, respectively.104 Analysis of the amino acid
sequences deduced from cloned cDNAs showed that
these proteins contain multiple repeats of a motif initially observed in epidermal growth factor (EGF) precursor molecule. These motifs have either six or eight
conserved cysteines, and many of them contain a consensus sequence for calcium binding.103,104 Such EGFlike motifs are quite frequent in ECM proteins, and
occur as several copies in, for instance, laminins, fibulins, nidogens, agrin, perlecan, tenascins, and latent
TGF--binding proteins (LTBPs). Besides important
structural functions for tissue architecture, it is now
clear that fibrillins regulate signaling events and control directly and indirectly cellular activities. Therefore, they play critical roles during development and
disease processes.105107
Modular domain structure of major

elastin-associated microfibullar proteins
TGF-
LTBP
(latent TGF- binding protein)
Figure 63-12 Regulation of TGF- activity. TGF- is synthesized and secreted in a latent, inactive form in a complex
with the latency-associated peptide and the latent TGF-binding protein. Therefore, it can be stored in an inactive
form in large ECM aggregates. Dissociation of the protein
complex leads to activation of TGF- and a rapid availability, depending on the biological requirements.
683
Section 9
::
684
Molecular cloning has identified seven fibulin genes

(see Table 63-5). Fibulins are widely distributed in connective tissues, including the skin, where they are
located within the elastic fibers.111,112 Fibulin-4- and
fibulin-5-deficient mice, developed by targeted ablation of the corresponding genes, demonstrate marked
reduction in elastogenesis. Fibulin-4-deficient mice
have a severe phenotype that leads to perinatal death,
primarily due to pulmonary and cardiovascular abnormalities.113 Particularly interesting is the phenotype of
fibulin-5 knockout mice, which show progressive laxity of skin in addition to vascular abnormalities and
emphysematous lung changes.114,115 The skin changes
are reminiscent of those noted in patients with congenital cutis laxa. In fact, mutations in the FBLN4 and
FBLN5 genes have been documented in some cases of
cutis laxa.116118
A number of other proteins unrelated to the fibrillins,
LTBPs, and fibulins are constituents of the microfibrils.
They include the lysyl oxidases,94,95 interface proteins
called emilins,119 and several proteins120 belonging to
the families of Microfibril-Associated Proteins (MAP)
or microfibril-associated glycoproteins (see Table 63-5).
Among the latter, microfibril-associated protein 1 is
remarkable in that it is extremely acidic, with glutamic
acid comprising 23% and aspartic acid 6% of the residues. The extremely acidic nature of the protein suggests that it may have an important function in the
assembly of the very basic tropoelastin molecules.
Finally, lysyl oxidases are critical for the cross-linking
and stabilization of the elastic fiber structures.
PROTEOGLYCANS AND
GLYCOSAMINOGLYCANS
Historically, terms such as ground substance or mucopolysaccharides were used to describe proteoglycans
because of their histologic appearance and their thick
and mucinous nature when isolated. Because of these
physical properties, proteoglycans were difficult to
study. Our understanding of proteoglycans has markedly advanced as a result of increased information
about their core proteins and the subsequent use of
molecular tools to study the expression and function of
both the protein core and glucosaminoglucan (GAG)
components. Now, proteoglycans are recognized as a
structurally unique and highly diverse group of macromolecules. The most distinguishing structural characteristic of proteoglycans is that they comprise both a
core protein and covalently linked linear carbohydrate
chains known as GAGs. Proteoglycans constitute an
important portion of external cellular membranes and
ECM of the skin. Their ability to bind proteins and
alter proteinprotein interactions or enzymatic activities has identified them as important determinants of
cellular responsiveness in development, homeostasis,
and disease. Because GAGs are highly polyanionic and
bear a high charge density, they are a critical component of the skin, and together with the core proteins,
they impart a unique set of functions that are critical to
a large number of biologic processes.
A prototype of proteoglycan structure
A
SO3- SO3Ser
SO3-
Core protein:
Defined by a single gene
linked to one or more GAGs
Location is intracelluar, on
cell surface or extracellular
GAGs:
Ser
Defined by protein
core and synthesis
Variable disacharides,
size, sulfation and charge
SO3- SO3-
SO3-
SO3-
B
Hyaluronic acid
Heparan sulfate
Chondroitin sulfate
SO3- SO3-
SO3- SO3-
SO3-
Dermatan sulfate
SO3- SO3SO3-
Galactosamine
Iduronic acid
Glucosamine
Xylose
Glucuronic acid
Galactose
Figure 63-13 A. Prototype of proteoglycan structure.

Core proteins may contain from 1 to 100 glycosaminoglycan (GAG) chains, depending on the core protein sequence. Two different GAG chains are shown: dermatan
sulfate (top left) and heparan sulfate (bottom right). Sites
of potential sulfation are indicated. Ser represents a serine
amino acid residue in the core protein to which GAGs are
attached. B. Disaccharide repeating units of GAGs shown
as tetrasaccharides. Structures of heparan sulfate, dermatan sulfate, chondroitin sulfate A (chondroitin 4-sulfate)/C
(chondroitin-6 sulfate), and hyaluronan are shown. Sulfation can vary in heparan sulfate and dermatan sulfate.
STRUCTURE AND SYNTHESIS

OF PROTEOGLYCANS
The prototypical proteoglycan consists of a single core
protein linked to one or more GAGs (Fig. 63-13). Each
core protein has the capacity to accept a variety of
GAG chains. Consequently, the nomenclature for proteoglycans is complicated in that individual molecules
must be defined based on the core protein and the
associated GAGs.
THE GLYCOSAMINOGLYCAN CHAINS

The GAG chains are defined based on the assembly of
essential sugar residues.121,122 These sugars are organized as disaccharide pairs that usually consist of an
direct synthesis of the GAG is encoded within the core

protein sequence itself. The final product, core protein
with attached GAG, defines the proteoglycan (see Fig.
63-13). Hyaluronan, the only GAG produced without
attachment to a core protein, is synthesized by an
enzyme complex at the plasma membrane and then
extruded into the extracellular space.
THE VARIETY OF PROTEOGLYCAN

CORE PROTEINS
For purposes of organization, it is useful to group proteoglycans according to their site of expression by the
cell. Specific proteoglycan core proteins have been
identified within the cell, attached to the cell surface,
bound within the ECM, and released in soluble form
(Table 63-6).
CELL SURFACE PROTEOGLYCANS: SYNDECANS AND GLYPICANS. Several cell surface pro-
teoglycans are very interesting because they act at the

interface between the plasma membrane and the extracellular environment. They are attached to the cell surface either by a phospholipid anchor (i.e., glypican
family) or as membrane-spanning core proteins (i.e.,
syndecan family).
The glypicans share the glycophosphatidyl inositol
anchorage mechanism and a unique cysteine motif
that is likely to impart a compact tertiary structure to
the proteoglycans. Consequently, glypicans can be
visualized as a compact protein presenting GAG
chains in close proximity to the outer surface of the
plasma membrane. Six isoforms (glypican-1 to 6) have
been described,124126 and expression of some glypicans
may be altered in inflamed skin and chronic wounds.127
The syndecan core proteins consist of a short C-terminal cytoplasmic region, a transmembrane domain,
and an extracellular region containing attachment sites
for GAG chains. Unlike glypicans, syndecans span the
plasma membrane and extend beyond the surface of
the cell. In this way, syndecans are in a unique position
to connect extracellular GAG to structures within the
proteoglycan and is found within the secretory granules of hematopoietic cells, including mast cells, leukocytes, and eosinophils. The core protein is processed
further to contain either heparan sulfate or chondroitin
sulfate GAG. The heparan sulfate form is found in
serosal mast cells and is a major source from which
heparin is pharmacologically derived. The serglycin
peptide core is composed primarily of tandem serine
glycine repeats and has an estimated mass of 1618
kDa before GAG addition and 60750 kDa after the
addition of multiple heterogenous GAG chains.123
Thus, serglycin is a unique proteoglycan because of its
distinctive core protein sequence, and intracellular
localization. In the skin, serglycin is found whenever
mast cells or eosinophils enter the dermal stroma. On
release, serglycin becomes a major source for the delivery of highly sulfated heparan sulfate GAG.
::
INTRACELLULAR PROTEOGLYCAN: SERGLYCIN. Serglycin is the best-known intracellular
Chapter 63
acidic sugar that is either an iduronic acid or glucuronic acid alternating with a hexosamine that is either
glucosamine or galactosamine. When the chains are
assembled as disaccharides, the choice of sugars and
the linkage between them is used to assign a name to
the GAG chain. Thus, several terms are used to define
GAGs (see Fig. 63-13), including hyaluronic acid, which
contains a glucuronic acid alternating with N-acetylglucosamine-linked 13 and 14; heparan sulfate,
containing iduronic or glucuronic acids alternating
with N-acetylglucosamine-linked 14; chondroitin sulfate, containing glucuronic acid alternating with
N-acetylgalactosamine-linked 13 and 14; and keratan sulfate, containing galactose alternating with
N-acetylglucosamine-linked 14 and 13. A fifth
general term used to describe GAGs, and of particular
importance to cutaneous biology, is dermatan sulfate.
This form of GAG (also known as chondroitin sulfate B)
is similar to other chondroitin sulfates except that it
contains a high proportion of iduronic acids in place of
glucuronic acid and has more variable sulfation. Dermatan sulfate shares features of both chondroitin sulfate (N-acetylgalactosamine) and heparan sulfate
(iduronate) (see Fig. 63-13).
The linear chains of linked disaccharide units in a
GAG are highly variable in size, ranging from as few
as ten disaccharides to several thousand. Thus, the
mass of naturally occurring GAGs typically ranges
between 5 103 Da and 5 107 Da for hyaluronic acid.
Further variability is introduced into the GAG chain
by epimerization reactions and sulfation reactions. The
control of these reactions depends on the nature of the
GAG, the core protein to which it may be attached,
the cell type, and the cell environment. For example,
the simplest GAG, hyaluronic acid, is never sulfated,
whereas other GAGs can be sulfated to varying degree.
The highly sulfated sugars tend to occur in specific
regions of the GAG chain and are interspersed with
areas of low sulfation. Such discrete domains of low or
high sulfation are believed to determine the interactions between proteoglycans and GAGs and their
many binding partners. The size, disaccharide composition, and sulfation are of critical importance in understanding GAGs. These parameters influence function
and are the mechanism by which instructions are
defined within the molecule. Thus, the linear GAG
should be considered as a molecule containing information, just as information is encoded in a protein.121,122
Synthesis of GAGs (with the exception of hyaluronan) occurs in the Golgi apparatus, and the sequence
information is determined by the activity and location
of multiple specific enzymes along this pathway. Today,
many of the enzymes that control heparan sulfate synthesis and those enzymes responsible for postsynthetic
modifications have been identified and characterized.
The sulfated GAGs are all synthesized on core proteins.
The tetrasaccharide xylosegalactosegalactoseglucuronic acid is first assembled on the core protein by
beginning with a xylosyltransferase that forms a linkage between xylose and a serine residue in the core protein. Subsequent elongation reactions that occur in the
Golgi apparatus define the nature of the GAG chain. It
is appreciated that part of the information necessary to
685
TABLE 63-6
Core Proteins of Proteoglycans
Section 9
::
Core Protein
Location
Usual GAG Component
Intracellular
Serglycin
Mast cells, basophils
HS, CS
Cell surface
Syndecan-1
Syndecan-2
Syndecan-3
Syndecan-4
NG-2
Glypican (GPC-1)
Cerebroglycan (GPC-2)
OCI-5 (GPC-3)
k-glypican (GPC-4)
Glypican-5 (GPC-5)
Glypican-6 (GPC-6)
Epican
Betaglycan
Endocan
Thrombomodulin
Keratinocytes, other epithelia

Fibroblasts, endothelia, bone
Neural cells, limbs
Ubiquitous, lymphoid
Neural, melanoma
Brain, vascular endothelia
Brain only
Intestine and mesenchymal
Kidney, brain
Brain, kidney, bone
Intestine, kidney, lung
Keratinocytes
Fibroblasts, epithelia
Endothelia
Endothelia
HS, CS
HS
HS
HS, CS
CS
HS
HS
HS
HS
HS
HS
HS, CS, KS
HS
DS
DS
Extracellular matrix
Aggrecan
Versican
Brevican
Neurocan
Phosphocan
Decorin
Biglycan
Epiphycan
OIF
Fibromodulin
Lumican
Agrin
Perlecan
Bamacan
Cartilage
Fibroblasts
Brain
Brain
Brain
Fibroblasts, others
Bone
Cartilage
Cartilage
Fibroblasts
Cornea
Brain
Basement membranes
Basement membranes
KS, CS
CS, DS
CS
CS
CS, KS
DS
DS
DS
KS
KS
HS
HS
CS
CS = chondroitin sulfate; DS = dermatan sulfate; GAG = glycosaminoglycan; HS = heparan sulfate; KS = keratan sulfate; NG-2 = NG2 proteoglycan;
OIF = osteoinductive factor.
686
cytoplasm.124,126 The intracellular domain endows syndecans to participate in several signal transduction
pathways, including the protein kinase C pathway.127129 Syndecan transcripts and proteins are
expressed in distinct patterns during development and
in mature tissues.130 Syndecan-1 is particularly abundant on keratinocytes and can vary the nature of
attached GAG chains as keratinocytes differentiate.131
During wound repair, syndecan-1 and syndecan-4 are
highly induced in the dermis and granulation tissue.132
Deletion of syndecan-4 from mice decreases the rate of
wound repair.133 During malignant transformation,
syndecan-1 expression decreases in the epidermis,134
and expression can alter malignant behavior in select
cell types.135 Thus, syndecans have received particular
attention as proteoglycans that modify cell function.
Because syndecans and other proteoglycans can contain more than one GAG species, either simultaneously or under different cellular circumstances, GAG
expression provides another mechanism of regulation
in addition to protein expression.
LARGE AGGREGATING EXTRACELLULAR

MATRIX PROTEOGLYCANS: AGGRECAN
AND VERSICAN. Aggrecan, a large proteoglycan
found in cartilage, has a core protein containing a

region with over 100 serineglycine dipeptides that
serve as attachment sites for up to 130 GAG chains. As
many as 100 aggrecan molecules can bind to a single
hyaluronic acid molecule. Thus, the overall proteoglycan aggregate (from which the name aggrecan is
derived) can have a mass near 200,000 kDa.135
In the skin, fibroblasts produce large aggregating
proteoglycans similar to aggrecan, the best known
being versican.135,136 The core protein of versican contains attachment sites for 1215 GAG chains, which are
primarily chondroitin sulfate or dermatan sulfate. Versican, like aggrecan, binds hyaluronic acid, which
enables it to form large aggregates. In skin, versican
has been identified in the dermis (fibroblasts) and epidermis (keratinocytes) and demonstrates selective
upregulation in response to TGF-.137 Thus, the size,
distribution, and abundance of versican in the skin
suggest that it is an important molecule in the regulation of the behavior of the skin.
SMALL EXTRACELLULAR MATRIX PROTEOGLYCANS: DECORIN. Several genes encoding
Ligand
Extracellular matrix
components
Collagens types I, III, IV, V

Fibronectin
Laminin
Pleiotrophin
Tenascin-X
Thrombospondin
Vitronectin
wnt-I
wnt-induced secretory protein
Growth factors (GFs)
Fibroblast GF family
Hepatocyte GF/scatter factor
Heparin-binding epidermal GF
Platelet-derived GF
Schwannoma-derived GF
Vascular endothelial GF
Growth factor binding

proteins (BPs)
Follistatin
Insulin-like GF BP-3
Transforming GF- BP
Cytokines
Transforming GF-
Interleukin 8
Interferon--inducible protein-10
Interferon-
Macrophage inhibitory protein-1
Cell adhesion
molecules (CAMs)
CD45
L-selectin
Mac-1
Neural cell adhesion molecule
Platelet/endothelial CAM
Proteases/
antiproteases
Elastase
Thrombin
Tissue plasminogen activator
Antithrombin III
Heparin cofactor II
Leuserpin
Plasminogen activator inhibitor-I
Protein C inhibitor
Protease nexin I
Pathogens
gC and gB of herpes simplex virus

gC-11 of cytomegalovirus
gp 120 of human
immunodeficiency virus
Staphylococcus aureus surface
proteins
Penetrin of Trypanosoma cruzi
Streptococcus mutans surface
proteins
Neisseria gonorrhoeae surface
proteins
Mycobacterial surface proteins
Adhesin proteins of Borrelia
burgdorferi
To understand how proteoglycans function in the skin

it is essential to appreciate the basics of their organization: (1) proteoglycans are part protein and part GAG;
(2) GAGs are heterogeneous but encode specific information; (3) proteoglycan core proteins are expressed in
different cellular compartments; and (4) proteoglycan
expression and GAG composition vary according to
cellular context. These characteristics are important,
because many proteoglycan functions depend on their
ability to bind other molecules in the environment, and
because both the core protein and GAG chains may be
mediating or influencing molecular interactions. Similar GAGs can be attached to diverse core proteins. This
ability to interchange GAGs among cores adds complexity to the study of proteoglycan function, and in
many cases, proteoglycan properties are defined by the
GAG chains. It implies that certain genes encoding different core proteins to which similar GAGs are attached
may have a similar function. The list of molecules to
which the major skin proteoglycans heparan sulfate
and dermatan sulfate bind is quite extensive (Table
63-7). Therefore, several functions for proteoglycans
have been proposed that include the particular biologic system in which the ligand is involved.
Some of the most compelling experimental evidence
for the functions of heparan and dermatan sulfate proteoglycans identifies the ability to bind several growth
factors, cytokines, and components of the ECM.141 For
instance, heparan sulfate is required for the function of
growth factors such as several members of the fibroblast growth factor family,142,143 hepatocyte growth fac-
Category
::
FUNCTION OF PROTEOGLYCANS
TABLE 63-7
Binding Interactions of Heparan Sulfate,

Dermatan Sulfate, and Heparin
Chapter 63
smaller ECM proteoglycans have been identified. One

family is characterized by a leucine-rich repeat motif.
The prototype of this family is decorin, an approximately 36-kDa secreted proteoglycan.125,135,136 Decorin
is a ubiquitous component of connective tissues and it
is found in abundance in skin. The decorin core protein
has a single dermatan sulfate chain covalently bound
to a serine residue at amino acid position 4 and, like
many other proteoglycans, also has N-linked oligosaccharides. Thus, after GAG addition, decorin can have a
mass of 80 kDa. Decorin received its name from observations that this molecule closely associates with collagens fibrils and can be seen to decorate the fibrils
in vivo. This interaction is attributed to the ability of
the decorin core protein to directly bind to collagens
type I.138 The single GAG chain of decorin also binds to
tenascin-X, another ECM protein that colocalizes with
collagens fibrils in connective tissues.139 These binding
interactions contribute to collagens fibril formation
and influence function. Interestingly, similar phenotypes showing abnormal collagens morphology are
seen in a patient deficient in tenascin-X and in the
murine decorin knockout model.140
687
Section 9
::
688
tor/scatter factor,144 and vascular endothelial growth

factor.145 In this model, the heparan sulfate proteoglycan is found either at the cell surface or in a soluble
form. The molecules then assemble to form a ternary
complex at the cell surface between the growth factor,
its specific high-affinity signaling receptor, and the
proteoglycan.146 Only after this ternary complex is
formed does the cell receive the growth factor signal to
begin to proliferate, differentiate, or migrate. Heparan
sulfate-dependent growth factors, such as members of
the fibroblast growth factor family, are induced in healing wounds and influence the wound repair process
through the stimulation of keratinocyte proliferation,
fibroblast growth, and angiogenesis. Because dermatan sulfate is the predominant GAG in wound fluid
and because it can bind a variety of growth factors,
cytokines, and ECM proteins, further study of this
GAG and the proteoglycans it comprises promises to
be an exciting area for future investigation.
In addition to binding to growth factors, heparan
sulfate proteoglycans play an important role in adhesion to the ECM. In the current model, cell surface proteoglycans, in conjunction with other matrix-binding
molecules such as the integrins, help the cell adhere to
the ECM.124,126 Furthermore, the formation of these
focal adhesions requires heparan sulfate and the subsequent activation of protein kinase C by a domain in
the syndecan-4 core protein cytoplasmic tail. In this
setting, both the extracellular GAG and intracellular
core protein of the proteoglycan have demonstrable
signaling function.128,129
Other proteoglycans also interact with ECM molecules. Chondroitin sulfate and dermatan sulfate bind
fibronectin and laminin. As mentioned earlier, decorin,
to which dermatan sulfate is typically attached, is
known to associate primarily with type I collagens via
its core protein.138 In mice, selective disruption of the
decorin gene leads to abnormal collagens morphology
and increased skin fragility.140 Thus, through targeted
disruption of the gene in the mouse, the function of
decorin as a stabilizer of collagens fibrils has been
directly confirmed.
The function of the large ECM proteoglycans in skin
is thought to relate primarily to the physical properties
inherent in their large mass and charge density. Hyaluronan has been studied extensively from this perspective because of its extreme hydrophilicity and
viscosity in dilute solution. As discussed earlier, hyaluronic acid is pure GAG and is synthesized extracellularly without a core protein. The genes for human
hyaluronan synthase have been cloned and identified.147 The expression of hyaluronan is developmentally regulated in skin and changes during wound
repair. It has been proposed that the physicochemical
properties of hyaluronan serve to expand the matrix
and thus aid cell movements. Other physical properties attributed to GAG and large proteoglycan complexes, such as those formed with versican or basement
membrane proteoglycans, include their ability to act as
anionic filters and elastic cushions and their function
in salt and water balance. In fetal skin, the high relative
content of hyaluronan has been associated with the
ability of fetal skin to heal without scar.
CELLULAR RECEPTORS
FOR PROTEINS OF THE
Many components of the ECM regulate cellular behavior directly and indirectly. An indirect mechanism is
provided by the modulation and control of the activity
of cytokines, growth factors, and chemokines by proteins in the ECM. A direct and most important mechanism relies on the control of cellular activities through
adhesive interactions between cell surface receptors
and ECM proteins (Fig. 63-14). Several classes of cell
surface receptors have been identified, such as the syndecans,124,126 DDRs (Discoidin Domain Receptors),148
and integrins.10,149152 The latter are noncovalently
linked heterodimers of one and one subunits. Integrins have a short cytoplasmic domain (except for the
1,000 residue-long intracellular domain of the integrin
4 subunit expressed by keratinocytes), a single stretch
transmembrane domain, and a large extracellular
domain interacting with specific proteins of the ECM or
with counter-receptor present on the surface of circulating cells, including microbial proteins. In human, 18
and 8 subunits have been characterized, assembling
into 24 different combinations. The integrin cytoplasmic domain lacks enzymatic activity; however, by associating with multiple proteins into signaling platforms,
Cellular interactions with the extracellular matrix
ECM
Integrins
Cell membrane
Focal
adhesion
Signaling
intermediates
Forces
Tension
Adhesion
Movement
Differentiation
Proliferation
Apoptosis
Gene expression
Nucleus
Figure 63-14 Cellular interactions with the extracellular

matrix (ECM). The main cellular receptors for ECM constituents are the integrins. They consist of one and one
subunits noncovalently associated. Together, the large extracellular domains of both subunits provide a binding site
for specific ECM ligands. The short intracellular portions of
the subunits are devoid of enzymatic activity and recruitment of cytoskeleton-associating and adaptor proteins
is required for signal transduction and transmission of
forces, both outside-in and inside-out. Through outside-in
signaling, the ECM regulates many cellular functions, like
adhesion, movement, survival, differentiation, and expression of specific genes. Inside-out transmission of forces is
thought to be important for organization of the ECM architecture.
Box 63-1 Molecular Mechanisms

of Extracellular MatrixAssociated Diseases
Mutations in genes coding for
extracellular matrix (ECM) components
enzymes required for posttranslational modifications of ECM components
proteins required for folding/assembly of ECM
proteins
enzymes required for ECM maturation, deposition,
turnover, degradation
Development of autoimmunity (blistering diseases,
Goodpasture, etc.)
Altered regulatory functions of the ECM
CUTANEOUS Collagens
DISEASES
The term collagens disease implies that a clinical condition
involves an abnormality in the structure, synthesis, or
degradation of collagens. This term is frequently used to
characterize a clinically heterogeneous group of inflammatory diseases, including lupus erythematosus, scleroderma, and dermatomyositis. In the classic nomenclature,
the use of the term collagens disease for these conditions
was based on morphologic changes, known as fibrinoid
degeneration, that have been interpreted to represent
changes in collagens fibers. However, there is currently
no evidence for a primary defect in collagens in these
diseases. On the basis of available biochemical evidence,
scleroderma is the only clinical condition among the
classic collagens diseases that involves dysregulation of
collagens metabolism (see also Chapter 157).
Collagens is an unusual protein in many respects,
and its structure and metabolism involve a number of
special features that are critical for deposition of normal collagens fibers. In a primary collagens disease,
such a defect could be an inherited abnormality in the
structure of the collagens or procollagens or in the
enzymes participating in the biosynthesis and degradation of collagens. Indeed, there are many diseases in
which a basic biochemical defect in collagens has been
described, and several heritable connective tissue diseases with cutaneous involvement are now known to
result from specific molecular defects in collagens
genes (see Chapter 137). Many of these diseases
involve insertions, deletions, or single-base substitutions in the genes that alter the primary structure of the
protein.9,13,14 In several acquired diseases, the regulation of collagens gene expression is disturbed, which
leads to altered deposition of collagens in tissues. The
diversity of collagens pathology is exemplified by
EhlersDanlos syndrome and fibrotic skin diseases
(see Chapters 137 and 157). EhlersDanlos syndrome
comprises a group of phenotypically similar conditions that frequently result from abnormalities in the
structure of collagens or in enzymes modifying collagens molecules.19,20,56,57 In contrast, the fibrotic skin diseases exemplify conditions with altered regulation of
collagens gene expression that leads to excessive accumulation of collagens in tissues.61
689
The many components of the ECM in the dermal compartment of the skin have an elaborate biosynthesis,
maturation, and turnover, often a complex structure,
and they are assembled into exquisitely complex networks. Therefore, it is not surprising that many diseases exist due to disturbances in the genetic
expression, structure, homeostasis, and assemblies of
ECM proteins.
Based on our understanding of the molecular biology and the metabolism of the ECM components, it is
now possible to identify discrete points at which
defects could occur. These can be located at different
levels (Box 63-1). Many mutations in the genes coding
for ECM proteins or in the enzymes involved in their
::
DISEASES OF THE DERMAL

posttranslational modifications or their supramolecular assemblies into defined networks have been identified as outlined in preceding paragraphs.
ECM deposition and assembly into insoluble and
complex polymers are tightly controlled mechanisms,
which undergo substantial variations during development, tissue remodeling, repair, ageing, wound healing, or fibrosis. Several ECM proteins are also targets
for circulating antibodies, leading to autoimmune diseases. Most interesting for dermatology are the autoimmune blistering diseases that are discussed in detail in
other chapters. There is also accumulating evidence
that many ECM proteins manifest regulatory functions,
which can be disturbed and lead to disease processes.
Chapter 63
they activate diverse molecular pathways.151,152 Adhesive interactions between integrins and ECM proteins
control many cellular functions, such as migration, survival, differentiation, contraction, transmission of
forces, and expression of specific genes.149,150 Expression
of a distinct set of integrins on the cell surface determines specificity, range, and versatility of the interactions with ECM proteins. For instance, fibroblasts
express, among others, integrins with the property to
interact with native fibril-forming collagens, fibronectin, and vitronectin.10 In addition, the repertoire of integrins expressed by a given cell type may adapt to the
differentiation stage during development and to specific physiological and pathological features of the
microenvironment, such as wound healing, aging,
inflammation, and fibrosis.153 Integrins are also
expressed by inflammatory cells and control their
migration and targeting to specific sites of inflammation.154 Finally, it has been suggested that integrins cross
talk or act in synergy with growth factors, cytokines,
and cognate receptors.155 Together, the many facets of
integrins endow these proteins with crucial roles in
various physiological and pathological processes such
as fibrosis, tissue repair, and carcinoma progression.
Section 9
::
690
PATHOLOGY OF THE ELASTIC

FIBERS IN CUTANEOUS DISEASES
Several heritable and acquired connective tissue diseases have been shown to be associated with aberrations in the elastic fibers, including pseudoxanthoma
elasticum, cutis laxa, and the BuschkeOllendorff syndrome (Table 63-8; see Chapter 137). In addition, clinically distinct entities with phenotypes closely resembling
pseudoxanthoma elasticum (e.g., elastoderma) or cutis
laxa (e.g., wrinkly skin syndrome) can be recognized.
There has been significant progress recently in identifying and understanding the molecular mechanisms
associated with mutations in the fibrillin genes.156 Heterozygous mutations that affect the structure or lead to
a reduced synthesis are the cause of the Marfan syndrome. This disease is clinically characterized by
abnormalities and disturbances in the ocular, skeletal,
and cardiovascular systems. The patients display a
thin skin, with extensive striae distensae; some, however, also have contractures. A careful analysis of
mouse models with similar molecular defects revealed
that the mutations in the fibrillin gene are associated
with increased TGF- signaling. Interestingly, the phenotype presenting with development of a mitral valve
prolapse in this mice could be reverted or delayed by
addition of TGF- neutralizing antibodies. These data
indicate that fibrillin-1 is likely to be involved in the
tight regulation of TGF- activity. In a clinical study,
application of angiotensin II inhibitors to patients
with Marfan syndrome consistently and significantly
slowed the progression of aortic root dilatation.157
also been reported to be characterized by abnormal

amounts of proteoglycans. These associations do not
imply that abnormal proteoglycan metabolism is
responsible for these disorders, but they suggest that
much of the pathophysiology of skin disease can be
influenced by the function of cutaneous proteoglycans.
EMERGING DISEASE MECHANISMS

Mutations in the genes coding for key ECM proteins
often lead to functional consequences, which are associated with severe clinical symptoms. Although structural alterations can certainly explain a number of
symptoms, it is clear that not all pleiotropic clinical
alterations are directly and solely due to the abnormalities in protein structure. Evidence is now accumulating that induction of endoplasmic reticulum stress
represents an additional mechanism explaining some
of the deleterious effects resulting from mutations
in the genes needed for the elaboration of ECM
proteins.22,163165 For instance, the accumulation of
misfolded or unfolded mutant polypeptides in the
endoplasmic reticulum induces the so-called unfolded
protein response.166168 It results in detrimental processes of diverse severity, ranging from increased protein targeting to the proteasome for destruction,
autophagy, general reduction in protein synthesis
including that of the abnormal protein, to complete
cellular dysfunction with apoptosis of the cells (Fig.
63-15). Such a deleterious outcome has been demonstrated for mutations in several ECM genes, often
DISEASES DUE TO ABNORMAL

PROTEOGLYCAN METABOLISM
Multiple cutaneous disorders are associated with
abnormal proteoglycan synthesis or deposition. A deficiency of decorin core protein has been described as
the cause of a variant form of EhlersDanlos syndrome.
Even infectious diseases are influenced by proteoglycan expression. A good example is provided by the
decorin-deficient mice, which are rather resistant to
infection with Borrelia burgdorferi. Presumably, the
resistance is caused by a partial dependence of the
organism on decorin for binding in the dermis.158 During aging, the composition of GAG in the skin undergoes marked changes and it has been proposed that
the decrease in hyaluronic acid explains diminished
skin turgor.159,160 Retinoids also modify this response.161
In keloids, hyaluronic acid synthesis is elevated.162
Thyroid hormone also has a marked effect on the synthesis of proteoglycans and GAGs. The manifestation
of this response is seen in thyroid dermopathy (Chapter 151), in which the mucinous material deposited is
predominantly hyaluronic acid and chondroitin sulfate. Other pathologic skin conditions, including pseudoxanthoma elasticum, scleroderma, psoriasis, a
variant form of EhlersDanlos syndrome, lichen myxedematosus, and ultraviolet B-irradiated skin, have
Mutant ECM gene product
Misfolded/unfolded protein
ER quality control
Targeting for
degradation
Proteasome
Autophagy
Reduced amount
of mutant protein
ER stress -> UPR

(unfolded protein response)
Partial cell
dysfunction
Complete
cell dysfunction
Reduced
general
protein
synthesis
Apoptosis
Figure 63-15 The endoplasmic reticulum stress as a

mechanism inducing a deleterious function of the extracellular matrix (ECM). Misfolded ECM polypeptide chains
harboring mutations, or excess of unfolded polypeptides,
are either targeted for degradation or their accumulation
within the endoplasmic reticulum induces the unfolded
protein response, leading to partial or complete cell dysfunction and apoptosis.
TABLE 63-8
Clinical Features, Histopathology, Inheritance, Associated Biochemical Findings, and Predisposing

Clinical Conditions in Cutaneous Diseases with Elastic Fiber Abnormalitiesa
Biochemical Findingsb
Related to Elastic Fibers
and Predisposing
Clinical Conditions
AR, sporadicc
Yellowish papules coalescing

into plaques
Inelastic skin
Cardiovascular and ocular
abnormalities
Accumulation of pleomorphic
and calcified elastic fibers in
the middermis
Deposition of calcium apatite

crystals, excessive accumulation
of glycosaminoglycans on elastic
fibers; d-penicillamine treatment;
mutations in the ABCC6 gene
BuschkeOllendorff
syndrome
AD
Dermatofibrosis lenticularis
disseminata and
osteopoikilosis
Accumulation of interlacing
elastic fibers in the dermis
Increased desmosine content in the

skin; mutations in LEMD3
Cutis laxa
AR, AD, or NH
Loose, sagging, inelastic skin

Pulmonary emphysema
Tortuosity of aorta
Urinary and gastrointestinal
tract diverticuli
Fragmentation and loss of

elastic fibers
Decreased desmosine content

and reduced elastin mRNA levels;
increased elastase activity in some
cases; d-penicillamine treatment,
inflammatory and urticarial skin
lesions (e.g., drug reaction); mutations
in the ELN, EBLN4FBLN4, or FBLN5,
LTBP4, or PYCR15 gene in limited cases
DeBarsy syndrome
AR
Cutis laxa-like skin changes

Mental retardation
Dwarfism
Rudimentary, fragmented
elastic fibers
Reduced elastin mRNA levels
Wrinkly skin
syndrome
AR
Decreased elastic recoil of

the skin
Increased number of palmar
and plantar creases
Decreased number and length

of elastic fibers
Middermal elastolysis
NH
Fine wrinkling of the skin,

primarily in exposed areas
Fragmentation and loss of

elastin in the middermis
Inflammatory; sun exposure
Anetoderma
NH
Localized areas of atrophic,

sac-like lesions
Loss and fragmentation of

elastic fibers in the dermis
Reduced desmosine content in

the lesions; often secondary to
inflammatory lesions
Elastosis perforans
serpiginosa
NH
Hyperkeratotic papules,
commonly on the face and
neck
Accumulation and
transepidermal elimination of
elastic fibers
Elastoderma
Unknown
Loose and sagging skin with

loss of recoil
Accumulation of pleomorphic
elastotic material without
calcification in the mid
and lower dermis and the
subcutaneous tissue
Isolated elastomas
NH
Dermal papules or nodules
Accumulation of thick elastic

fibers in the dermis
Elastofibroma dorsi
NH
Deep subcutaneous tumor,

usually on subscapular area
Accumulation of globular
elastic structures encased in
collagenous meshwork
Trauma on the lesional area
Actinic elastosis
NH
Thickening and furrowing of

the skin
Accumulation of irregularly
thickened elastic fibers in
upper dermis
Long-term sun exposure
Marfan syndrome
AD
Skeletal, ocular, and

cardiovascular abnormalities
Hyperextensible skin
Striae distensae
Fragmentation of the elastic

structures in the aorta
Mutations in the FBN1 gene
Congenital
contractural
arachnodactyly
AD
Camptodactyly and joint

contractures
Williams syndrome
AD
Supravalvular aortic stenosis

Velvety skin
Dysmorphic facies
-penicillamine-induced
abnormalities in elastin cross-linking
Pseudoxanthoma
elasticum
::
Skin Histopathologic
Findings
Chapter 63
Clinical
Inheritance Manifestations
Disease
Mutations in the FBN2 gene
Disruption of smooth muscle

and matrix relationship
affecting blood vessels
Allelic deletion of the ELN gene;

contiguous gene deletion syndrome
AD = autosomal dominant; AR = autosomal recessive; NH = not a heritable disease; mRNA = messenger RNA.
a
Most of these conditions represent a group of diseases with clinical, genetic, and biochemical heterogeneity.
b
The biochemical abnormalities have been demonstrated in only a limited number of patients in each group, and it is not known whether the biochemical changes are
the same in each patient with any given disease.
c
Rare cases with a distinct acquired form of pseudoxanthoma elasticum have been described.
691
resulting in severe clinical subsets of osteogenesis

imperfecta or some inheritable cartilage diseases.
However, it remains to be seen whether these mechanisms could play a much broader role and apply to
other inherited or acquired disorders of the ECM.
KEY REFERENCES
Section 9
::
2. Hynes RO: The extracellular matrix: Not just pretty

fibrils. Science 326:1216, 2009
8. Eckes B, Krieg T: Regulation of connective tissue homeostasis in the skin by mechanical forces. Clin Exp Rheumatol 22:S73, 2004
9. Myllyharju J, Kivirikko KI: Collagens, modifying
enzymes and their mutations in humans, flies and
worms. Trends Genet 20:33, 2004
11. Gordon MK, Hahn RA: Collagens. Cell Tissue Res 339:247,
2010
19. Mitchell AL et al: Molecular mechanisms of classical
Ehlers-Danlos syndrome (EDS). Hum Mutat 30:995, 2009
34. Ortega N, Werb Z: New functional roles for non-collagenous domains of basement membrane collagens. J Cell
Sci 115:4201, 2002
45. Myllyl R et al: Expanding the lysyl hydroxylase toolbox: New insights into the localization and activities of
lysyl hydroxylase 3 (LH3). J Cell Physiol 212:323, 2007
48. Myllyharju J: HIF prolyl 4-hydroxylases and their potential as drug targets. Curr Pharm Des 15:3878, 2009
53. Apte SS: A disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif (ADAMTS)
superfamily: Functions and mechanisms. J Biol Chem
284:31493, 2009
60. Uitto J, Kouba D: Cytokine modulation of extracellular
matrix gene expression: Relevance to fibrotic skin diseases. J Dermatol Sci 24:S60, 2000
61. Gabrielli A, Avvedimento EV, Krieg T: Scleroderma. N
Engl J Med 360:1989, 2009
68. Page-McCaw A et al: Matrix metalloproteinases and the
regulation of tissue remodelling. Nat Rev Mol Cell Biol
8:221, 2007
69. Kessenbrock K et al: Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell 141:52, 2010
77. Kielty CM: Elastic fibres in health and disease. Expert Rev
Mol Med 8:1, 2006
95. Lucero HA, Kagan HM: Lysyl oxidase: An oxidative
enzyme and effector of cell function. Cell Mol Life Sci
63:2304, 2006
99. Uitto J: Biochemistry of the elastic fibers in normal connective tissues and its alterations in diseases. J Invest Dermatol 72:1, 1979
104. Ramirez F, Sakai LY: Biogenesis and function of fibrillin
assemblies. Cell Tissue Res 339:71, 2010
107. Ramirez F, Rifkin DB. Extracellular microfibrils: Contextual platforms for TGFb and BMP signaling. Curr Opin
Cell Biol 21:616, 2009
111. Timpl R et al: Fibulins: A versatile family of extracellular
matrix proteins. Nat Rev Mol Cell Biol 4:479, 2003.
141. Iozzo RV: Basement membrane proteoglycans: From cellar to ceiling. Nat Rev Mol Cell Biol 6:646, 2005
167. Bateman JF et al: Genetic diseases of connective tissues:
Cellular and extracellular effects of ECM mutations. Nat
Rev Genet 10:173, 2009
Chapter 64 :: Morphea

:: Stephanie Saxton-Daniels & Heidi T. Jacobe
MORPHEA AT A GLANCE
Occurs in children and adults.
Linear subtype predominates in children.
Circumscribed and generalized
predominate in adults.
A self-limited or chronically relapsing
autoimmune disorder targeting the skin with
the following major features:
Inflammatory, sclerotic, atrophic phases.
Thickened sclerotic skin.
Systemic disease including arthritis and
neurological disorders.
Differentiated from scleroderma by lack of
acrosclerosis/sclerodactyly.
692
Complications may cause significant

irreversible cosmetic and functional
impairment including the following:
Atrophy of dermis, fat, and subcutaneous
structures.
Contracture.
Limb length discrepancy.
Bony abnormalities.
Treatment based on the following:
Disease subtype.
Depth of involvement.
Stage (inflammatory, sclerotic, atrophic).
Potential for complications.

of Morphea
Most Likely
Scleroderma (systemic sclerosis)
Lipodermatosclerosis
Trauma-induced fat necrosis (intramuscular injections)
Nephrogenic systemic fibrosis
Chronic graft-versus-host disease
Morphea is a chronic autoimmune disease characterized by sclerosis of the skin. The term localized scleroderma is also used in an attempt to highlight the
systemic features of morphea. This causes confusion
with systemic sclerosis (scleroderma) often resulting in
unnecessary evaluation and anxiety. It is the opinion of
the authors this term should be avoided. Morphea
itself has a spectrum of manifestations ranging from
skin only to multiple organ involvement. Of note,
organ involvement in morphea is distinctly different
from systemic sclerosis (Box 64-1).
EPIDEMIOLOGY
Morphea has an estimated incidence of 2.7 per 100,000
with a female:male ratio of 2 to 3:1.1 Morphea is more
common in Caucasians.25 The relative frequency of the
different subtypes varies between studies. This is likely
due to use of different classification systems. Twenty to
thirty percent of morphea begins in childhood, but it
can occur at any age.25 Linear morphea is the most
common pediatric subtype (although all subtypes
occur at any age).1,2,6 Twenty-five to eighty-seven percent of pediatric cases are linear morphea, with limb or
trunk involvement in approximately 70%80% and en
The etiology and pathogenesis of morphea is poorly

understood. Most pathologic events ascribed to morphea are extrapolated from studies in systemic sclerosis (assuming the two disorders arise from the same
etiology). Morphea probably arises from a genetic
background that increases disease susceptibility, combined with other causative factors (infectious, environmental exposures) that modulate disease expression.
Like many autoimmune connective tissue diseases,
morphea is likely a complex genetic disease. Familial
clustering is rarely seen,5,9,10 and morphea is also associated with higher than expected rates of familial autoimmune disorders.5,11,12
Although there are no definitive associations, development of morphea lesions has been linked to local tissue trauma including radiation (eFig. 64-0.2 in online
edition), surgery, insect bites, and intramuscular injections.13 Although controversial, infectious agents have
also been linked to lesion development.
Increasing amounts of evidence support autoimmune-mediated inflammation early in the course of
morphea.14 Early morphea lesions are characterized by
the influx of large amounts of mononuclear lymphocytes (usually activated T lymphocytes), plasma cells,
and eosinophils.15 This is likely the result of autoimmunity, as there is widespread autoimmune reactivity
in morphea patients (elevated ANAs, cytokines, and
adhesion molecules).5,12,16 Morphea patients also have
concomitant autoimmune disease at higher expected
frequency than a healthy population.5,11
Vessel damage and upregulation of adhesion molecules (ICAM-1, VCAM 1, and E-selectin) occur related
to the inflammatory cell infiltrate which facilitates
local monocyte recruitment.17 These adhesion molecules are upregulated by cytokines classically associated with a Th2 immune response (Il-4, Il-1, and TNFs).
Cytokines found in the sera and skin of morphea
patients in increased concentration include IL-4, IL-6,
and IL-8.18 These cytokines (especially IL-4) upregulate
TGF-, initiating a cascade of events resulting in
increased production of collagen and other extracellular matrix components via induction of connective tissue growth factor, platelet-derived growth factor, and
matrix metalloproteinases. These cytokines and
growth factors inhibit interferon- (a suppressor of collagen synthesis and Th1-related cytokine). Chimerism
or nonself cells may play a role in the pathogenesis of
morphea by initiating a local inflammatory reaction.19
Morphea
POEMS = polyneuropathy, organomegaly, endocrinopathy,

M protein, and skin changes.
::
Always Rule Out

Carcinoma of the breast metastatic to skin
(carcinoma en cuirase)
Chapter 64
Consider
Lichen sclerosus
Pretibial myxedema
Connective tissue nevi
Morpheaform basal cell carcinoma
Chemical mediated sclerosing skin conditions (toxic
oil syndrome, rapeseed oil, etc.)
Lyme disease (acrodermatitis atrophicans)
Phenylketonuria
Scleromyxedema, scleroderma chronica, pretibial
myxedema
POEMS syndrome
coup de sabre (ECDS) or progressive facial hemiatrophy (PHA; formerly described as ParryRhomberg) in
22%30%.1,2,4,5,7,8 In adults, circumscribed and generalized subtypes predominate. Deep morphea/morphea
profunda is uncommon in both adults and children
with a frequency of 2%4%.1,2,4,7,8
Periods of disease activity vary from 3 to 6 years, but
reactivation after periods of remission occurs in 20%.2,8
(eFig. 64-0.1 in online edition). Others have a chronic
course persisting for decades. The prognostic markers for
recurrent or chronic disease have yet to be determined.
693
Pathology
Clinical
manifestation
Inflammatory
initiation
Erythematous patch
or thin plaque
Inflammation and
early sclerosis
Central sclerosis
with personal
erythema
Sclerosis and
waning inflammation
Central sclerosis and

violaceous, hyperpigmented border
Scarring and
damage
Atrophy dermal,
subcutaneous, or
muscle
Sclerosis
Section 9
Figure 64-1 Lichen sclerosis can overlie morphea lesions.

(Reproduced with permission from Jacobe H: Morphea (localized scleroderma) in adults. In: UpToDate, edited by DS
Basow. Waltham, MA, UpToDate, 2011. Copyright 2011
UpToDate, Inc. For more information visit www.uptodate.
com.)
Inflammation
Stages of morphea lesions
::
CLINICAL FINDINGS
Morphea is currently divided into five subtypes (Table
64-1).20 Superficial or deep disease (involving subcutis,
fascia, or below) may occur with any subtype. Morphea lesions may also occur with overlying lichen sclerosus change (Fig. 64-1).
CUTANEOUS LESIONS
STAGES OF CUTANEOUS LESIONS. (Fig. 64-2).
Morphea begins as erythematous plaques or patches,
sometimes with a reticulated appearance. Later
hypopigmented sclerotic plaques develop at the center
of the lesion, surrounded by an erythematous or violaceous border (inflammatory stage) (Fig. 64-2A). Pain
and/or itching can precede the initial skin findings.
Figure 64-2 Stages of morphea lesions. A. Typical active

morphea plaque in inflammatory stage, with violaceous
border. B. Severe atrophy in patient with linear morphea
(atrophic stage). (Reproduced with permission from
Jacobe H: Morphea (localized scleroderma) in adults. In:
UpToDate, edited by DS Basow. Waltham, MA, UpToDate,
2011. Copyright 2011 UpToDate, Inc. For more information visit www.uptodate.com.)
Sclerosis develops centrally, which turns into a shiny
white color, as lesions expand with surrounding
hyperpigmentation (sclerotic stage). There is loss of
hair follicles, producing alopecia. Over months to
years, the sclerotic plaque softens and becomes atrophic with hypo- or hyperpigmentation (atrophic stage)
(Fig. 64-2B). The atrophic stage is associated with cigarette paper wrinkling (papillary dermis), cliff drop
(dermal), or deep indentions (subcutis or deeper).
TABLE 64-1
Proposed Classification of Morphea Subtypes

Morphea Subtype
Modifiers
Clinical
Circumscribed
Superficial
Deep
Single or multiple oval/round lesions limited to epidermis and dermis

Single or multiple oval/round lesions involving subcutaneous tissue, fascia, or muscle.
Linear
Trunk/Limbs
Linear lesions involving possible primary site of involvement in subcutaneous tissue

without involvement of skin, dermis, subcutaneous tissue, muscle, or bone
En coup de sabre, progressive facial hemiatrophy, linear lesions of the face (may
involve underlying bone)
Head
Generalized
1. Coalescent plaque
2. Pansclerotic
3. Mixed
694
More than or equal to four plaques in at least two of seven anatomic sites (head
neck, right/left upper extremity, right/left lower extremity, anterior/posterior
trunk); isomorphic pattern: coalescent plaques inframammary fold, waistline, lower
abdomen, proximal thighs; symmetric pattern: symmetric plaques circumferential
around breasts, umbilicus, arms, and legs
Circumferential involvement of majority of body surface area (sparing fingertips
and toes), affecting skin, subcutaneous tissue, muscle or bone; no internal organ
involvement
Combination of any above subtype: e.g., linear-circumscribed
Adapted from Laxer RM, Zulian F: Localized scleroderma. Curr Opin Rheumatol 18:606-613, 2006.
Chapter 64
CIRCUMSCRIBED MORPHEA. Circumscribed

morphea represents oval to round lesions undergoing
the stages of activity described in the previous section
that are not diffuse enough to meet criteria for generalized disease (Table 64-1). Patients with circumscribed
morphea should be closely followed, as both linear
and generalized morphea may begin with circumscribed lesions.
Atrophroderma of Pasini and Pierini are thought to
be the residua of plaque-type morphea. The borders of
Morphea
Figure 64-3 Generalized morphea. A. Isomorphic plaques involving bra and waistband areas. B. Symmetric plaques on
a patient with generalized morphea. (Reproduced with permission from Jacobe H: Morphea (localized scleroderma) in
adults. In: UpToDate, edited by DS Basow. Waltham, MA, UpToDate, 2011. Copyright 2011 UpToDate, Inc. For more information visit www.uptodate.com.)
::
the atrophoderma lesions have a cliff-drop appearance resembling burnt-out morphea lesions.
GENERALIZED MORPHEA. Generalized morphea is characterized by more than or equal to four

lesions on at least two of seven different anatomic sites.
There are likely three variants of generalized morphea:
(1) isomorphic, (2) symmetric, and (3) pansclerotic
(Table 64-1; Figs. 64-3 and 64-4).21,22 In direct contrast to
systemic scleroderma, generalized morphea does not
Figure 64-4 Pansclerotic morphea: sclerosis encompassing majority of body surface area (A), characteristically sparing
the fingertips (B). (Reproduced with permission from: Jacobe H: Morphea (localized scleroderma) in adults. In: UpToDate,
edited by DS Basow. Waltham, MA, UpToDate, 2011. Copyright 2011 UpToDate, Inc. For more information visit www.
uptodate.com.)
695
Section 9
::
Figure 64-5 A. Multiple linear lesions involving trunk and

extremities. B. En coup de sabre. C. Multiple hyperpigmented linear morphea lesions on the face. (Reproduced with
permission from: Jacobe H: Morphea (localized scleroderma) in adults. In: UpToDate, edited by DS Basow. Waltham,
MA, UpToDate, 2011. Copyright 2011 UpToDate, Inc. For
more information visit www.uptodate.com.)
present with acrosclerosis or sclerodactyly. Instead,

lesions frequently begin on the trunk and spread
acrally, sparing the fingers and toes (Fig. 64-4).
696
LINEAR MORPHEA. Linear morphea usually

affects the extremities and face, but it can occur on the
trunk (where it is often misclassified as circumscribed)
(Table 64-1, Fig. 64-5A). The presence of multiple linear
lesions is not uncommon. A recent study suggests that
linear morphea may follow Blaschkos lines.23 Linear
morphea may involve the dermis, subcutaneous tissue, muscle, or even underlying bone, causing significant deformities. Bone marrow inflammation has also
been reported.24,25 ECDS cut of the sword may pres-
ent as an atrophic band linear plaque on the forehead

(Fig. 64-5B), extending to the scalp (where cicatricial
alopecia occurs), brow, nose, and lip. Other linear
lesions on the head and neck present on the temple or
chin, and are generally hyperpigmented atrophic
plaques (Fig. 64-5C). PHF is characterized by a slowly
progressive, unilateral atrophy of skin, soft tissues,
muscles, and/or bony structures. The atrophy may be
accompanied by classic linear morphea lesions on the
face or elsewhere.
DEEP MORPHEA. Deep morphea, or morphea profunda, involves the deep dermis, subcutaneous tissue,
fascia, and muscle. Plaques are poorly circumscribed
LABORATORY ABNORMALITIES
SERUM AUTOANTIBODIES. Autoantibodies

reported in patients with morphea include ANA, antisingle-stranded DNA, antidouble-stranded DNA,
antihistone, antitopoisomerase II, antiphospholipid,
anticentromere, anti-Scl-70, and rheumatoid factor
(MMP-1).5,16,26,2934 The clinical and prognostic significance of these autoantibodies remains unclear. ANA
occur in 39%80% of patients and are more common in
patients with linear or generalized disease.5,8,16,26
and symmetrical (Fig. 64-6). The skin feels thickened

and bound down to the underlying fascia and muscle.
A groove sign (depression) may be present at the site
of tendons and ligaments. Deep morphea lesions may
underlie any clinical subtype of morphea, particularly
linear and generalized, or occur alone.
EF, or Shulman syndrome, is a related disorder presenting with rapid onset of symmetric areas of pain
and edema, usually on the extremities. EF may occur
with cutaneous induration similar to morphea, or
remain without skin involvement.

Extracutaneous manifestations develop in 22%56% of
morphea patients.1,4,5,7,8,26 Articular and muscular (eFig.
64-6.1 in online edition) involvement (arthritis, myalgias, neuropathies, and carpal tunnel syndrome) is the
most common finding (12%) and can occur unrelated
to skin lesions.11,27 Cutaneous disease itself produces
limited range of motion, limb length discrepancy, joint
deformity, and contracture (45%56% linear morphea).
Patients with lesions crossing joint lines are most at
risk.8,26 ECDS is associated with neurologic and ocular
complications (3.6%) including seizures, headaches,
adnexal abnormalities (eyelids, eyelashes), uveitis, and
episcleritis.11,27,28 Facial morphea may produce dental
malocclusion, altered dentition, and atrophy of the
tongue and salivary glands. Another possible finding
is Raynaud phenomenon, although more strongly
associated with systemic sclerosis.5
Morphea
Figure 64-6 Morphea profunda: involved areas have

cobblestone appearance with subcutaneous atrophy.
(Reproduced with permission from Jacobe H: Morphea (localized scleroderma) in adults. In: UpToDate, edited by DS
Basow. Waltham, MA, UpToDate, 2011. Copyright 2011
UpToDate, Inc. For more information visit www.uptodate.
com.)
MRI provides a complete assessment of the extent of

disease, including depth of involvement and disease
activity.25 This is especially helpful when deep involvement is suspected. It is also possible to evaluate the
response to treatment, although not currently routine
practice.
Ultrasonography (US) is a sensitive tool to evaluate
or monitor tissue thickness, loss of subcutaneous fat
and muscle, or other architectural alterations. Disease
activity can be correlated with the detection of hyperemia and echogenicity.35 Discussion with the radiologist performing the MRI or US studies is crucial to
adequately detect and evaluate change related to the
morphea.
::
IMAGING STUDIES
Chapter 64
OTHER SERUM ABNORMALITIES. Peripheral

eosinophilia, hypergammaglobulinemia, and increased
ESR/CRP may occur with active disease of any type,
but particularly deep morphea (may correlate with disease activity).
COMPLICATIONS
Children with morphea can have significant morbidity
related to morphea, including effects on growth, function, and quality of life (fewer studies exist in adults).
Muscle weakness may occur in affected extremities or
face. Behavioral changes, learning disabilities, and seizure (sometimes preceding cutaneous lesions)36,37 have
been reported in children with (and without) facial
involvement. In addition, disfigurement and physical
symptoms (fatigue, pain, itch) associated with morphea
affect psychosocial development and play a substantial
role in the quality of life for patients with morphea.
Pansclerotic morphea has been associated with an
increased risk of squamous cell carcinoma due to
chronic ulcers. The resulting sclerosis of the skin can
cause significant contracture, and produces restrictive
pulmonary defects and dysphagia. Circumferential
sclerosis of the arms or legs may also produce compartment syndrome, bullae, and ulcers.
Morphea may coexist with other autoimmune diseases (systemic lupus erythematosis, vitiligo, primary
biliary sclerosis, autoimmune hepatitis, Hashitmotos
thyroiditis, and myasthenia gravis).3843 In particular,
generalized morphea has been associated with an
increased rate of autoimmune disease.5
697

COURSE
treatments, no consistent recommendations exist for

therapy. This section aims to provide evidence-based
algorithm for the rational evaluation and management
of morphea patients (Figs. 64-7A and 64-7B).
Although morphea causes functional and aesthetic

impairment, it is rarely life-threatening. Morphea may
be self-limited, but frequently has a remitting relapsing
or chronic course producing significant disease burden
over time.12 (eFig. 64-0.1 in online edition)
PATIENT EVALUATION
In determining which therapy is appropriate, the following must be considered:

EVALUATION AND TREATMENT

Section 9
OVERVIEW
::
The natural history of morphea is poorly understood.

At least some cases undergo spontaneous remission
after a few years of activity. However, even when
spontaneous remission occurs, residual damage created by active disease remains. In addition, new evidence suggests at least a subset of morphea patients
have continued disease activity over many years, ultimately leading to extensive disease burden and related
morbidity.12 Despite the large number of reported
Disease Activity and Damage: Existing studies

indicate that early, active disease is most responsive
to any therapy.44 Indicators of active disease include
development of new lesions or extension of existing
lesions (photographs are critical), erythema and/
or induration of the advancing edge of the lesion,
patient reported symptoms such as itch or tingling.
Disease damage (reversible or irreversible) includes
pigmentary change, induration of the lesion center
(controversial), atrophy (dermal, subcutaneous,
muscle), contracture, limb length discrepancy, and
scarring alopecia. Disease damage is much more
difficult to treat and therapy should be aimed at
preventing disease damage. Further, patients with
Algorithm for morphea patient evaluation
Determine subtype
Linear morphea
Head/face
Muscle pain/
tightness or
deep fixed lesion
Jaw/Dental
symptoms
Neurological
symptoms
All patients
Generalized morphea
MRI or U/S for

fascial/muscle
involvement
CK/Aldolase
Imaging/Ref.
Imaging/Ref.
Optho/exam
Extremity
Muscle pain/
tightness or
deep fixed lesion
MRI or U/S for

fascial/muscle
involvement
CK/Aldolase
Repeat for evaluation of

therapy Q4-6 months
Joint swelling/
pain/reduced
weight beanna
Decreased ROM
contracture/limb
length discrepency
Rheumatology
consultation
PT/OT
orthopedics
rheumatology
Repeat for evaluation of

therapy Q4-6 months
A
698
Figure 64-7 A. Algorithm for the evaluation of patients with morphea. (continued)
Circumscribed morphea
Additional evaluation
rarely needed, although
close follow-up is
indicated as both linear
and beneralized mayl
begin with plaque-like
lesions
Therapeutic algorithm for morphea based on existing evidence
ACTIVE
New lesions, disease extension,
inflammation (erythema, edema),
sclerotic or indurated periphery
Superficial
Localized
Phototherapy
Localized or
whole body
NB UVB, BB
UVA, UVA-1
15-20 treatments
Generalized
Localized
Generalized
Phototherapy (whole body)

NB UVB, BB UVA, UVA-1
Chapter 64
Topical (bid, occluded)

Calcipotriene
Tacrolimus
IL Kenalog+
Topical high potency
steroids+
Deep
If local
phototherapy
::
Morphea
Systemic
MTX
PCMT
Continued progression/
deep involvement
INACTIVE/DAMAGE
Pigmentary changes,
static size, atrophy
Functional impairment
PT/OT
Orthotics
Orthopedics
Podiatry
Rheumatology
Cosmetic impairment
Confirmed long-term disease

inactivity
Deep muscle, fascia,

bone involvement
Surgical correction of
functional/cosmetic
defect, plastic
surgery, orthopedics
etc.
Work-up negative for deep

muscle, fascia, bone
involvement
Local excision
Inject fillers (face)
Figure 64-7 (continued) B. Therapeutic algorithm for morphea based on existing evidence. Superficial involvement is
defined by histological evidence of papillary dermal involvement. Deep involvement is defined as sclerosis or inflammation of the deep dermis, subcutis, fascia, or muscle. Histological examination and/or MRI are encouraged to evaluate
lesions for depth of involvement and, likewise, determine appropriate treatment as well as evaluation of therapeutic efficacy. *There is very little evidence for any therapy addressing disease damage in morphea. The risk of disease reactivation
is also unknown, but possible with the use of invasive procedures. Therefore, surgery and the like should only be undertaken after prolonged inactivity of disease. There is no evidence for efficacy in the literature. (Reproduced with permission from Jacobe H: Morphea (localized scleroderma) in adults. In: UpToDate, edited by DS Basow. Waltham, MA, UpToDate,
2011. Copyright 2011 UpToDate, Inc. For more information visit www.uptodate.com.)
699
Section 9
::
active disease at risk for significant damage (facial

lesions, PFH, lesions crossing joint lines, large
BSA involvement, rapid progression) likely need
aggressive therapy (phototherapy and/or systemic
immunosuppresives).
Depth of Involvement: Morphea involving the
superficial to middermis would logically be amenable to topical therapy or phototherapy; however,
involvement of the deep dermis and beyond should
be treated systemically. Deep involvement can occur
in all subtypes of morphea, but is especially prominent among linear and some generalized patients.
Disease Progression: Many generalized and linear
morphea patients are initially diagnosed with
circumscribed morphea, but progress to have much
more extensive disease.12 Therefore, patients who
initially present with 13 plaques (which may be
amenable to localized therapy) should be closely
followed. If these patients progress, therapy should
then be aimed at preventing further progression
(i.e., phototherapy or systemic therapy).
Systemic Involvement: Systemic involvement is
usually an indication for systemic immunosuppressive therapy.
Disease Subtype: Patients with linear and generalized (particularly those with rapid onset of confluent plaques) are likely at risk for severe, extensive
disease and should be treated aggressively either
with phototherapy or systemic immunosuppressives depending on the depth of involvement.
ROLE OF HISTOLOGY AND

LABORATORY TESTING
The diagnosis of morphea is usually made by the clinical appearance of the lesions. Histological examination
may aid therapeutic decision-making because it is
sometimes difficult to determine the degree of activity
or depth of involvement by clinical examination alone.
Biopsy of the advancing edge of a lesion may provide
insight into both (eFig. 64-6.2 in online edition). Biopsies should be taken from the inflammatory or indurated border or sclerotic center (indicate on pathology
requisition) and include fat. For lesions with minimal
clinical change, biopsy of site-matched unaffected skin
is helpful. Although a large number of laboratorybased assessments are reported to reflect disease activity and prognosis in morphea, there are no widely
accepted biomarkers for morphea. Consequently, laboratory-based tests are not recommended for evaluation
morphea in the absence of specific signs and symptoms indicating the need for further assessment.
Assessment via MRI and ultrasound is becoming
increasingly useful for determination of lesion activity
and depth and should be considered when deep morphea is present or suspected.
SPECIFIC TREATMENTS
700
See Table 64-2.
TABLE 64-2
Morphea Therapy
Treatment
Level of
Evidencea
BB UVA
1, 2
UVA-1
1, 2
Calcitriol, oral (inefficacy 1)
1, 2
IFN- (inefficacy 1)
PUVA bath
PUVA cream
ECP
Calcipotriene, topical
MTX monotherapy
PCMT
Tacrolimus, topical
Steroids, oral
MTX plus oral steroids,

hydroxychloroquine, MMF, cyclosporine,
Bosentan, infliximab, imiquimod,
antimicrobials, d-penicillamine, 585-nm
long-pulse laser, wide surgical resection,
orthopedic surgery, Apligraf
Minimal
evidence
(level 3)
Level of Evidence:
1. Indicates randomized controlled trial
2. Uncontrolled trial
3. Case report, case series
Reproduced with permission from Jacobe H: Morphea (localized
scleroderma) in adults. In: UpToDate, edited by DS Basow. Waltham, MA,
UpToDate, 2011. Copyright 2011 UpToDate, Inc. For more information
visit www.uptodate.com.
PHOTOTHERAPY. Phototherapy has the greatest

evidence for efficacy (level 1, randomized controlled
trials: broadband ultraviolet (UV) A, narrowband (NB)
UVB, and UVA 1; level 2: PUVA systemic and topical).4550 NB UVB should be considered for lesions
affecting the superficial dermis (relatively thin on palpation or with sclerosis and inflammation in the papillary and superficial reticular dermis). UVA-based
therapies are more appropriate for deeper dermal
lesions due to greater depth of penetration. UVA-1 in
particular has evidence for normalization of dermal
collagen and effect on inflammation in morphea so is
appropriate for both inflammatory and sclerotic disease.45 In the absence of access to UVA-1 phototherapy,
use of broadband UVA is also supported by the literature.50 Disease is expected to improve (progression
halted and erythema improved) after 1020 treatments
and most trials stopped after 2030 treatments. Evidence suggests that patients continue to improve after
cessation of therapy, and some authors recommend
using a greater number of treatments3050 for further
therapeutic benefit. Uncontrolled trials demonstrated
increased benefit with medium to high dose UVA-1
versus low dose, but controlled trials were less convincing. Optimum dose and regimen for UVA-1 phototherapy has yet to be determined. Phototherapy is
likely ineffective for deep involvement (subcutis, fascia, muscle), and therefore should not be considered as
primary therapy.
Other Immunomodulators.
Level-2 evidence
suggests the use of occluded topical tacrolimus 0.1%
ointment might be effective for active, inflammatory
superficial plaque-type morphea.56 Recent case series
utilizing oral mycophenolate mofetil indicate potential
utility in patients refractory to methotrexate or sensitive to corticosteroid side effects.57 Case reports on the
use of oral cyclosporine, bosentan, infliximab, and topical imiquimod have also reported some efficacy, but
more definitive studies are lacking.
ANTIMICROBIALS. Despite the widespread use of

antimicrobials in morphea (antibiotics and hydroxy-
Morphea
methotrexate combined with systemic corticosteroids

is effective based on level-2 evidence.28,44,5355 Optimum
dose and route, indications for addition of corticosteroids, and duration of therapy have not been determined. In most studies with combined therapy,
corticosteroids are used for induction therapy either
orally or via intravenous pulse (IVMP 30 mg/kg/day
for 3 days per month or 1 mg/kg/day prednisone)
over the first 3 months. Methotrexate is used as steroid
sparing agent and started simultaneously (0.6 mg/kg/
week in children or 1525 mg/week in adults) and
maintained for a prolonged period (12 years). Most
study participants responded in a mean of 25 months.
The best responders were all early in their disease
course. Importantly, relapse was noted frequently after
cessation of therapy, underscoring that therapy likely
only suppresses disease activity.
ADJUNCTIVE THERAPY. A significant number of

morphea patients suffer irreversible sequelae. When
these patients come to medical attention, they may no
longer have disease activity, but rather damage from
the past or a mixture of active disease and damage.
Consequently, every morphea patient should be examined for the presence of limitation in range of motion,
contracture, limb length discrepancy, or other functional impairment. In these cases, consultation with
rheumatology, physical/occupational therapy, physical medicine and rehabilitation, plastic surgery, orthopedics, and oral maxillofacial surgery is highly
recommended to maximize cosmesis, function, and
minimize further damage.
::
IMMUNOMODULATORS
Methotrexate With or Without Corticosteroids. The use of methotrexate (monotherapy) and
LACK OF EVIDENCE. The most commonly used

treatment for morphea, topical steroids, shows no evidence for efficacy in the literature. There are also no
studies investigating the use of intralesional steroids.
In the hands of the authors, intralesional steroids have
been extremely effective in treating circumscribed
plaques or as an adjuvant for recalcitrant areas in
patients receiving phototherapy or systemic treatment.
Current evidence does not support the use of penicillamine or interferon-.60
Chapter 64
VITAMIN D DERIVATIVES. Only one study provides level-1 evidence on the effect of vitamin D
derivatives in morphea, and it showed no difference
between oral calcitriol and placebo.51 In fact, placebo
and treatment groups improved equally. The authors
also point out that the study was underpowered by
their own calculations, making definitive conclusions regarding the efficacy of oral calcitriol difficult.
The efficacy of topical vitamin D derivatives has
been explored via uncontrolled trials and case
reports52 (level-2 evidence) and showed improvement in most or all patients, albeit over several
months of therapy (an interval in which lesions
might improve independent of therapy). Importantly, calciprotriene was applied under occlusion in
these studies.
chloroquine), no published clinical trials exist.58 Literature supporting the use of antimalarials is limited to a
case series in which two patients improved with
hydroxychloroquine (while simultaneously receiving
oral steroids and methotrexate).59 In a retrospective
review, 7/11 patients continued to have active disease
3153 months after starting hydroxychloroquine.4 At
this time, the use of these agents in severe morphea is
likely not indicated pending more definitive evidence
of efficacy.
KEY REFERENCES
4. Christen-Zaech S et al: Pediatric morphea (localized
scleroderma): Review of 136 patients. J Am Acad Dermatol
59:385, 2008
5. Leitenberger JJ et al: Distinct autoimmune syndromes in
morphea: A review of 245 adult and pediatric cases. Arch
Dermatol 145:545, 2009
7. Zulian F et al: Juvenile localized scleroderma: Clinical and
epidemiological features in 750 children. An international
study. Rheumatology (Oxford) 45:614, 2006
12. Saxton-Daniels S, Jacobe HT: An evaluation of long-term
outcomes in adults with pediatric onset morphea. Arch
Dermatol 2010
44. Uziel Y et al: Methotrexate and corticosteroid therapy for
pediatric localized scleroderma. J Pediatr 136:91, 2000
46. Kreuter A et al: A randomized controlled study of lowdose UVA1, medium-dose UVA1, and narrowband UVB
phototherapy in the treatment of localized scleroderma. J
701
Chapter 65 :: Lichen Sclerosus

:: Ulrich R. Hengge
LICHEN SCLEROSUS AT A GLANCE
Infrequent chronic inflammatory
dermatosis with anogenital and extragenital
manifestations.
Section 9
Preferentially affects women in the fifth or

sixth decade of life and children younger
than the age of 10 years; gender ratio 5:1
femalemale.
::
Antibodies to extracellular matrix protein-1

and T cells with receptor rearrangement
point to an autoimmune pathogenesis.
Anogenital manifestations cause severe

discomfort (pruritus, dyspareunia, dysuria,
and painful defecation) and present with
polygonal papules and porcelain-white
plaques, erosions, and various degrees of
sclerosis.
Vulvar lichen sclerosus is associated with an
increased risk of squamous cell carcinoma;
the role of human papillomavirus infection
or prior radiotherapy remains to be
elucidated.
Potent topical corticosteroids and skin
care are the most successful therapeutics;
calcineurin antagonists have also recently
demonstrated benefit.
Interdisciplinary management is essential for
long-term control.
Lichen sclerosus (LS) is a chronic inflammatory dermatosis of the anogenital area that affects quality of life
due to the severe itching. LS may also present with
extragenital manifestations that are generally nonpruritic. Of note, vulvar disease seems to have an increased
risk of squamous cell carcinoma, but the role of additional cofactors (e.g., human papillomavirus infection
or prior radiotherapy) has not been defined.
EPIDEMIOLOGY
702
The incidence of LS has not been precisely determined.

It has been estimated to be in the order of 14 per 100,000
persons per year.1 LS is more prevalent in females,
accounting for a 5:1 gender ratio. It preferentially affects
women in the fifth or sixth decade of life and children
younger than the age of 10 years.1,2 Up to 15% of LS
cases occur in children, particularly in girls, and one
study reported a prevalence of 1 in 900 premenarchal

girls.3 A 0.07% incidence in males has recently been
determined in a study of 153,432 male soldiers.4 Among
blacks and Hispanics, the incidence in this group was
1.06%, whereas the incidence was only 0.051% in white
soldiers.4 LS seems to be a prominent cause of phimosis; in one study, 14% of adolescent boys had LS,
whereas 40% of phimosis cases in adult men were associated with LS.5 Similarly, a recent study of foreskins
examined after therapeutic circumcision for phimosis
confirmed many cases of unrecognized LS.6 As genital
LS in males is almost exclusively seen in uncircumcised
men, the rate of circumcision in a given population has
a strong impact on the occurrence of the disease.

The cause of LS is unknown. While a genetic predisposition has generally not been found,7 a recent observational cohort study reported a high rate of familial LS
cases.8 Of 1,052 females with LS, 126 (12%) had a positive family history of LS. Vulvar cancer was significantly
increased in those patients with a family history of LS
compared with those without (4.1% vs. 1.2%).8 This
report proposes a likely genetic component in the etiology of LS. Evidence for the presumed infectious cause,
such as acid-fast rods, spirochetes, or Borrelia, has not
been found.7 Serologic and clinical evidence of thyroid
disease, alopecia areata, pernicious anemia, and vitiligo
suggested an association with LS. Extragenital LS is
commonly seen in association with plaque-type morphea, and some authors have suggested a common
pathomechanism. Recently, low-titer autoantibodies
against the extracellular matrix protein-1 (ECM-1) and
collagen XVII have been identified in 67% of LS.9,10
ECM-1 (see Chapter 137) may be involved in basement
membrane and interstitial collagenous fiber assembly
and growth-factor binding,11 and may also regulate
blood vessel function.12 In addition, antibodies to the
basement membrane protein bp180 have been detected
in childhood vulval LS lesions in four of nine children
analyzed.13 All antibodies were IgG-type. There was no
clinical and family history of autoimmune diseases or
autoantibodies in the children studied. Local irritation
also seems to play a role in some cases. The disturbed
function of fibroblasts with increased production of collagen has been demonstrated in LS.14,15
CLINICAL FINDINGS
CUTANEOUS LESIONS
Polygonal papules and porcelain-white plaques with
atrophic fragile skin, fissures, telangiectasias, purpura,
erythema, erosions, and different degrees of sclerosis
are present in the anogenital area (Figs. 65-1A65-1F);
::
Chapter 65
Lichen Sclerosus
Figure 65-1 A. Early sclerosis and significant hemorrhage on the glans in early lichen sclerosus. B. Sclerosis of the frenulum and increased vulnerability with bleeding upon sexual intercourse. C. Significant sclerosis of the glans and conglutination with the preputium in advanced lichen sclerosus. Note narrowing of the urethral orifice and hemorrhage. D. In
addition to the well-demarcated white vulvar plaque that is classic for lichen sclerosus, the waxy and crinkled texture,
purpura (small arrows), and erosions (large arrow) are diagnostic. E. Sclerotic vulva with disappearance of the smaller
labia and shrinkage of the introitus. Significant erythema and erosions are seen on the vulva and the anus in a figure-8
configuration. The patient complained of severe pruritus and dyspareunia. F. Erosive, sclerotic vulva in an 8-year-old girl.
703
LABORATORY TESTS
HISTOPATHOLOGY
Section 9
::
Figure 65-2 Extragenital lichen sclerosus with confluent

whitish papules and plaques on the skin over the thoracic
and lumbar spine.
often the classical figure-8 pattern of the vulva and
anus may be observed (see Fig. 65-1E). Blisters (occasionally hemorrhagic) may develop when the lichenoid
infiltrate separates epidermis from the sclerotic dermis.
The size of LS lesions may vary from a few millimeters
to large portions of the trunk. Anogenital LS frequently
causes intractable itching and soreness, dyspareunia,
dysuria, discomfort with defecation, or genital bleeding and, with time, may lead to destructive scarring
(see Fig. 65-1F). Gradual obliteration or synechiae of the
labia minora and clitoris, as well as stenosis of the
introitus, may also result (see Chapter 78). Male genital
LS is usually confined to the glans penis, prepuce, or
foreskin remnants (see Fig. 65-1A65-1C). Penile shaft
involvement is less common, whereas scrotal involvement is rare. Many male genital LS cases are simply
diagnosed as phimosis. In severe cases, erections may
become painful (see Chapter 77). Extragenital manifestations typically affect the thigh, the neck, trunk and
lips; lesions are usually asymptomatic (Fig. 65-2). A
recent clinical histopathological study has revealed 27
adult cases with lip involvement.16 Clinical presentation consisted of asymptomatic vitiligo-like lesions in
70% with a variable degree of dermal sclerosis confined
to the papillary layer. This was in contrast to genital LS
lesions that showed both papillary and reticular dermal
sclerosis in the majority of cases. Therefore, the vitiligolike LS needs to be added to this spectrum of oral
lichenoid lesions.
Classical LS shows an atrophic epidermis and a lichenoid infiltrate at the dermalepidermal junction.17 Papillary edema is usually seen in early LS, but is gradually
replaced by fibrosis with homogenization of acid mucopolysaccharides as the lesion matures (Fig. 65-3). The
lymphocytic infiltrate in LS contains abundant T cells, B
cells, and antigen-presenting dendritic cells that are
major histocompatibility complex class II+, CD8+, and
CD57+.18,19 A monoclonal T-cell receptor -chain rearrangement has alluded to the existence of an LS antigen,
potentially the ECM-1 protein, which is also recognized
by the recently described autoantibodies.8,20 Epidermal
hyperplasia and/or dysplasia associated with LS on
vulvar specimens are associated with an increased risk
of malignant transformation, especially in conjunction
with infection by high-risk papillomaviruses.
SPECIAL TESTS
Imaging studies are only needed in special situations
(e.g., urinary obstruction secondary to stenosing genital LS). High-resolution ultrasound is occasionally
used to document the depth of sclerosis.
704
Except for the association with autoimmune thyroid

disease, alopecia areata, pernicious anemia, morphea,
and vitiligo, which should be ruled out, no additional
related findings have been reported. In particular, genital infections by herpes simplex virus or Candida do
not seem to be increased in LS patients.
Figure 65-3 Hyperkeratotic epithelium without rete

ledges and basal degeneration of keratinocytes. Collagen fibers are homogenized in the papillary dermis, and
a lichenoid lymphocytic infiltrate is present. The dermal
vessels are dilated.

DIAGNOSIS
Rule Out
Cicatricial (scarring) pemphigoid
Erythroplasia of Queyrat (Bowen disease)
Leukoplakia
Paget disease
EXTRAGENITAL MANIFESTATIONS
Consider
Anetoderma
Atrophoderma of Pasini and Pierini
Lipoid proteinosis (mild forms, see Chapter 137)
Lichen nitidus
Lichen planus
Morphea
Pinta
Tinea versicolor
Lichen Sclerosus
Besides dyspareunia, urinary obstruction, constipation, secondary infection related to ulceration,

and steroid use, squamous cell carcinoma represents the main complication in females (Fig. 65-4).
The lifetime risk of developing squamous cell cancer as a complication of long-standing LS has been
estimated in the order of 4%6%.1,29 Age, long duration of LS, human papillomavirus infection, and
Consider
Balanitis plasmacellularis (Zoon disease)
Child abuse (sexual)
Complications of dermatologic laser surgery
Contact dermatitis, including excessive genital
hygiene
Lichen planus
Vitiligo
::
COMPLICATIONS
GENITAL MANIFESTATIONS
Chapter 65
A skin punch biopsy of a mature lesion will confirm the

diagnosis if the diagnosis is not obvious by clinical
examination. ECM-1 autoantibodies may be detected
by specialized laboratories; a commercial enzymelinked immunosorbent assay (ELISA) has recently
become available.21 Despite the described association
with autoimmune diseases, an autoimmune workup
(e.g., antinuclear antibody, parietal cell antibody, vitamin B12 levels, thyroid function tests) is not generally
recommended due to their relatively low occurrence.22
For the same reason, Borrelia antibody titers should not
be analyzed, as they are not associated with LS.23 To
exclude squamous cell carcinoma, repetitive biopsies
may be indicated.
The differential diagnosis of LS and localized
scleroderma (morphea) may be difficult (Box 65-1;
see Fig. 65-2). Clinically, morphea may be confused
with extragenital LS. Morphea represents a circumscribed connective tissue disease with a number of
different presentations. Typical early plaque-type
lesions show a lilac ring with progressive central
induration and whitening and peripheral hyperpigmentation (see Chapter 64). Histologically, early
morphea presents as a dense lymphocytic, superficial, and deep perivascular infiltrate with degeneration of collagen fibers. In later stages, inflammation
is replaced by dermal fibrosis much like the changes
seen in LS. Patients have been described with lesions
typical of both plaque-type morphea and the chalky
white, atrophic plaques of LS, suggesting that morphea and LS may share a common pathomechanism.24 Antinuclear antibodies may be positive in
either morphea or LS.
Constipation is a common complication in children with anogenital LS.25 The associated purpura
and discoloration often raise concern about child
abuse, especially if LS is not recognized (see Chapter
106). LS in children has occasionally been associated
with a perineal pyramidal protrusion, a common
lesion that can be confused with condyloma and is
also associated with constipation. This association
further (erroneously) increases the suspicion of sexual abuse.26,27 It should be noted, however, that LS
and child abuse may coexist28 and that some cases of
LS have been linked with trauma of the anogenital
region (see Chapter 106). See Box 65-2 for pitfalls in
the diagnosis of LS.

of Lichen Sclerosus
Rule Out
Graft-versus-host disease (scleroderma-like)
Extramammary Paget disease
Box 65-2 Pitfalls in the Diagnosis

of Lichen Sclerosus
Wrong/incomplete diagnosis in the case of squamous cell carcinoma
Lichen sclerosus, especially when bullous, hemorrhagic, or erosive; may be confused with child
abuse
Inappropriate surveillance for steroid adverse
effects
Irritant dermatitis due to overwashing of the anogenital area may imitate lichen sclerosus and facilitate the occurrence of contact dermatitis
705
Section 9
::
706
Figure 65-4 A. A 1.5-cm, sharply demarcated ulcer of long-standing lichen sclerosus on the right major labium. B. Histology reveals squamous cell carcinoma.
evidence of hyperplastic changes represent significant risk factors.30,31 In males, painful erections and
urinary obstruction represent the most frequent
complications.

COURSE
The prognosis of LS is good for most anogenital cases,
especially for those in prepubertal children that may
resolve spontaneously or may be healed after treatment with ultrapotent topical steroids.32 However, a
recent study reported that childhood onset vulvar LS
does not resolve at puberty.33 The authors prospectively studied 12 cases, of which nine patients, who
still had active LS at puberty, continued to require
maintenance therapy after menarche. Six of the 12
experienced significant disturbance of the vulvar
architecture. Therefore, prepubertal LS does not necessarily resolve at puberty. A further case series reported
the efficacy of topical clobetasol propionate 0.05% in
childhood LS.34 Nine of 15 young girls suffered from a
relapse about 1 year following the first clearing of the
lesions. The authors also concluded that early aggressive treatment with ultrapotent corticosteroids enables
the best clinical course of childhood LS.34 The disease is
usually self-limiting, but requires treatment due to the
severity of patient discomfort. Recalcitrant chronic LS
causing erosions and progressive scarring may result
in severe sexual dysfunction. Cosmetic improvement
for extragenital cases and for chronic atrophic genital
disease is rather poor.
TREATMENT
Various attempts to treat LS have been undertaken.
The single most effective treatment of LS is ultrapotent
topical corticosteroids such as clobetasol.20,3243 However, there is no systematic trial to support this common practice. Due to corticosteroid adverse effects, the
treatment period with ultrapotent steroids should be
limited, generally to 46 weeks. Treatment should be
continued, when necessary, with less potent corticosteroids or calcineurin inhibitors (see below).
Case series using topical tacrolimus and pimecrolimus have shown clinical effectiveness.4448 Although
many of the effects of topical tacrolimus parallel
those of corticosteroids,49 adverse effects such as
atrophy, telangiectasias, and pigment changes do not
occur. A recent multicenter, phase II trial has assessed
the safety and efficacy of twice-daily application of
tacrolimus ointment 0.1% in 84 patients (49 women,
32 men, and 3 girls) with longstanding LS (mean
duration, 5.8 years), with a follow-up period of 18
months.50 Clearance of active LS was reached by
42.9% of patients, with at least 50% improvement in
an additional 34.3% of patients. However, the duration of treatment to achieve an optimal response was
up to 24 weeks.
Systemic therapy with retinoids, including isotretinoin, etretinate, and acitretin and oral tacrolimus,
have been useful in small trials. Systemic antibiotics
against borreliosis and penicillamine have not proved
effective.
Destructive surgical therapies, such as cryotherapy,51 the tissue-vaporizing carbon dioxide lasers,
and nonablative lasers such as the pulsed dye and
PREVENTION
No truly preventive measures of LS have been
reported. An interdisciplinary management is essential for the long-term control of LS. Specialists from
gynecology, urology, pediatrics, and psychosomatic
medicine should be involved in patient care and collaborate to prevent significant complications, including the monitoring for squamous cell cancer and
corticosteroid adverse events. It has also been helpful to circulate information via patient organizations
for LS.
KEY REFERENCES
1. Powell JJ, Wojnarowska F: Lichen sclerosus. Lancet
353:1777, 1999
3. Powell JJ, Wojnarowska F: Childhood vulvar lichen sclerosus: An increasingly common problem. J Am Acad Dermatol 44:803, 2001
8. Sherman V et al: The high rate of familial lichen sclerosus
suggests a genetic contribution: An observational cohort
study. J Eur Acad Dermatol Venereol 24:1031, 2010
9. Oyama N et al: Autoantibodies to extracellular matrix
protein 1 in lichen sclerosus. Lancet 362:118, 2003
13. Baldo M et al: Childhood vulval lichen sclerosus: Autoimmunity to the basement membrane zone protein BP180 and its
relationship to autoimmunity. Clin Exp Dermatol 35:543, 2010
16. Attili VR, Attili SK: Lichen sclerosus of lips: A clinical and
histopathologic study of 27 cases. Int J Dermatol 49:520, 2010
18. Farrell AM et al: Lichen sclerosus: Evidence that immunological changes occur at all levels of the skin. Br J Dermatol
140:1087, 1999
30. von Krogh G, Dahlman-Ghozlan K, Syrjanen S: Potential
human papilloma-virus reactivation following topical corticosteroid therapy of genital lichen sclerosus and erosive
lichen planus. J Eur Acad Dermatol Venereol 16:130, 2002
33. Smith SD, Fischer G: Childhood onset vulvar lichen sclerosus does not resolve at puberty: A prospective case
series. Pediatr Dermatol 26:725-729, 2009
34. Patrizi A et al: Childhood lichen sclerosus: A long-term
follow-up. Pediatr Dermatol 27:101, 2010
39. Dahlman-Ghozlan K, Hedblad MA, von Krogh G: Penile
lichen sclerosus et atrophicus treated with clobetasol
dipropionate 0.05% cream: A retrospective clinical and
histopathological study. J Am Acad Dermatol 40:451, 1999
51. Stucker M et al: The outcome after cryosurgery and intralesional steroid injection in vulvar lichen sclerosus corresponds to preoperative histopathological findings. Dermatology 210:218, 2005
Chapter 66 :: D
ermal Hypertrophies and Benign
Fibroblastic/Myofibroblastic Tumors

:: Christine J. Ko
DERMAL HYPERTROPHIES AND BENIGN FIBROBLASTIC/MYOFIBROBLASTIC
TUMORS AT A GLANCE
Common benign dermal fibrous lesions include
hypertrophic scar, keloid, dermatofibroma, and
acrochordon.
Certain benign tumors with a prominent
dermal connective tissue component (e.g.,
angiofibroma, fibrofolliculoma/trichodiscoma,
acrochordon-like lesions, and connective
tissue nevi) may be associated with genetic
disorders.
Some dermal hypertrophies and tumors (e.g.,
desmoid tumor, infantile fibromatosis, infantile
myofibromatosis) can at times be aggressive
with high rates of recurrence.
Chapter 66 :: Dermal Hypertrophies and Benign Fibroblastic/Myofibroblastic Tumors
Erb:YAG lasers, have been reported to work in LS but

should only be used with caution. More recently,
PUVA and UVA1 treatment have shown some promising success in LS. Vulvectomy should be limited to
cases in which squamous cell carcinoma has been
detected.5254
Female LS patients should be particularly monitored for any sign of secondary genital malignancy.
Prepubertal LS in girls may resolve spontaneously;
however, some of these patients may eventually
suffer from vulvodynia in adulthood. In case of LSassociated dyspareunia that interferes with sexual
activity, the use of topical anesthetics should be
considered.
Circumcision will generally resolve male genital
LS and the associated phimosis, although potent
topical steroids may obviate the need for surgery.
Asymptomatic extragenital LS usually requires no
treatment other than cover makeup in selected
cases.
Other entities that present in infancy and

childhood include fibrous hamartoma of infancy,
fibromatosis colli, infantile digital fibromatosis,
calcifying aponeurotic fibroma, juvenile hyaline
fibromatosis, and infantile systemic hyalinosis.
Other entities that primarily affect adults include adult
fibromatoses (palmoplantar, penile, knuckle pads),
pachydermodactyly, reactive lesions (nodular fasciitis,
elastofibroma), solitary lesions (acquired digital
fibrokeratoma, dermatomyofibroma, pleomorphic
fibroma, collagenous fibroma, myofibroma, solitary
fibrous tumor), and clinically distinctive hypertrophies
(cutis verticis gyrata, pachydermoperiostitis,
cerebriform fibrous proliferation).
707
TABLE 66-1
Fibroblastic/Myofibroblastic Tumors of Infancy and Childhood
Section 9
Skin Involvement
Entity
Typical Site(s)
Often solitary
Infantile digital fibromatosis

Myofibroma
Calcifying aponeurotic fibroma
Plantar fibromatosis
Infantile fibromatosis
Fibrous hamartoma of infancy
Fibromatosis colli
Cranial fasciitis
Digits
Head/neck
Palms/soles
Soles
None
Upper arm/trunk
Clavicle area
Head/neck
Often multiple
Juvenile hyaline fibromatosis
Ears/face and other sites
Often multiple with visceral involvement
Infantile systemic hyalinosis

Infantile myofibromatosis
Ears/face and other sites

None
::
Dermal hypertrophies and benign fibrous tumors are

quite common. Some of the entities described have
characteristic clinical presentations and histopathologic features. Many primarily present in infancy and
childhood (Table 66-1). A unifying histologic feature of
hypertrophic scars and most of the rarer entities
described is the presence of myofibroblasts, contractile
spindle cells that express smooth muscle actin but not
desmin (Table 66-2). Malignant fibrous tumors of the
dermis are discussed in Chapter 125.
Hypertrophic Scars
and Keloids
Keloids and hypertrophic scars are related clinical
lesions.1 These lesions present at sites of prior dermal
injury and wound repair. They often occur after local
skin trauma (e.g. laceration, tattoo, burn, injection, ear
piercing, vaccination, or surgery) or inflammatory skin
disorders (e.g. acne, bites, or infections). There may be
growth of keloids during pregnancy.2 The predisposition to keloids in darker skin3 and reports of a familial,
autosomal dominant inheritance4 suggest genetic influences. Hypertrophic scars and keloids show differences morphologically and histologically (Table 66-3),5,6
suggesting differences in pathogenesis. There also is

an apparent association with melanin pigment, as
albino and vitiliginous skin do not form keloids.7 Multiple keloids may also be associated with a genetic syndrome (Table 66-4).
Keloids appear as well-circumscribed pink to purple
or hyperpigmented firm nodules (Fig. 66-1) or plaques.
The surface of keloids is usually smooth, but can be
nodular and borders are often smooth, but can be irregular (Table 66-3). The surface and borders of hypertrophic scars are always smooth and regular. There is a
predilection for developing keloids at sites of increased
tension, such as the shoulders, sternum, mandible, and
arms. Keloids also commonly affect the earlobes.
Keloids and hypertrophic scars are often painful, hyperesthetic, or pruritic. Ulceration can occur. Multiple
keloids are common, but several rare entities may be
considered in the clinical differential diagnosis (see Box
66-1).811 Histopathologically, keloids are composed of
thick, haphazard, eosinophilic, collagen bundles.
Hypertrophic scars are more cellular with myofibroblasts either in disorganized whorls or sometimes
oriented parallel to the epidermis.
Although the exact mechanism of keloid formation
is still unclear,1219 TGF-beta and its signaling pathway
are important (see Table 66-5).12 Hypertrophic scars are
associated with HLA-DRB16.20 In most studies, keloids
TABLE 66-2
Differences Between Fibroblasts, Myofibroblasts, and Smooth Muscle Cells
708
Fibroblast
Myofibroblast
Smooth Muscle Cell
Nucleus
Tapered
Tapered to cigar-shaped
Cigar-shaped
Positive immunohistochemical stains
Vimentin
CD34 (sometimes)
Vimentin
Smooth muscle actin
Muscle specific actin
Vimentin
Smooth muscle actin
Desmin
Negative immunohistochemical stains
Smooth muscle actin

Desmin
Desmin
TABLE 66-3
TABLE 66-4
Differences Between Keloids and

Hypertrophic Scars
Keloid
Selected Genetic Syndromes Associated with

Superficial Dermal Hypertrophies and Fibrous
Tumors
Hypertrophic
Scar
Especially third
decade
Any
Onset after injury
Delayeda
Immediate
Growth beyond border

of original wound
Yes
No
Spontaneous
regression
Rare
Occasional
Recurrence
Common
Rare
Distorted shape
Common
Rare
Histopathology
Thick, hyalinized
collagen
Fascicles of
myofibroblasts
arranged
haphazardly
Poor
Good
Associated Genetic
Syndrome
Keloids
RubinsteinTaybi
Goeminne
Acrochordon-like
lesions
BirtHoggDuba
Gorlin (Nevoid basal cell
carcinoma)b
Fibrous papules/
angiofibromas
Tuberous sclerosisc
Multiple endocrine neoplasia type I
BirtHoggDub
Fibrofolliculomas/
trichodiscomas
BirtHoggDub
Connective tissue
nevus
Tuberous sclerosisd
BuschkeOllendorfe
Familial cutaneous collagenoma
Multiple endocrine neoplasia type I
BirtHoggDub
EhlersDanlos (hypermobile, type III)
Hunter/Hurler
Sclerotic fibroma
(circumscribed
storiform collagenoma,
plywood fibroma)
Cowden
Desmoid tumor
Gardner/Familial adenomatous
polyposisf
Familial infiltrative fibromatosis/
Hereditary desmoid disease
Cutis verticis gyrata
Turner
Noonan
Fragile X
Klinefelter
Tuberous sclerosis
BeareStevenson
EhlersDanlos
Apert
Knuckle pads
BartPumphrey
Cerebriform fibrous
proliferation
Proteus
Gardner fibroma
Gardner/Familial adenomatous
polyposis
May occur spontaneously.
and scars show the same biochemical and pathologic

abnormalities. Keloids express increased levels of the
gli-1 protein, an oncogene product also present in neoplasms such as basal cell carcinoma.21 Collagen synthesis and collagenase activity are increased in both
keloids and hypertrophic scars. a1-Globulin (a collagenase inhibitor usually not present in normal scars) may
contribute to increased collagen deposits. Hypertrophic scars have decreased levels of the profibrotic
agent tumor necrosis factor.22 Keloids contain tenascin
C, a protein associated with inflammation and wound
healing.23 Fibroblasts from keloid-prone patients have
altered cytokine patterns24 and increased sensitivity to
transforming growth factor- b1 (TGF- b1),25 TGF-b2,26
Age
Treatment response
Histopathology is that of a fibrofolliculoma/trichodiscoma.

Histopathology is that of basal cell carcinoma.
c
Referred to as adenoma sebaceum by some when associated with
tuberous sclerosis.
d
Referred to as a shagreen patch.
e
Referred to as dermatofibrosis lenticularis disseminata.
f
Generally tumors are intra-abdominal.
b
Figure 66-1 Keloid. Firm, nontender erythematous nodule

on the ear that developed after ear-piercing.
platelet-derived growth factor, and epidermal growth

factor.27 Carbon dioxide laser treatment reduces TGFb1 levels in keloids.28 At least, part of the fibroblast
stimulation may be secondary to infiltration of the scar
by activated T cells.29 Also, there seem to be decreased
709
Box 66-1 Clinical Differential

Diagnosis of Multiple Keloidal
Lesions
TABLE 66-5
Factors Associated with Keloids
Keloid
Lobomycosis
Keloidal scleroderma/morphea
Non-Langerhans cell histiocytoses
Section 9
::
levels of apoptosis, as shown by terminal transferase

dUTP nick end labeling (TUNEL) assays and increased
Bcl-2 and p53 expression in keloid-associated fibroblasts.30
The treatment of hypertrophic scars and keloids differs slightly.7,31 Hypertrophic scars tend to be more
responsive than keloids and generally flatten with
time. Although injection of hypertrophic scars and
keloids with intralesional steroids is a first-line treatment in many cases, depending on the situation (e.g. a
wound previously infected, a wound across lines of
tension or a joint), hypertrophic scars may respond
quite well to surgery as an initial treatment. Surgery
alone is generally not recommended for keloids, as
they often recur as larger lesions. An exception to this
may be keloids on the earlobes.32 An algorithm for
treatment is outlined in Treatment Box 66-2.
DERMATOFIBROMA (FIBROUS
HISTIOCYTOMA, SCLEROSING
HEMANGIOMA)
Dermatofibroma is a common, benign tumor that has a
predilection for the lower legs of women. Any age may
be affected, but typically dermatofibromas appear in
the 20s and 30s. Dermatofibromas may be solitary or
Increased
Decreased
Transforming growth
factor-
Platelet-derived growth
factor
Vascular endothelial
growth factor
Collagen
Cytokines (e.g., IL-1, IL-6)
Cyclooxygenase 2
Plasminogen activator
inhibitor-1
Matrix metalloproteinase-2
SMAD proteins (e.g., SMAD7)

Apoptosis
multiple and eruptive (see Box 66-3).33 Trauma, such as

secondary to insect bites, has been thought to induce
some lesions, suggesting a reactive/reparative process. The recent demonstration of clonal X-inactivation
in some cases of dermatofibroma supports a neoplastic
nature.34,35
Usually asymptomatic, they occasionally are pruritic or painful. Some tumors grow very rapidly,
whereas others remain static for many years. Characteristically, a dermatofibroma is firm, measuring from
0.5 mm to 1 cm in diameter, and lateral compression
produces a dimple-like depression in the skin. The surface may be shiny or keratotic, and the color is variable, often brown but sometimes pink, red, tan, or flesh
colored (Fig. 66-2A).
Histologically, the epidermis is usually hyperplastic
and hyperpigmented. There may be follicular or sebaceous induction. The dermis has fascicles or haphazardly arranged collections of spindle cells that lack
atypia in most cases (see Figs. 66-2B and 66-2C). The
Box 66-2for Hypertrophic Scars and Keloids

Hypertrophic Scars
Keloids
First-line
Intralesional steroids or sometimes

surgical excision/revision
Potential modalities for use in combination with first-line or second-line

treatment
Often not necessary
Cryotherapy
Pressure
Silicone gel sheeting
Second-line
Often not necessary
Laser therapy
Intralesional 5-fluorouracil
Surgerya
Radiation
Bleomycin
Often combined with postoperative steroid injections, topical imiquimod application, pressure application, radiation, intralesional
verapamil.
710
Box 66-4 Atypical, Cellular,

Deep, and Indeterminate Fibrous
Histiocytomas
Systemic lupus erythematosus

Human immunodeficiency virus infection
Immunosuppression of other cause (e.g., immunosuppressive drugs, especially in the setting of patients
with autoimmune disease, lymphoma/leukemia,
organ transplant)
Case reports of atopic dermatitis, pulmonary hypertension, hydronephrosis, myasthenia gravis, pemphigus, pregnancy, sarcoidosis, hyperlipidemia
Clinical Features
Often >2 cm in size
Sometimes facial
Any age, but some predilection for young adults
Often recur after incomplete excision
Rare potential for metastasis
Some authors consider 15 to be a cutoff.
edges of the lesion are poorly defined with individual

cells hugging collagen bundles (collagen entrapment). Mitotic figures may be present, but atypical
forms are not a feature. Dermatofibromas are generally
factor XIIIa-positive36 and CD34.37 There are many histologic variants of dermatofibroma, most without clinical significance. Exceptions are in Box 66-4.
Histologic Features
Background of dermatofibroma/fibrous
histiocytoma
Variable areas of atypical cells, high cellularity
May extend deeply into subcutaneous, sometimes
in a honeycomb pattern
May stain with CD34
a
Occasionally overlaps with aneurysmal variant.
Figure 66-2 A. Dermatofibroma on the right thigh of a young

man. B and C. Haphazardly arranged spindle cells in the dermis.
The lesion edge is poorly defined with spindle cells infiltrating
between thickened collagen fibers [(hematoxylin and eosin 100
magnification (B); 200 magnification (C)].
Box 66-3 Conditions Associated

with Multiple (At Least 8a)
Dermatofibromas
711
pink or slightly hyperpigmented), firm, and dome

shaped. It must be differentiated from an early, nodular, basal cell carcinoma, and biopsy may be necessary.
Unlike a basal cell carcinoma, it rarely bleeds and
stays relatively stable in its smaller size. Histologically, the dermis shows fibrosis with stellate fibroblasts and dilated vessels. Identical histology is seen
in pearly penile papules and periungual fibromas
(Koenens tumors) (see Chapter 140). No treatment is
necessary, and a simple shave or punch excision is
usually curative.
Section 9
FIBROFOLLICULOMA/
TRICHODISCOMA
::
Figure 66-3 Soft fibromas or skin tags on the neck overlying acanthosis nigricans.
No treatment is necessary unless symptomatic. A

common reason for removal is repeated trauma to the
dermatofibroma, often secondary to shaving the lower
legs. Cryosurgery may be helpful in flattening out the
dermatofibroma but usually is not curative. Lesions
termed atypical, cellular, deep, and/or indeterminate are generally best treated with complete
excision, particularly if clinical size is >2 cm (see
Box 66-4).3844
ACROCHORDON
(FIBROEPITHELIAL POLYP, SKIN
TAG, SOFT FIBROMA)
Acrochordons are pedunculated papules or tumors
that are most commonly located on the eyelids, neck,
axillae, and groin. There is a familial disposition, and
acrochordons are more commonly seen in obese individuals, sometimes overlying acanthosis nigricans
(Fig. 66-3). Acrochordon-like clinical lesions may be a
feature of a genetic syndrome, although histologically
there are differences (see Table 66-4).45,46 Histologically,
an acrochordon is a polypoid lesion with a central collagenous core. Adnexal structures are generally absent.
Although usually asymptomatic, lesions can become
irritated or necrotic. Patients often request removal for
cosmetic reasons.
Fibrofolliculomas/trichodiscomas are 2- to 4-mm,

dome-shaped, yellowish to skin-colored papules
located on the head, neck, and upper trunk; multiple
lesions may be associated with BirtHoggDub syndrome (see Table 66-4).45
CONNECTIVE TISSUE NEVUS/

COLLAGENOMA/ELASTOMA
These hamartomas can be divided into familial, those
associated with genetic disease (see Table 66-4),47,50,5357
and other isolated variants. Connective tissue nevi
present as asymptomatic, flesh-colored to yellow
brown papules or plaques that may be solitary
or grouped, linear, or irregular in distribution (Fig.
66-4).58 The overlying epidermis is usually smooth.
Histologically, connective tissue nevi show a normal
epidermis overlying collagen in the lower dermis.
The collagen may be subtly increased, thickened, or
oriented vertically to the epidermis, and muscin may
be increased. Elastic fibers may also be increased
(elastoma).
Familial cutaneous collagenoma is an autosomal
dominantly inherited condition of multiple, often papular connective tissue nevi usually appearing postpuberty on the trunk and upper extremities.59,60 There
FIBROUS PAPULE
(ANGIOFIBROMA)
712
A fibrous papule is a common papule on the lower

portion of the nose or the central face. It usually presents in adulthood. Multiple lesions are a feature of certain genetic syndromes (see Table 66-4),4751 but
occasionally may be seen in patients with no other
stigmata of a genetic disorder.52 The fibrous papule is
small (25 mm), nontender, flesh colored (sometimes
Figure 66-4 Cutaneous collagenoma, a connective tissue

nevus involving almost the entire back.
may be associated systemic abnormalities such as progressive cardiomyopathy.
DESMOID TUMOR (AGGRESSIVE

FIBROMATOSIS)
Infantile fibromatosis presents as a rapidly growing

nodule on the head and neck, shoulder/upper arm, or
thigh; generally before age 2. The lipofibromatosis
variant has a predilection for the hands and feet.69 Histologically, the tumor may have an immature mesenchymal pattern, variable amounts of adipose tissue,69
or a desmoid tumor-like pattern. Local recurrence is
common, but surgery is the treatment of choice.70,71
INFANTILE MYOFIBROMATOSIS
Infantile myofibromatosis generally presents before age
2, with many cases being congenital.72,73 Multiple nodules
involving the skin and other organs (gastrointestinal, kidney, lung, heart) are seen, with mortality approaching
75%.73 Prognosis is generally excellent if only a solitary
nodule (then termed myofibroma, see below) or multiple
nodules limited to the skin are seen. For multiorgan
involvement, treatment with surgical resection, chemotherapy and radiotherapy have been described.
Histologic diagnosis relies on the identification of
two separate componentsa fascicular myofibroblastic pattern at the periphery with a hemangiopericytoma-like pattern in the center. In the past, many cases
were considered to be infantile or childhood hemangiopericytomas. Mitotic figures, vascular invasion, and
tumor necrosis can be found, but do not predict malignant transformation.74 Biopsy of these lesions, especially in infants and young children, is important to
ensure that the lesions do not represent congenital
infantile fibrosarcoma. Histopathologic examination
as well as cytogenetic and molecular pathology studies
will distinguish myofibromas (chromosome 8 abnormalities) from congenital infantile fibrosarcomas
(translocation between chromosomes 12 and 15ETV6
and NTRK3 genes).75
FIBROUS HAMARTOMA
OF INFANCY
Figure 66-5 Desmoid tumors involving upper chest and

epigastric region. These represent recurrences after multiple surgical interventions. This patient also had intraabdominal desmoid tumors.
Fibrous hamartoma of infancy is a rare benign tumor

that presents before age 2 (up to 25% congenital)76,77 as
a solitary, painless, rapidly growing, flesh-colored, illdefined, subcutaneous nodule, or plaque. There is a
male predominance. The most common locations are
the axillary region, upper arm, upper trunk, inguinal
region, and external genital region.76,77 These lesions
rarely present with overlying skin changes such as
hypertrichosis, alteration in pigmentation, and eccrine
gland hyperplasia.77 Histologic features are characteristic, with an organoid pattern of fibrous trabeculae,
myxoid areas with spindle cells, and adipose tissue.76,78
The treatment of choice is complete excision.73 An
aggressive approach should be avoided because the
overall prognosis is excellent.79
Desmoid tumors, also known as deep or aggressive

fibromatoses, are a type of fibromatosis. All types
(extra-abdominal, abdominal wall, intra-abdominal)
may be induced by trauma (Fig. 66-5). Mutations
have been found in the adenomatous polyposis coli
(APC) gene (5q21).61 Hormonal influences (e.g., pregnancy) are implicated in abdominal wall tumors.62
Tumors associated with Gardner/Familial adenomatous polyposis (FAP) (see Table 66-4)63 are often intraabdominal,64 may be more aggressive and surgically
unresectable, and are associated with a 10% mortality.65 Extra-abdominal tumors are deep-seated, often
located in the area of the shoulder and pelvic girdle,
chest wall, or head and neck.66 Although surgery is
widely accepted as first-line treatment,67 complete
surgical excision is difficult to achieve, and recurrences are common. Intra-abdominal tumors, particularly those associated with Gardner/FAP, may be
best treated, if symptomatic, with radiation or chemotherapy.68
INFANTILE FIBROMATOSIS
(LIPOFIBROMATOSIS, PEDIATRIC
DESMOID TUMOR)
713
Section 9
Figure 66-6 A. Well-defined pink nodules of infantile digital fibromatosis in a 9-month-old patient. B. The patient at age
2.5 years, with spontaneous resolution of the nodules. (Used with permission from Richard J. Antaya, MD.)
::
FIBROMATOSIS COLLI
(STERNOCLEIDOMASTOID TUMOR
OF INFANCY)
Fibromatosis colli is an often self-limiting, rapidly
growing tumor, presenting in the first few weeks of life.
It is characterized by a benign proliferation of fibroblasts in the lower one-third of the sternocleidomastoid
muscle, rarely bilateral, and occasionally associated
with torticollis or facial asymmetry.80 The tumor often
resolves within the first year of life.80 Fine-needle aspiration is the preferred technique for diagnosis.81,82
INFANTILE DIGITAL FIBROMATOSIS

Infantile digital fibromatosis is a rare form of superficial juvenile fibromatosis presenting as (an) asymptomatic, flesh-colored, firm nodule(s) on the fingers
and toes (tending to spare the thumb or hallux) (Fig.
66-6A), primarily in infants and less commonly in children. One-third of cases are congenital.83 Histologically, poorly circumscribed, interlacing bundles of
myofibroblasts are observed. The pathognomonic
finding is eosinophilic, perinuclear inclusion bodies
composed of actin filaments, which stain red with
Masson trichrome stain and purple with phosphotungstic acid-hematoxylin.84 Multiple clinically similar
tumors, but without inclusion bodies on histopathologic examination, are associated with brachydactyly
and facial dyspigmentation.85 Despite the observation
of spontaneous regression over years (Fig. 66-6B) and
a high recurrence rate after excision, surgical intervention is common because deformities of the digit and
contractures can occur with larger lesions.83
CALCIFYING APONEUROTIC
FIBROMA
714
Calcifying aponeurotic fibroma is an uncommon,

benign fibrous tumor. It is most commonly found on
the palms and soles of male children and young adults

(peak incidence between the ages of 8 and 14).86,87 However, it can present in any area that is closely related to
aponeuroses.86 It is a very slow growing, deep-seated
firm proliferation that presents as an asymptomatic
infiltrative soft tissue mass, usually measuring less
than 3 cm in diameter.86 If symptomatic, surgical excision may be performed, although there is a 50% local
recurrence rate. Local recurrence is more common in
children younger than 5 years of age.86
On histopathologic examination, it is an ill-defined,
poorly circumscribed tumor composed of spindled
fibroblasts surrounding central calcified foci. The lesion
typically is organized into nodules, with central hyalinization and incipient calcification surrounded by a palisade of chondrocyte-like cells. Less cellular areas contain
spindled fibroblastic cells between coalescing calcified
nodules. Osteoclastic giant cells may border the calcific
deposits. These lesions may demonstrate actin and
CD99 and S100 proteins with immunostaining.
JUVENILE HYALINE
FIBROMATOSIS/INFANTILE
SYSTEMIC HYALINOSIS
Juvenile hyaline fibromatosis (JHF) is a rare, autosomal recessive condition secondary to a defect on chromosome 4q21 associated with the locus of the capillary
morphogenesis gene-2 (CMG2).88 From infancy, subcutaneous, pearly papules and firm, large nodules that
progressively enlarge and may ulcerate appear on the
nose, chin, ears, scalp, hands (Fig. 66-7), back, and
knees.89 Histologically, cells with perinuclear vacuoles
are seen in a hyalinized and chondroid stroma. Patients
tend to have gingival hypertrophy, which can result in
periodontal disease and caries. Progressive joint contractures, osteolysis, and muscular weakness can result
in severe debilitation.
Preliminary genotypephenotype analyses suggest
that abrogation of binding by von Willebrands factor
type A domain of CMG2 results in severe disease
Ledderhose disease is characterized by plantar fibrosis especially over nonweight-bearing areas of the sole
and has similar features to Dupuytren disease histologically.93,96 Contractures are uncommon.96,98 Typically
adults are affected, but children can manifest disease.93
These lesions may be treated with surgical excision.
PEYRONIE DISEASE
(PENILE FIBROMATOSIS)
typical of infantile systemic hyalinosis (ISH), whereas

in-frame mutations affecting the highly conserved
cytoplasmic domain result in a milder phenotype.90
Although the fibrous skin lesions, joint contractures,
gingival hypertrophy, and osteolysis are shared with
JHF, the manifestations of ISH are present within the
first months of life and often at birth.91 Patients may
also show diffusely thickened skin, hyperpigmented
plaques on bony prominences, visceral involvement,
frequent infections, and persistent diarrhea with failure to thrive, leading to death during infancy. The histologic and ultrastructural appearance of biopsied
lesional skin resembles that of JHF.
Currently, no widely accepted effective treatment
exists for JHF or ISH. Surgical excision is often not feasible due to the number and size of the tumors, and
anesthesia can be complicated because of the oral and
dental issues.
PALMOPLANTAR FIBROMATOSES
Dupuytren contracture (palmar fibromatosis) is characterized by progressive fibrosis of the palmar fascia,
most commonly presenting as one or more nodules
over the fourth and fifth metacarpal head. Nodules
become cords, and joint contractures and flexion deformities of the fingers may follow.92 Significant risk factors for development of Dupuytren contracture include
old age, male sex, white northern European ancestry,
family history, seizures, alcohol-induced liver disease,
trauma, smoking, and diabetes mellitus.9395 This condition rarely occurs before age 30 and is very rare in
children.93 Concurrent plantar disease, knuckle pads,
and/or keloids may be seen.93,96
Histologically, there are uniform, spindled fibroblasts separated by collagen.93 Surgical correction may
be the treatment of choice of progressive disease.92
Recurrence is more common in patients with greater
initial deformity, but less common if good surgical correction is achieved and postoperative rehabilitation
provided.97
KNUCKLE PADS
Knuckle pads are circumscribed, thickened plaques
over the dorsal aspects of the interphalangeal joints.
Many patients have coexisting palmar, plantar, or
penile fibromatosis.93 Histologically, these lesions are
very similar to Dupuytren disease. False knuckle pads
are due to repetitive mechanical trauma.
PACHYDERMODACTYLY
Pachydermodactyly is a rare form of benign digital
fibromatosis consisting of symmetric, painless, circumscribed swelling of the proximal interphalangeal joints
of the fingers, often sparing the thumb.104 It primarily
affects adolescent males. Some consider this a variant
of knuckle pads. It may be associated with tuberous
sclerosis, atrophia maculosa varioliformis cutis (noninflammatory pitted scarring, usually on the face) and
carpal tunnel syndrome. Histologically there is hyperkeratosis, acanthosis, and increased dermal fibrosis.
Figure 66-7 Juvenile hyaline fibromatosis. Tumors involving the hand. Both hands were affected.
Fibrosis of the dorso-lateral penis, resulting in curvature of the penis and erectile dysfunction, is
termed Peyronie disease. Risk factors include genetic
predisposition, trauma to the penis, smoking, alcohol consumption, and history of diabetes or hypercholesterolemia.99,100 Over several years, patients may
have stabilization and rarely spontaneous regression
of the disorder.101 Conservative management is often
recommended.102 Surgery is reserved for those with
compromised sexual function or disabling deformity.101,103
NODULAR FASCIITIS
Nodular fasciitis is a benign, self-limiting proliferation
of fibroblasts of uncertain etiology that often follows
trauma, observed most frequently on the upper
extremity.105 Although it is seen most commonly in
young adults, it can occur at any age, without racial or
sex predilection. It presents as a rapidly growing, painful mass (generally less than 2 cm) in the subcutis, fascia, or muscle. Cranial fasciitis is the most common
variant in children and involves the head and neck.
Histologically, nodular fasciitis presents as a poorly
demarcated nodule in the subcutis, fascia, or dermis
that is composed of spindled tissue-culture-like
715
fibroblasts and myofibroblasts in a loose, myxoid,

highly vascular stroma that resembles granulation tissue. These lesions often have associated hemorrhage.
Mitotic figures are present, but atypia and nuclear
polymorphism are not seen. Despite the possibility of
spontaneous involution, excision is the treatment of
choice, with recurrences being rare.
ELASTOFIBROMA
(ELASTOFIBROMA DORSI)
Section 9
::
Elastofibroma is a rarely diagnosed, benign, fibroproliferative, soft-tissue tumor that occurs predominantly in the periscapular region of middle-aged
to elderly women.106 Many patients have bilateral
involvement. Although the exact etiology is unknown,
it is suspected that chronic subclinical microtrauma
may lead to reactive hyperplasia of elastic fibers, with
consequently increased production of fibrous tissue.
Clinically, this tumor presents as a poorly circumscribed, firm, mobile mass; typically, the lesions are
concealed with retraction and protuberant with protraction of the shoulders. More than 50% of patients
are asymptomatic and present with a painless swelling. Magnetic resonance imaging often shows a characteristic layering of fibrous tissue and adipose
tissue.107 Typical histologic findings are thickened collagen and chenille-like elastic fibers admixed with
adipose tissue.
ACQUIRED DIGITAL
FIBROKERATOMA
(ACRAL FIBROKERATOMA)
This lesion is a keratotic papule acquired in adulthood, often on the digits or occasionally the palms/
soles (Fig. 66-8).108 Histologically, there is overlying
hyperkeratosis with abundant dermal collagen that
is perpendicular to the epidermis in the papillary
dermis.
DERMATOMYOFIBROMA
This is a 12 cm, ill-defined, indurated plaque, most
commonly seen in young women on the shoulder or
upper arm.109,110 Histologically, in the deep dermis,
there are fascicles of slender spindle cells parallel to the
epidermis, with sparing of adnexal structures.
PLEOMORPHIC FIBROMA
Pleomorphic fibromas are usually solitary and appear
in middle-aged to older individuals. They are generally nondescript, slow-growing, dome-shaped, or
polypoid lesions with a predilection for the extremities.111 Clinical behavior is benign; histologically, a
polypoid lesion with a collagenous core has multinucleated cells and scattered large cells with atypical
nuclei. Even with incomplete removal, recurrence is
uncommon.
COLLAGENOUS FIBROMA
(DESMOPLASTIC
FIBROBLASTOMA)
Collagenous fibroma usually presents in the fifth to
sixth decades with a 5:1 malefemale ratio.112 It is a
benign tumor that appears as a slow-growing, painless, mobile mass (120 cm) located in the subcutaneous tissue or just deep to skeletal muscle. This tumor
has a predilection for the upper arm and shoulder; but
may also occur on the posterior neck, upper back,
lower extremities, hand, abdominal wall, and hip joint.
Histologically, the tumor has an infiltrative appearance
into fascia or skeletal muscle and is composed of bland
stellate and spindle-shaped fibroblasts and myofibroblasts in a collagenous matrix.
MYOFIBROMA
All ages may be affected by myofibroma. This is a
tumor that some consider of vascular origin113 that is
similar histologically to the tumors of infantile myofibromatosis.72,73 When solitary or multiple in the skin,
the prognosis is excellent, with spontaneous regression
in some cases.72 These tumors have a wide distribution, but are often on the extremities in adults
(Fig. 66-9), and are painless.73 Histologic findings are
diagnostic, commonly with multiple nodules or poorly
circumscribed fascicles of spindle cells that express
smooth muscle actin intermixed with thick collagen,
sometimes with peripheral cells having a pericytic
appearance.
SOLITARY FIBROUS TUMOR

716
Figure 66-8 Acquired digital fibrokeratoma. A hyperkeratotic papule with a collarette on the palm, a slightly
unusual location.
Solitary fibrous tumor is a tumor once thought to only

involve the pleural cavity but now known to be a rare
Box 66-5 Conditions Associated

with Cutis Verticis Gyrata
PACHYDERMOPERIOSTITIS
Figure 66-9 Myofibroma. A somewhat ill-defined, focally

firm and focally spongy, pink to flesh-colored tumor (with
smaller nodules within it) on the ankle. This asymptomatic
lesion had been present since at least age 9 and had been
growing slowly over the last 15 years.
soft tissue tumor.114 It usually behaves nonaggressively. Histologically, there are dilated vessels, sometimes staghorn (some consider solitary fibrous tumor
and hemangiopericytoma to be part of a spectrum),
with interspersed spindle cells that are arranged in a
patternless pattern. Cells are CD34+. Malignant
tumors have been described and should be ruled out
when there is increased cellularity, pleomorphism, or
mitoses.
Pachydermoperiostosis (primary hypertrophic osteoarthropathy) is a rare genetic syndrome with most cases
having autosomal dominant transmission.118 At puberty,
there is progressive enlargement of the joints due to
pachydermia, periostosis, and clubbing. Other features
include thickened skin on the face and scalp (resembling
cutis verticis gyrata), palmoplantar hyperhidrosis, and
acro-osteolysis. Arthralgias can be quite debilitating. Disease progresses for 520 years before stabilizing. Primary
hypertrophic osteoarthropathy should be distinguished
from secondary hypertrophic osteoarthropathy, which is
generally secondary to pulmonary or cardiac disease.
CEREBRIFORM FIBROUS
PROLIFERATION
In patients with Proteus syndrome, the soles (and
sometimes the palms) have cerebriform overgrowth
with gigantism. There is increased dermal fibrosis.
KEY REFERENCES
CUTIS VERTICIS GYRATA

This rare condition presents on the scalp, often at
puberty, and when primary, affects males more commonly. The scalp appears folded, with furrows running anteriorly to posteriorly. Primary disease is
idiopathic or associated with neuropsychiatric disorders.115117 Histologically, the areas of folded scalp
appear normal. Cutis verticis gyrata may also be seen
secondarily in association with a variety of inflammatory or neoplastic diseases (see Table 66-4 and Box
66-5).115 Clues for secondary involvement include
early onset of disease (sometimes congenital), asymmetric disease, and disordered furrows that are not
oriented anterior to posterior.115 If the face and acral
sites are involved, pachydermoperiostitis should be
considered.

13. Seifert O, Mrowietz U: Keloid scarring: Bench and bedside. Arch Dermatol Res 301:259, 2009
31. Wolfram D et al: Hypertrophic scars and keloidsA
review of their pathophysiology, risk factors, and therapeutic management. Dermatol Surg 35:171, 2009
41. Horenstein MG et al: Indeterminate fibrohistiocytic
lesions of the skin: Is there a spectrum between dermatofibroma and dermatofibrosarcoma protuberans? Am J
Surg Pathol 24:996, 2000
43. Guillou L et al: Metastasizing fibrous histiocytoma of
the skin: A clinicopathologic and immunohistochemical
analysis of three cases. Mod Pathol 13:654, 2000
93. Fetsch JF, Laskin WB, Miettinen M: Palmar-plantar
fibromatosis in children and preadolescents: A clincopathologic study of 56 cases with newly recognized
demographics and extended follow-up information. Am
J Surg Pathol 29:1095, 2005
116. Polan S, Butterworth T: Cutis verticis gyrata: A review with
report of seven new cases. Am J Ment Defic 57:613, 1953
Neuropsychiatric (e.g., schizophrenia, mental

retardation, seizures)
Genetic syndromes (see Table 66-4)
Inflammatory (e.g., eczema, psoriasis, folliculitis,
impetigo, erysipelas)
Local neoplasms (e.g., congenital melanocytic nevus,
neurofibroma, fibroma, hamartoma)
Systemic illness (e.g., myxedema, acromegaly, amyloidosis, syphilis, leukemia, acanthosis nigricans, insulin
resistance syndrome)
717
Chapter 67 :: A
netoderma and Other Atrophic
Disorders of the Skin

:: Catherine Maari & Julie Powell
ANETODERMA AT A GLANCE
Circumscribed 1- to 2-cm areas of flaccid skin
that may be elevated, macular, or depressed.
Often circumscribed sac-like protrusions.
Section 9
Primary or secondary to a preceding

dermatosis in the same location.
::
Association with antiphospholipid

syndrome.
Pathology consists of loss of elastic tissue in

the dermis.
ANETODERMA
EPIDEMIOLOGY
The lesions in anetoderma usually occur in young
adults between the ages of 15 and 30 years and more
frequently in women than men. Anetoderma is rare,
but the incidence is unknown. Several hundred cases
have been reported.14
PATHOGENESIS
The pathogenesis of anetoderma is unknown. The key
defect is damage to the dermal elastic fibers. Anetoderma may be considered to be unusual scars, because
scars also have decreased elastic tissue. The loss of dermal elastin could be the result of an impaired turnover
of elastin caused by either increased destruction or
decreased synthesis of elastic fibers.
CLINICAL FINDINGS
718
All types of anetoderma are characterized by a circumscribed loss of normal skin elasticity. The characteristic
lesions are flaccid circumscribed areas of slack skin
with the impression of loss of dermal substance forming depressions, wrinkling, or sac-like protrusions
(Fig. 67-1). These atrophic, skin-colored, or bluewhite
lesions are 530 mm in diameter. The number varies
from a few to hundreds. The skin surface can be wrinkled, thinned, and often depigmented, and a central
depression may be seen. Coalescence of smaller lesions
can give rise to larger herniations. The examining finger sinks without resistance into a distinct pit with
sharp borders as if into a hernia ring (buttonhole sign).

The protrusion reappears as soon as the pressure from
the finger is removed.4
The most common sites for these asymptomatic
lesions are the chest, back, neck, and upper extremities.
They usually develop in young adults, and new lesions
often continue to form for many years as the older
lesions fail to resolve.
Primary anetoderma occurs when there is no underlying associated skin disease (i.e., it arises on clinically
normal skin). It is historically subdivided into two
types: (1) those with preceding inflammatory lesions,
mainly erythema (the JadassohnPellizzari type), and
(2) those without preceding inflammatory lesions (the
SchweningerBuzzi type). This classification is only of
historical interest, because the two types of lesions can
coexist in the same patient; the prognosis and the histopathology are also the same.4
True secondary anetoderma implies that the characteristic atrophic lesion has appeared in the exact same
site as a previous specific pathology; the most common
causes are probably acne and varicella. Numerous and
heterogeneous dermatoses have been associated with
secondary anetoderma, namely syphilis, Lyme disease, molluscum contagiosum, pilomatricomas,
juvenile xanthogranuloma, xanthomas, granuloma
annulare, leprosy, discoid lupus, sarcoidosis, and
lichen planus, to mention only a few. Anetoderma has
also been described in premature infants and, in some
cases, it may have been related to the use of cutaneous
monitoring leads or adhesives.5 Both types may
be associated with an underlying disease, mainly
antiphospholipid syndrome6 and human immunodeficiency virus. Although most cases are sporadic, rare
cases of familial anetoderma have been recently
described and are usually not associated with preexisting lesions.7
PATHOLOGY
In routinely stained sections, the collagen fibers within
the dermis of affected skin appear normal. Perivascular lymphocytes are often present in all types of anetoderma and do not correlate with clinical inflammatory
findings.8
The predominant defect as revealed by elastic tissue
stains is a focal partial or complete loss of elastic tissue
in the papillary and/or midreticular dermis. There are
usually some residual abnormal, irregular, and fragmented elastic fibers (Fig. 67-2).9 Presumably, the
weakening of the elastic network leads to flaccidity
and herniation. Direct immunofluorescence sometimes
shows linear or granular deposits of immunoglobulins
and complement along the dermalepidermal junction
or around the dermal blood vessels in affected skin.10
Chapter 67
::
Electron microscopy demonstrates that the elastic

fibers are fragmented and irregular in appearance and
occasionally can be engulfed by macrophages.
Anetoderma must be differentiated from other disorders of elastic tissue as well as atrophies of the connective tissue (Box 67-1).
Keloids form nodules that are much firmer on palpation. A history of trauma is often elicited, and the
pathology is very distinct.
Glucocorticoid-induced atrophy occurs most commonly over the triceps or buttocks at sites where injections are usually given. Clinically, the lesions resemble
atrophoderma. History is obviously most helpful in
making the diagnosis. On histopathology, polarization
may show the steroid crystals in the dermis.
Nevus lipomatosus superficialis of Hoffman and
Zurhelle presents as a clustered group of soft, skincolored to yellow nodules usually on the lower trunk
and buttocks and present since birth. Histology shows
ectopic mature lipocytes located in the dermis.
Papular elastorrhexis is an acquired disorder characterized by white, firm nonfollicular papules measuring
13 mm, evenly scattered on the chest, abdomen, and
back. It usually appears in adolescence or early adulthood. The pathology demonstrates focal degeneration
of elastic fibers and normal collagen. There are no associated extracutaneous abnormalities. This is believed
by some authors to be a variant of connective tissue
nevi11 or an abortive form of the BuschkeOllendorff
Anetoderma and Other Atrophic Disorders of the Skin
Figure 67-1 Anetoderma. Primary anetoderma. A. Multiple, sharply defined, depressed lesions that look punched out in
the supraclavicular region. B. Soft, sac-like protrusions on the back. When depressed, there is the buttonhole phenomenon. This is the same patient as in A.

Primary Anetoderma
Figure 67-2 Anetoderma. Pathology shows decrease of

elastic fibers in the papillary and reticular dermis (Weigerts stain). (Used with permission from Victor Kokta, MD.)
ELEVATED
DEPRESSED
Secondary anetoderma
Acne scars
Keloids
Nevus lipomatosus superficialis
Papular elastorrhexis
Connective tissue nevi
Secondary anetoderma
Glucocorticoid-induced
atrophy
Acne scars
719
syndrome,12 whereas others think that these represent

papular acne scars.13 They are differentiated from anetoderma by being firm noncompressible lesions.
Middermal elastolysis (MDE) usually consists of
larger areas with diffuse wrinkling without herniation
and with elastolysis limited to the middermis (See
below).
TREATMENT
Section 9
::
There is no regularly effective treatment. In secondary

anetoderma, appropriate treatment of the inflammatory underlying condition might prevent new lesions.
In patients with limited lesions that are cosmetically
objectionable, surgical excision may be useful. Various
therapeutic modalities have been tried but with no
improvement of existing atrophic lesions, including
intralesional injections of triamcinolone and systemic
administration of aspirin, dapsone, phenytoin, penicillin G (benzylpenicillin), and vitamin E. Some authors
have reported improvement with hydroxychloroquine.
OTHER ATROPHIC DISORDERS

OF THE SKIN
MIDDERMAL ELASTOLYSIS
MDE is a rare acquired disorder of elastic tissue. It is
characterized by patches and plaques of diffuse, fine,
wrinkled skin, most often located on the trunk, neck,
and arms. In 1977, Shelley and Wood reported the first
case of wrinkles due to idiopathic loss of middermal
elastic tissue.14 Since then, fewer than 100 cases have
been reported. The vast majority of patients are Caucasian women between the ages of 30 and 50 years.15,16
720
PATHOGENESIS. The pathogenesis of this acquired

elastic tissue degeneration is still unknown. Ultraviolet
(UV) exposure has been postulated to be a major contributing factor in the degeneration of elastic fibers,17 including narrowband UVB.18 Other possible mechanisms
include defects in the synthesis of elastic fibers, autoimmunity against elastic fibers, and damage to elastic fibers
through the release of elastase by inflammatory cells or
fibroblasts. More recent data suggest that inflammatory
processes and an altered balance between matrix metalloproteinase and tissue inhibitor of metalloproteinases
are possibly involved in the pathogenesis of MDE.19
CLINICAL FEATURES. MDE is characterized by
asymptomatic, well-demarcated, or diffuse areas of
fine wrinkling (Fig. 67-3A). Rarely, erythematous
patches, telangiectasias, or a reticular variant can be
seen. Discrete perifollicular papules can be seen in
some cases, leaving the hair follicle itself as an indented
center. Lesions are typically found on the trunk, neck,
and upper extremities. They are chronic and give the
skin a prematurely aged appearance. There is usually
no history of a preceding inflammatory dermatosis,
but some patients report mild-to-moderate erythema.
There is no associated systemic involvement.
HISTOPATHOLOGY. The pathology shows a normal epidermis and, occasionally, a mild perivascular
infiltrate in the dermis. The characteristic histology is
seen on elastic tissue stains and reveals a selective
band-like loss of elastic fibers in the middermis (see
Fig. 67-3B). There is preservation of normal elastic tissue in the superficial papillary dermis above, in the
reticular dermis below, and along adjacent hair follicles. Electron microscopy studies have shown phagocytosis of normal as well as degenerated elastic fiber
tissue by macrophages.20
Figure 67-3 Middermal elastolysis. A. Well-circumscribed area of fine wrinkling on the neck of a middle-aged woman.
(Used with permission from Richard Dubuc, MD.) B. Histology of middermal elastolysis. Note selective loss of elastic fibers
in the middermis. Normal elastic tissue is preserved in the superficial papillary dermis and in the reticular dermis (Weigerts
stain). (Used with permission from Danielle Bouffard, MD.)
DIFFERENTIAL DIAGNOSIS. MDE must be dif-
STRIAE
(See Chapters 108 and 151)
Striae are very common and usually develop
between the ages of 5 and 50 years.
They occur about twice as frequently in women as in
men. They commonly develop during puberty, with an
overall incidence of 25%35%,23,24 or during pregnancy,
with an incidence of 77%.25
The factors leading to the development of striae
have not been fully elucidated. Striae distensae are the
results of breaks in the connective tissue, resulting in
dermal atrophy. Many factors, including hormones
(particularly corticosteroids), mechanical stress, and
genetic predisposition, appear to play a role.
During puberty, striae appear in areas where there is
a rapid increase in size. In girls, the most common sites
are the breasts, thighs, hips, and buttocks, whereas in
boys, they are seen on the shoulders, lumbosacral
region, and thighs. Other less common sites include
the abdomen, upper arms, neck, and axillae.
Striae distensae are a common finding on the abdomen, and less so on the breasts and thighs, of pregnant
women, especially during the last trimester. They are
more common in younger primigravidas than in older
pregnant women and are associated with larger weight
gain and with babies of higher birth weight. Striae
gravidarum can be associated with a higher risk of lacerations during vaginal delivery.26
HISTOPATHOLOGY. Histologic findings show a

decrease in dermal thickness and in collagen in the
upper dermis. The collagen bundles are thinned and
lie parallel to the epidermis, but they are also
arranged transversely to the direction of the striae.
Alterations in elastic fibers are variable, but dermal
elastin can be fragmented, and specific elastin staining can demonstrate a marked reduction in visible
elastin content compared with adjacent normal dermis.27 There is absence of both hair follicles and other
appendages.
DIFFERENTIAL DIAGNOSIS. The diagnosis of
striae distensae is usually simple, but the differential
diagnosis does include linear focal elastosis (elastotic
striae) that was first described by Burket et al in
1989.28 Linear focal elastosis is characterized by rows
of yellow palpable striae-like bands on the lower
back. Unlike striae, the lesions are raised and yellow
rather than depressed and white. Elderly men are
most commonly affected, although cases in teenagers
have been described. Linear focal elastosis is probably not an uncommon condition. Histologically, there
is a focal increase in the number of elongated or fragmented elastic fibers and a thickened dermis. It is
postulated that linear focal elastosis may represent an
excessive regenerative process of elastic fibers
and could be thought of as a keloidal repair of striae
distensae.29
TREATMENT. Striae distensae have no medical
consequences, but they are frequently distressing to
those affected. As stretch marks tend to regress spontaneously to some degree over time, the usefulness of
treatments that have been tried without case controls
is difficult to assess. Topical treatments that have
shown some improvement of early stage striae are:
tretinoin 0.1% cream,30 a combination of 0.05% tretinoin/20% glycolic acid, or 10% l-ascorbic acid/20%
glycolic acid.31 Several lasers have been used in treating striae: the 585-nm pulsed-dye laser has been
demonstrated to be of some efficacy in improving the
appearance of striae rubra but has no effect on stria
alba32; improvement in the leukoderma of the striae
alba was noted with 308-nm excimer laser but maintenance treatment is required to sustain the cosmetic
benefit.33 The long-term future of treatment strategies is encouraging with the advance in laser
technologies.
There is no known effective treatment for MDE. Sunscreens, colchicine, and topical retinoic acid have been
tried without good success.15,16
symmetric, well-defined linear atrophic lesions that

follow the lines of cleavage. Initially, striae appear as
red-to-violaceous elevated lines (striae rubra) (see Fig.
107-3). Over time, the color gradually fades, and the
lesions become atrophic, with the skin surface exhibiting a fine, white, wrinkled appearance (striae alba).24
The striae can measure several centimeters in length
and a few millimeters to a few centimeters in width.
The striae associated with systemic corticosteroid therapy and Cushing syndrome can be larger and more
widely distributed.
::
TREATMENT
Chapter 67
ferentiated from the other common disorders of elastic

tissue.
Solar elastosis differs by its onset in an older age
group, location in only sun-exposed areas, yellowish
color, and coarser wrinkling, as well as by hyperplasia
and abnormalities of elastic fibers and basophilic
degeneration of the collagen in the papillary dermis.
Anetoderma is characterized clinically by smaller
soft macules and papules instead of diffuse wrinkling,
and histologically by elastolysis that can occur in any
layer of the dermis.
Perifollicular elastolysis differs by a selective and
almost complete loss of elastic fibers surrounding hair
follicles compared with preservation of elastic fibers
around follicles in MDE. Elastase-producing Staphylococcus epidermidis was found in the hair follicles and is
the presumed etiology of this condition.21
Postinflammatory elastolysis and cutis laxa were
originally described in young girls of African descent.
An inflammatory phase, consisting of indurated
plaques or urticaria, malaise, and fever, preceded the
diffuse wrinkling, atrophy, and severe disfigurement.
Insect bites may be the trigger for the initial inflammatory lesions.22
CLINICAL FINDINGS. Striae are usually multiple,
721
IDIOPATHIC ATROPHODERMA
OF PASINI AND PIERINI
Section 9
::
EPIDEMIOLOGY AND PATHOGENESIS. Idiopathic atrophoderma of Pasini and Pierini is a form of

dermal atrophy that presents as one or several sharply
demarcated depressed patches with no outpouching,
usually on the back of adolescents or young adults.34
Whether atrophoderma is a nonsclerotic, primarily
atrophic variant of morphea or a separate distinct
entity is still debated.3539 Its relationship to morphea is
favored by its striking clinical and histologic similarities to the atrophy seen at sites of regressing plaques of
morphea. Antibodies to Borrelia burgdorferi have been
reported.37 Typical lesions of morphea, lichen sclerosus, and atrophoderma have been observed to occur
simultaneously in the same patient but in different
areas, supporting the view that these conditions are
related. In a series of 139 patients, 17% had white induration in the central portions of their atrophic lesions,
and 22% had superficial plaques of morphea coexisting in areas outside of their atrophic foci.35 However, to
some, the different course and outcome of atrophoderma of Pierini and Pasini as compared with morphea justifies preservation of a distinct name.
This disorder is more frequently encountered in
women than in men, with a ratio of 6:1. It usually starts
insidiously in young individuals in the second or third
decades of life. A congenital case was recently
reported.40 The lesions usually occur on the trunk,
especially on the back and lumbosacral region, followed in frequency by the chest, arms, and abdomen.37
The distribution is often symmetric and bilateral.
The lesions are single or multiple and usually round
or ovoid, ranging in size from a few centimeters to
patches covering large areas of the trunk (Fig. 67-4).
They are usually asymptomatic and lack inflamma-
tion. When lesions coalesce, they can form large, irregular, brown patches but can be hypopigmented.41 The
surface of the skin is normal in appearance, and there
is no skin induration or sclerosis.
The borders or edges of these lesions are sharply
defined, and they are usually described as abrupt,
cliff drop borders ranging from 1 to 8 mm in depth,
although they can have a gradual slant.34 These
depressed patches are characteristic and give the
impression of inverted plateaus, or, if multiple lesions
are present, they can have the appearance of Swiss
cheese. They are even more apparent when present on
the back because the dermis is thicker in this area. The
skin surrounding the patches is normal in appearance,
and there is no erythema or lilac ring as in morphea.
COURSE. The course of this benign disease is progressive, and lesions can continue to appear for
decades before reaching a standstill. Transformation to
generalized morphea has not been observed.
HISTOPATHOLOGY. The histologic picture is generally not diagnostic. The epidermis is usually normal
or slightly atrophic. Collagen bundles in the mid- and
reticular dermis show varying degrees of homogenization and clumping. Dermal thickness is eventually
reduced when compared with adjacent normal skin.38
Some irregular clumping and loss of elastic fibers were
described in earlier case reports,34 but in most series,
no abnormality was seen with elastic tissue stains35,37;
therefore, this is not of diagnostic value. The appendages are usually preserved. If sclerodermatous changes
appear in preexisting patches, the histology reveals
varying degrees of collagen sclerosis resembling morphea.
DIFFERENTIAL DIAGNOSIS. The differential diagnosis is to be made with active lesions of morphea that
usually present as indurated, often hyperpigmented
plaques with a characteristic peripheral lilac rim.
THERAPY. No treatment has been proved effective.
Dramatic response to oral hydroxychloroquine was
recently reported in one patient.42
FOLLICULAR ATROPHODERMA
Follicular atrophoderma refers to dimple-like depressions at the follicular orifices. It can occur as an isolated
defect of limited extent, in association with a variety of
disorders in which hair follicles are plugged with keratin, or with rare genodermatoses.43,44
Distinctive ice-pick depressions around hair follicles
can be seen most commonly on the back of the hands
or feet and on the cheeks. These pitted scars can present at birth or early in life. A family history may be
present. Follicular atrophoderma occurs in the conditions described in the following sections.
722
Figure 67-4 Atrophoderma of Pasini and Pierini. Brownish depressed lesions on the lower back.
ATROPHODERMA VERMICULATUM. Atrophoderma vermiculatum is a term that applies when

the lesions are found exclusively on the cheeks. It is a
Chapter 67
::
Figure 67-6 Ulerythema ophryogenes. Erythematous follicular papules and scarring alopecia of the eyebrow.
condition that can either occur sporadically, be inherited as an autosomal dominant disorder, be part of a
group of related diseases including keratosis pilaris
atrophicans, or be associated with various syndromes.
Multiple inflammatory symmetric papules on the
cheeks, presumably centered around hair follicles,
may precede the atrophic lesions. These papules then
go on to develop pitted, atrophic, and depressed scars
in a reticulated or honeycomb pattern (Fig. 67-5). These
lesions can extend to the forehead and preauricular
regions. This condition usually has its onset in childhood or, less often, around puberty. Men and women
seem to be affected equally.45 It usually has a slow progressive course.
ated with plugging, inflammation, and sclerosis of dermal collagen.
Keratosis Pilaris Atrophicans. Keratosis pilaris

atrophicans46 can include atrophoderma vermiculatum but also a group of closely related disorders that
includes keratosis follicularis spinulosa decalvans and
ulerythema ophryogenes. These conditions are characterized by keratotic follicular papules, variable degrees
of inflammation, and secondary atrophic scarring. Keratosis follicularis spinulosa decalvans begins in infancy
with keratotic follicular papules over the malar area
and progresses to involve the eyebrows, scalp, and
extremities, with scarring alopecia. This condition is
inherited in an X-linked recessive fashion in some
patients. Ulerythema ophryogenes (or keratosis pilaris
atrophicans faciei) differs from atrophoderma vermiculatum by affecting primarily the lateral portion of the
eyebrows (ophryogenes) with erythema, follicular
papules, and alopecia (Fig. 67-6).
The underlying pathologic defect in these disorders
appears to be abnormal follicular hyperkeratinization
of the upper third of the hair shaft leading to obstruction of the growing hair and production of chronic
inflammation. The end result of this process is scarring
below that level. Histopathology is usually not very
helpful and shows dilated follicles, sometimes associ-
Associated Syndromes. The various syndromes
that include atrophoderma vermiculatum are the

Rombo syndrome (milia, telangiectasias, basal cell carcinomas, hypotrichosis, acral cyanosis, and, rarely,
trichoepitheliomas), NicolauBalus syndrome (syringomas and milia), Tuzun syndrome (scrotal tongue),
and finally the BraunFalcoMarghescu syndrome
(palmoplantar hyperkeratosis and keratosis pilaris).
Therapy. These disorders are mainly a cosmetic but
vexing problem. Various topical treatments, including

emollients, corticosteroids, tretinoin, and keratolytics,
have shown no consistent benefit. Systemic isotretinoin
has been shown to stop progression and to induce remission in some cases.46 Dermabrasion as well as carbon
dioxide and 585-nm pulsed-dye lasers are other options
to improve the appearance of the atrophic scars.47
Figure 67-5 Atrophoderma vermiculatum. Multiple, small,

pitted scars on the cheek of a young girl.
BAZEXDUPRCHRISTOL
SYNDROME
(OMIM #301845). BazexDuprChristol syn-
drome is characterized by follicular atrophoderma,

milia, multiple basal cell carcinomas, hypotrichosis,
and localized hypohidrosis.4850 The follicular atrophoderma described as multiple ice-pick marks or patulous follicles can be found most commonly on the
dorsa of the hands. It is inherited in an X-linked dominant fashion, and the gene has been linked to Xq24
q27.48 Subsequently reported findings include facial
hyperpigmentation, hair shaft dystrophy, and multiple
genital trichoepitheliomas.
CONRADIHNERMANNHAPPLE SYNDROME (X-LINKED DOMINANT CHONDRODYSPLASIA PUNCTATA, CDPX2, OMIM

#302960)). ConradiHnermann syndrome is an
X-linked dominant disorder that occurs only in girls
723
because it is usually lethal in hemizygous males. The

underlying molecular defect consists of mutations in
the emopamil-binding protein gene at Xp11.23p11.22.50 The clinical manifestations include an ichthyosiform scaling erythroderma patterned along the
lines of Blaschko that usually resolves during the first
year of life and is replaced by bands of follicular atrophoderma.43 Hyperpigmentation, cataracts, scarring
alopecia, saddle-nose deformity, asymmetric limb
reduction defects, and stippled calcifications of the
epiphyses can be seen. Ichthyosis with keratotic follicular plugs containing dystrophic calcification in
newborns are distinctive histopathologic features.51
::
Many systemic conditions [scleroderma (see Chapter

157), lupus erythematosus (see Chapter 155), dermatomyositis (see Chapter 156)], and genodermatoses
(poikiloderma congenitale, dyskeratosis congenita,
Cockayne syndrome, HallermannStreiff syndrome)
have skin atrophy as an associated finding and are
described in other chapters.
Section 9
OTHER ATROPHIES OF THE

CONNECTIVE TISSUE

4. Venencie PY, Winkelmann RK, Moore BA: Anetoderma:
Clinical findings, associations, and long-term follow-up
evaluations. Arch Dermatol 120:1032, 1984
7. Thomas JE et al: Familial anetoderma. Int J Dermatol 42:75,
2003
9. Venecie PY, Winkelmann RK: Histopathologic findings in
anetoderma. Arch Dermatol 120:1040, 1984
16. Gambichler T: Mid-dermal elastolysis revisited. Arch Dermatol Res 302:85-93, 2010.
24. Ammar NM et al: Adolescent striae. Cutis 65:69, 2000
35. Kencka D, Blaszczyk M, Jablonska S: Atrophoderma PasiniPierini is a primary atrophic abortive morphea. Dermatology 190:203, 1995
41. Saleh Z et al: Atrophoderma of Pierini and Pasisni: A clinical and histopathological study. J Cutan Pathol 35: 11081114, 2008
45. Frosch P et al: Atrophoderma vermiculatum: Case reports
and review. J Am Acad Dermatol 18:538, 1988
46. Callaway SR, Lesher JL: Keratosis pilaris atrophicans:
Case series and review. Pediatr Dermatol 21:14, 2004
48. Vabres P et al: The gene for BazexDuprChristol syndrome
maps to chromosome Xq. J Invest Dermatol 105:87, 1995
49. Torrelo A et al: What syndrome is this? Basex-DuprChristol syndrome. Pediatr Dermatol 23:286-290, 2006
Chapter 68 :: Ainhum and Pseudoainhum

:: Robert T. Brodell & Stephen E. Helms
Ainhum and pseudoainhum are
syndromes related to external
constricting bands
Constricting bands are classified as ainhum
and pseudoainhum.
Ainhum is defined by a constricting band
around a digit and is most common in tropic and
subtropic latitudes occurring around the fifth toe
or toes of people accustomed to walking barefoot.
Pseudoainhum constrictions clinically mimic
ainhum and are much more common in the
developed world. It may be caused by (1)
amniotic bands; (2) constrictions associated
with keratotic disorders or those associated
with infections or trauma; and (3) constriction
by external forces such as hairs and threads.
Autoamputation can result from ainhum and
pseudoainhum.
724
KEY REFERENCES
Treatment can simply be the removal of

foreign strands wrapped around a digit
or limb or surgical intervention in more
advanced cases (Z-plasty or amputation).
AINHUM AND PSEUDOAINHUM

Constricting bands are classified as ainhum and pseudoainhum. Ainhum describes the development of constricting bands around toes in underdeveloped countries
of Africa and may ultimately result in autoamputation.
In the African Yorub language, ainhum means to saw
or file and in the Brazilian patois, it means fissure.
In the remainder of the world, constricting bands that
mimic ainhum are termed pseudoainhum.
EPIDEMIOLOGY
Ainhum (dactylolysis spontanea) is traditionally a disease of middle-aged African males accustomed to
going barefoot.1 In the tropic and subtropic climates, its
incidence has been reported as between 0.015% and 2%
of the population.2 This same condition is rarely seen
throughout the rest of the world. Occasional isolated
cases were reported in the United Kingdom and North
America.1,3 Pseudoainhum of all types is very rare.

The pathogenesis of ainhum has not been clearly elucidated. Chronic trauma, infection, hyperkeratosis,
Figure 68-1 Congenital constricting bands about two

digits. No etiology was identified.
of the toes or even the hands (Fig. 68-3; eFig. 68-3.1 in

online edition). In children, when chronic dermatophyte infection is identified and appropriately treated,
complete reversal of the constriction may occur. Severe
hyperkeratosis as occurs with Vohwinkel syndrome
(keratoderma hereditarium mutilans)6,16 may show
constricting bands due to palmar and plantar hyperkeratoses as well as starfish-like and linear keratoses.
Figure 68-2 Pseudoainhum (congenital constricting

band) of the leg in an infant. (Used with permission from
Ilona Frieden, MD.)
Ainhum and Pseudoainhum
Ainhum usually affects the fifth toe; it may be unilateral, but 75% of the cases are bilateral. One or
more digits can be involved. All toes can be involved,
even the great toe.11 In early lesions, a groove or sulcus appears at the plantar junction of the toe and the
sole. As this sulcus deepens, edema develops distally and roentgenographic examination shows
resorption of the underlying bone and ultimately
autoamputation.12
Congenital constricting bands (Streeter bands) usually involve more than one part of the body (Fig. 68-1)
and frequently encircle large structures such as limbs
or even the trunk. They persist throughout life and
interfere with normal growth of the involved segment unless surgically treated13 (Fig. 68-2). Autoamputation can occur. More than 50% of cases are
associated with other congenital anomalies usually
syndactyly or clubfoot when constricting bands are
found on the feet.14
Factitious pseudoainhum may prove to be a most
challenging diagnosis. Strands of hair, fibers, or threads
are intentionally wrapped around digits or other body
parts such as a nipple or penis. This phenomenon is
most commonly encountered in children, but can occur
in mentally ill adults.15 Because of soft-tissue swelling,
the ligating band may not be visible and the true cause
of the condition may not be immediately recognized.15
Acquired constricting bands are associated with a
variety of medical and dermatological conditions. In
general, pseudoainhum is more likely to involve any
::
CLINICAL FINDINGS
Chapter 68
decreased vascular supply, and impaired sensation

may produce excessive fibroplasia in a susceptible
host.4 Dent et al described impaired blood supply to
the foot proximal to the groove at the plantar digital
junction. Poor perfusion was the result of attenuation
of the posterior tibial artery and absence of the plantar
arterial arch leading to abnormal healing following
mechanical trauma. Ainhum has also been blamed on
rotational stress applied to the bare, mechanically
unstable foot.5
There are three pathophysiological categories of
pseudoainhum: (1) congenital constricting bands are
caused by the umbilical cord; (2) constriction by
external forces, such as hairs or threads, which are
generally factitial; and (3) constricting bands secondary to other diseases. These may be hereditary or nonhereditary. Hereditary causes include pachyonychia
congenita, Mal de Meleda, mutilating keratoderma,6
lamellar ichthyosis,7 and psoriasis.810 Nonhereditary
diseases include vascular anomalies as seen in Raynaud disease, diabetes mellitus, linear scleroderma,
systemic sclerosis. Sensory changes associated with
leprosy, tertiary syphilis, syringomyelia, and spinal
cord tumors as well as trauma resulting in scar formation from burns, frostbite, and physical trauma can
also cause constricting bands to form. When associated with chronic trauma and infection of the extremities, the pathophysiology may be identical to true
ainhum.
725
TREATMENT
Section 9
Figure 68-3 Pseudoainhum of hand with autoamputation due to amniotic bands. (Used with permission from
Ilona Frieden, MD.)
::
The pathology of ainhum and pseudoainhum are

similar with fibrotic bands resembling scar tissue.4,12
The bands in ainhum usually extend deep into the subcutaneous layers and may impinge upon underlying
skeletal and vascular structures. Additionally, moderate inflammation and epidermal or verrucous hyperplasia may be present. In pseudoainhum the bands
tend to be more superficial. Also, in pseudoainhum
there may be histologic clues to the associated disorder, such as dermatophytosis, foreign bodies, or distinct patterns of keratinization.
COMPLICATIONS
The constricting bands of both ainhum and pseudoainhum ultimately produce a dangling, twisted digit,
which can become gangrenous or infected. When this
tenuous connection produces necrosis, autoamputation occurs.

COURSE
Diseases caused by constricting bands proceed slowly
and often painfully over many years eventuating in
autoamputation in severe cases.
726
Surgery is the mainstay of therapy and early intervention is important. In most cases of ainhum, prompt
amputation may allow the patient to escape pain and
infection. Early cases of ainhum or pseudoainhum may
respond to conservative plastic repair with a Z-plasty
or similar relaxing closure by avoiding further disease
progression and damage to underlying structures.12
Impending amputation i n Vohwinkel syndrome can
sometimes be aborted by therapy with oral etretinate.16
When chronic fungal or bacterial infections or psoriasis are
diagnosed in the early phase of band formation, treatment
may reverse the threat to the digit (eFig. 68-3.2 in online
edition). Other predisposing causes of underlying diseases
should be treated aggressively in the hope of forestalling
progression. For example, a case of infantile psoriasis with
pseudoainhum was successfully treated with narrowband
UVB phototherapy and pimecrolimus.17
PREVENTION
Ainhum is rarely seen in people who are protected by
wearing shoes. Congenital pseudoainhum cannot be
prevented. Psychological counseling may prevent
recurrences of pseudoainhum in patients with factitial
disease. Control of the underlying disease process may
delay progression or prevent recurrence in pseudoainhum of the acquired type.
KEY REFERENCES
1. Cole GJ: Ainhum: An account of fifty-four patients with
special reference to etiology and treatment. J Bone Joint
Surg Br 47:43, 1965
2. Carvalho N et al: Ainhum (Dactylolysis Spontanea): A
case report. Foot Ankle 6:189-192, 2000
4. Kerhisnik W: The surgical pathology of ainhum (dactylolysis spontanea). J Foot Surg 25:95, 1986
5. Dent DM et al: Ainhum and angiodysplasia. Lancet 2:396,
1981
9. Almond SL et al: Case Report: Pseudoainhum in chronic
psoriasis. Br J Dermatol 149:1064-1066, 2003
12. Pickus EJ et al: Digital constriction bands in pseudoainhum: Morphological, radiographic, and histological
analysis. Ann Plast Surg 47:194, 2001
Chapter 69 :: Acquired Perforating Disorders

:: Julia S. Minocha & Bethanee J. Schlosser
ACQUIRED PERFORATING
DISORDERS AT A GLANCE
Acquired perforating disorders represent
a group of separately identified cutaneous
disorders that occur most often in the setting
of chronic renal disease or diabetes mellitus.
Treatment is challenging with no universally

effective therapy, and patients often exhibit a
chronic course.
INTRODUCTION
Acquired perforating disorders represent a group of
separately identified cutaneous disorders that occur
in adult patients, most often in the setting of chronic
kidney disease (CKD) or diabetes mellitus (DM).1
Kyrles disease (KD), acquired elastosis perforans serpiginosa (AEPS), acquired reactive perforating collagenosis (ARPC), and perforating folliculitis (PF) were
previously considered distinct disorders.25 Given
their shared clinical and histopathological characteristics, these four disorders are now classified under
the umbrella term of acquired perforating dermatosis
(APD).1 APD is characterized clinically by the presence of umbilicated papules and/or nodules with a
central keratotic plug or crust and histologically by
the transepidermal extrusion of dermal components
(collagen, elastin, and/or fibrin).6 Although some
cases may exhibit clinical and histological characteristics that typify one of the four classically recognized
disorders, use of the comprehensive term APD is
encouraged.
Acquired Perforating Disorders
Histopathological examination of lesional

skin demonstrates invagination of the
epidermis with extrusion of dermal material
(collagen, elastin, and/or fibrin) through the
cup-shaped epidermal depression.
Kyrle, in 1916, first described KD in a young diabetic

woman and termed it hyperkeratosis follicularis et
parafollicularis in cutem penetrans.5 In 1953, Lutz
published the initial description of elastosis perforans
serpiginosa (EPS) as keratosis follicularis serpiginosa.7 The first case of AEPS associated with CKD
was identified in 1986 by Schamroth, Kellen, and
Grieve.2 Mehregan, Schwartz, and Livingood
reported the earliest description of reactive perforating collagenosis (RPC) in 1967, and the first case associated with DM was recognized by Poliak et al in
1982.3,8 PF was originally described by Mehregan and
Coskey in 1968.4 In 1989, Rapini, Heber, and Drucker
recognized the common clinical and histopathologic
characteristics of these disorders and introduced the
term acquired perforating dermatosis.1 Various terminology has been used in the literature to refer to APD
(Table 69-1).
APD occurs worldwide without gender predilection.17 The most common systemic diseases associated
with APD are CKD and DM. APD has been documented in 4.5%10% of hemodialysis patients in North
America and in 11% of a dialysis population (both
hemodialysis and peritoneal dialysis) in Great Britain.17,18 APD has also occurred in patients with CKD
who are not undergoing dialysis as well as those who
have received renal transplants. The most common
cause of CKD among APD patients is diabetic nephropathy.18 Table 69-2 lists less commonly reported associated conditions. APD has rarely been associated with
the use of certain therapeutics, including tumor necrosis factor- inhibitors, indinavir, and sorafenib.4446 A
predominance of blacks among hemodialysis patients
with APD has been reported in one study, but not confirmed in others.11 AEPS is well recognized as a potential adverse effect of prolonged d-penicillamine
therapy.47 AEPS has also been reported in patients with
CKD in the absence of penicillamine exposure or other
associations.2
::
Lesions present as umbilicated papules and/

or nodules with a central keratotic plug or
crust distributed preferentially on extensor
surfaces of the extremities.
EPIDEMIOLOGY
Chapter 69
The previously recognized Kyrles

disease (KD), acquired elastosis perforans
serpiginosa (AEPS), acquired reactive
perforating collagenosis (ARPC), and
perforating folliculitis (PF) are now classified
under the umbrella term of acquired
perforating dermatosis.

The precise etiology and pathogenesis of APD are
unknown. APD pathology likely involves a complex
interaction between the epithelium, connective tissue,
and inflammatory mediators. Superficial trauma to the
epidermis may be the primary inciting factor in susceptible patients.8 Predisposing conditions include
vasculopathy/angiopathy (related to DM), microdeposition of exogenous materials within the dermis
(including calcium salts and silicon, pertinent to the
increased frequency of APD in dialysis patients), and
epidermal or dermal change related to metabolic
derangements including vitamin A deficiency.13,18,43,48,49
727
TABLE 69-1
Synonyms for Acquired Perforating Dermatosis
Section 9
::
728
Acquired reactive perforating collagenosis9

Hyperkeratosis follicularis et parafollicularis in cutem
penetrans5
Hyperkeratosis penetrans10
Keratosis follicularis serpiginosa7
Kyrles disease11
Kyrle-like lesions12
Perforating disorder13
Perforating folliculitis8
Perforating folliculitis of hemodialysis14
Reactive perforating collagenosis of diabetes mellitus (DM)
and renal failure15
Uremic follicular hyperkeratosis16
Given APDs common association with CKD,

scratching due to chronic pruritus has been thought to
lead to microtrauma and subsequent transepidermal
elimination of dermal components. Koebnerization,
predominant localization to trauma-prone areas, and
resolution of APD lesions with discontinuation of
manipulation/trauma support this mechanism.6 Diabetic vasculopathy has been proposed as an additional
predisposing factor for APD in DM patients by creating a relatively hypoxic environment in which trauma
from scratching causes dermal necrosis. The finding of
TABLE 69-2
Conditions Associated with Acquired

Perforating Dermatosis
Common Associations
Chronic kidney disease
Diabetes mellitus (insulin-dependent and noninsulindependent)
Scabies19,20
Rare Associations
Acquired immunodeficiency syndrome (AIDS)21,22
Arthropod bites23,24
Atopic dermatitis25
Cutaneous cytomegalovirus infection26
Hyperparathyroidism9
Liver diseases (hepatitis C, hepatitis B, steatohepatitis, primary
biliary cirrhosis)6,27
Lupus vulgaris28
Myelodysplastic syndrome29
Malignancy (Hodgkin lymphoma, mixed histiocytic
lymphocytic lymphoma, hepatocellular carcinoma,
pancreatic carcinoma, prostate carcinoma, papillary thyroid
carcinoma)3037
Mikuliczs disease38
Neurodermatitis9
Poland syndrome39
Primary sclerosing cholangitis40
Pulmonary aspergillosis41
Pulmonary fibrosis25
Salt water application13
Thyroid disease (hypothyroidism, sick euthyroid syndrome,
Hashimoto thyroiditis)9,27,42
Vitamin A deficiency43
PAS-positive thickening of vessel walls in the upper

dermis of diabetic patients with APD48,50 supports this
hypothesis, but has not been noted in all studies.6,51
Imbalances in fibronectin, transforming growth
factor-3 (TGF-3), and matrix metalloproteinases in
APD lesions have also been demonstrated; these molecules are essential to normal epithelial differentiation
and wound healing, and their aberration may predispose to the development of APD lesions.48,51,52 In AEPS,
it is hypothesized that penicillamine alters dermal
elastic fibers in affected patients.53 Elastic fiber abnormalities, including bramble bush-appearing fibers of
variable thickness and increased numbers of fibers in
the papillary and reticular dermis, have been described
in patients with penicillamine-induced AEPS.54
CLINICAL FINDINGS
HISTORY
Most patients report lesional pruritus, ranging from
mild-to-severe and intractable, of skin lesions. Lesions
may also be painful.6
CUTANEOUS LESIONS
APD characteristically manifests as round, umbilicated, skin-colored, erythematous or hyperpigmented
papules and nodules with a central crust or keratotic
plug, predominantly involving the extensor surfaces
of the extremities and the trunk (Fig. 69-1). Lesions less
commonly involve the face or scalp. In rare cases, purple annular plaques or pustules mixed with papules
have been observed. Some lesions may be follicular
(PF) (Fig. 69-2). AEPS lesions exhibit papules in a serpiginous configuration, often with central atrophy, and
typically occurring on the neck, trunk, and extremities
(Fig. 69-3). Scratching can lead to koebnerization with
linear umbilicated papules arising in excoriated skin.
Figure 69-1 Acquired perforating dermatosis. Multiple,

round, hyperpigmented papules, each with a central keratotic plug, distributed on the extensor aspects of the hand
and wrist in a patient with chronic kidney disease.
Figure 69-4 Reactive perforating collagenosis. Collagen

bundles can be seen crossing from the reticular dermis
through the epidermis into an epidermal depression containing necrotic debris. (Hematoxylin and eosin stain.)
::
HISTOPATHOLOGY
The diagnosis of APD is based on clinical and histopathologic findings. Folliculitis and prurigo nodularis
may occur concomitantly, especially in patients with
CKD; multiple biopsies should be taken if lesions show
different clinical morphologies. APD is characterized
histologically by transepidermal elimination of dermal
material through an epidermal invagination, which
may be follicular or perifollicular. Lesions typically
demonstrate a central keratotic plug with crusting or
hyperkeratosis; parakeratosis is variable. Within the
dermis surrounding the perforation, there is often a

focal inflammatory infiltrate with neutrophils predominating in early lesions and lymphocytes, macrophages,
or multinucleated giant cells present in older lesions.
The four initially identified acquired perforating disorders [(1) RPC, (2) AEPS, (3) KD, and (4) PF] were
classically differentiated histopathologically on the
basis of the nature of the eliminated dermal material.
In RPC, collagen bundles are detected within the plug
(Fig. 69-4); in AEPS, elastic fibers are instead noted
(Fig. 69-5). In KD, amorphous dermal material and/or
keratin comprise the extruded material. PF is characterized by perforation of the follicular epithelium by
degenerating collagen and extracellular matrix (Fig.
69-6). Clear identification of the eliminated material
may be impossible and, in addition, multiple substances (i.e., collagen and elastic fibers) may be simultaneously detected, reinforcing the clinical and
histopathologic overlap within APD.

Although most common in patients receiving hemodialysis, especially for diabetic nephropathy,18 APD has
also been seen in CKD patients without hemodialysis
or who have undergone renal transplantation.
Table 69-2 lists medical conditions that are less often
associated with APD.
Chapter 69
Figure 69-2 Perforating folliculitis. Multiple follicular, erythematous, firm papules with variable central crusting.
LABORATORY TESTS
Laboratory evaluation for comorbidities should
include fasting blood glucose, glucose tolerance test,
serum creatinine, glomerular filtration rate or creatinine clearance, serum uric acid, liver function tests,
and thyroid function tests. A comprehensive past medical history and review of systems should be obtained.
Additional diagnostic testing for associated conditions
(Table 69-2) should be performed as indicated.
Figure 69-3 Acquired elastosis perforans serpiginosa in a

patient taking penicillamine for Wilsons disease. Annular
plaque with variably crusted erythematous papules at the
periphery and central cribriform scarring.
(Box 69-1)
The differential diagnosis of APD is broad and
includes both infectious and inflammatory disorders,
including those that koebnerize (Box 69-1). APD can be
especially difficult to differentiate from prurigo nodularis. Perforating pseudoxanthoma elasticum should
be distinguished from AEPS.
729
Section 9
::
Figure 69-5 Acquired elastosis perforans serpiginosa. A. Dilated follicular structure with transepidermal elimination of
densely eosinophilic elongated bundles. (Hematoxylin and eosin stain.) B. Transepidermally eliminated elongated bundles
are elastin fibers (elastin stain).
COMPLICATIONS
Most complications that occur in patients with APD
arise from underlying systemic illnesses. However,
patients should be monitored for secondary infection
(bacterial, fungal, and viral) as well as parasitic infestation. In an attempt to relieve the associated pruritus,
patients may apply products to their skin that may
result in irritant or allergic contact dermatitis. In
darker skinned patients with more excoriations,
postinflammatory pigmentary alteration and scarring
can be significant.
TREATMENT
Treatment of APD is difficult. Table 69-3 details the
therapeutic options that have been described in the literature to date. There have not been any well-designed
clinical trials of APD, and current treatment strategies
are based largely on anecdotal reports. In patients with
CKD, improvement in APD lesions has been reported
after changing the type of dialysis tubing or modification of the dialysis procedure.18 In a few cases, APD has
resolved following renal transplantation.17,14,80 The
most commonly employed treatments for APD include
topical and oral retinoids, topical and intradermal
PROGNOSIS
The prognosis of APD is heavily linked to the presence
of underlying diseases. Some studies have shown that
APD may improve with successful treatment of the
underlying illness.25 Most cases of APD continue for
years unless treated.
730
Figure 69-6 Perforating folliculitis. Dilated follicular unit

exhibits necrosis and disruption of the epithelium.

Acquired Perforating Dermatosis
Actinic granuloma (annular elastolytic giant cell
granuloma)
Arthropod bites
Discoid lupus erythematous
Flegel disease (hyperkeratosis follicularis perstans)
Folliculitis (bacterial, yeast)
Keratosis follicularis (Darier disease)
Keratosis pilaris
Lichen planus
Multiple keratoacanthomas (FergusonSmith
familial keratoacanthomas, Grzybowski eruptive
keratoacanthomas)
Perforating granuloma annulare
Perforating periumbilical calcific elastosis
Perforating pseudoxanthoma elasticum
Porokeratosis
Prurigo nodularis
Psoriasis
Sarcoidosis
Scabies
Table 69-3
Treatment of Acquired Perforating Dermatosis
Topical Therapies
Retinoic acida
Tretinoina
Tazarotenea
Beclomethasonea
Triamcinolone acetonidea
Imiquimod
Phenol
Capsaicin
Retinoid
Retinoid
Retinoid
Corticosteroid
Corticosteroid
Immune response modifier
Antipruritic
Capsaicinoid
0.025% gel55
0.1% cream one to three times daily56,57
0.1% gel daily58
0.1% cream17
10 mg/mL intralesional injection17
Daily for 6 weeks then three times per week for 4 weeks59
0.5% phenol with 10% glycerin in sorbolene cream60
0.025%0.075% ointment
Systemic Therapies
Isotretinoinb
Acitretinb
Prednisolone
Allopurinolb
Doxycycline
Metronidazole
Clindamycin
Hydroxychloroquine
Retinoid
Retinoid
Corticosteroid
Xanthine oxidase inhibitor
Antibiotic
Antibiotic
Antibiotic
Antimalarial
Isotretinoin 0.5 mg/kg/day61,62

2530 mg/day 60,63
30 mg daily64
100 mg daily65,66
100 mg daily20,67,68
500 mg twice daily69
300 mg three times daily70
200 mg daily71
Physical Modalities
UVBa
Phototherapy
NUVBa
Phototherapy
PUVAb74
Liquid nitrogen
Phototherapy
Cryotherapy
Carbon dioxide laser
Laser
TENS
Surgical debridement70,79
Other
MED for 2 minutes every other day with increments of 30 seconds

for 24 weeks72
Three times a week for 23 months60 400 mJ/cm2 increased to 1,500
mJ/cm2, two to three times per week, 1015 exposures73
Four times per week for total of 326 J/cm275
10 seconds, on five occasions over 4 months, one occasion 3
months later76
Five lesional passes at 300 J (pattern 5, size 7, density 7), followed
by three resurfacing passes at 300 J (pattern 2, size 8, density 5),
power of 80 W77
1 hour daily for 3 weeks78
Dosing
::
Action
Chapter 69
Treatment
UVB = ultraviolet B; NUVB = narrowband ultraviolet B; PUVA = psoralen and ultraviolet A; TENS = transcutaneous electrical nerve stimulation.
a
First-line therapy.
b
Second-line therapy.
corticosteroids, and UVB phototherapy. Phototherapy

has been shown to be effective for uremic pruritus and
therefore may be particularly beneficial for patients
with CKD by reducing koebnerization.73 Several
authors have reported improvement in APD following
treatment with allopurinol in cases of elevated or normal uric acid levels.73 Currently available therapeutic
options may not provide complete resolution of APD
lesions or associated symptoms.
KEY REFERENCES
1. Rapini RP, Herbert AA, Drucker CR: Acquired perforating
dermatosis. Evidence for combined transepidermal elimi-
nation of both collagen and elastic fibers. Arch Dermatol

125(8):1074-1078, 1989
3. Poliak SC et al: Reactive perforating collagenosis associated with diabetes mellitus. N Engl J Med 306(2):81-84,
1982
4. Mehregan AH, Coskey RJ: Perforating folliculitis. Arch
Dermatol 97(4):394-399, 1968
5. Kyrle J: Uber einen ungewohnlichen fall von universeller
follicularer und parafollikularer hyperkeratose (hyperkeratosis follicularis et parafollicularis in cutem penetrans). Arch Dermatol Syph 123, 1916
8. Mehregan AH, Schwartz OD, Livingood CS: Reactive
perforating collagenosis. Arch Dermatol 96(3):277-282,
1967
47. Pass F et al: Elastosis perforans serpiginosa during
penicillamine therapy for Wilson disease. Arch Dermatol
108(5):713-715, 1973
51. Gambichler T et al: Up-regulation of transforming growth
factor-beta3 and extracellular matrix proteins in acquired
reactive perforating collagenosis. J Am Acad Dermatol
60(3):463-469, 2009
731
Disorders of Subcutaneous Tissue
Chapter 70 :: Panniculitis

:: Iris K. Aronson, Patricia M. Fishman, &
Sophie M. Worobec
INTRODUCTION
Inflammation in subcutaneous fat often poses a diagnostic problem for clinician and pathologist alike, since
the clinical and histopathological findings in the various inflammatory disorders of adipose tissue (AT)
have overlapping features. Specificity in diagnosis is
potentially difficult since similar clinical presentations
are sometimes associated with disparate histopathological features. Diagnostic problems may also relate
to the corollary observation that a range of clinical presentations may have similar histopathologic findings.
There is no universally accepted classification of
panniculitis, but from the point of view of many
pathologists, a useful classification begins by dividing
panniculitis into septal and lobular forms, septal
signifying inflammation confined predominantly to
the septa, and lobular indicating inflammation predominantly involving the fat lobule itself. The septal
form has been most classically associated with erythema nodosum (EN) and the lobular form with all or
most other types of panniculitides. But even this
beginning point has not been proven adequate since
lobular granulomatous panniculitis may be seen in
clinically classic EN,1 and lobular panniculitides may
have mixed lobular and septal inflammation.2 This
classification has been expanded by making note of
the presence or absence of vasculitis in the septa or
lobules,3 by the composition of the inflammatory infiltrate, and by additional specific features when present
(Fig. 70-1).
Since diverse clinical conditions may be expressed
by similar histopathologic features, and the spectrum
of histopathologic features in EN and other panniculitides may be variable,4 it may not be possible to make
a specific diagnosis of panniculitis based on histopathology alone. This necessitates correlation with clinical features, including location of lesions, systemic
symptoms, laboratory findings, and etiological factors.
A significant aid to success in the diagnosis of inflammation in AT is obtaining a tissue sample that will
adequately represent the histopathologic changes in
the lesion. This can only be done with large excisional
biopsies, as small punch biopsies are unlikely to obtain
adequate AT, and the inflammatory infiltrate can be

missed. An additional consideration is that inflammation in AT is not a static process, and as samples taken
at different stages of an evolving lesion will present
with different histopathologic features, more than one
biopsy may be necessary to come to a conclusive diagnosis.
Under the best of circumstances, with optimal histopathologic sampling and clinical correlation, there
may be no specific etiology for many inflammatory
reactions in AT. But even with a specific diagnosis or
etiology, underlying questions remain. Why were the
inflammatory cells accumulating in the AT? What were
they doing there?
ADIPOSE TISSUE REGIONAL

DIFFERENCES
One of the characteristics of certain types of panniculitides is the preferential localization, such as the pretibial areas for EN, the calf for erythema induratum
(EI), and the upper arms, shoulders, and face for lupus
panniculitis. Location of panniculitis is a helpful
adjunct for differential diagnosis of inflammation in
AT and the question of why that occurs may be traced
to the origin of the adipocyte regions from different
areas of the mesoderm and the varying gene expression in different fat depots.25 The differences in gene
expression between fat depots are large, up to 1,000fold, and appear to be intrinsic, autonomous, and independent of the tissue microenvironment.25 Different
AT depots may also contain variable percentage of adipocytes of different developmental origins,25 including
brown AT (BAT) that has been observed to be present
in white AT depots.25,26
The role of AT in innate immunity, inflammation,
adaptive immunity, and energy homeostasis places the
adipocyte itself centrally in the inflammatory disorders that affect it. The presence of adipocyte transmembrane PRRs, TLRs, and cytosolic PRRs, NLRs, and
RLRs and receptors for interaction with macrophages
and lymphocytes, as well as production and secretion
of multiple cytokines and adipokines reflect the role of
10
One approach to clinical classification

Sclerosis of
the septa
Postirradiation panniculitis
Crystal storing histiocytosis
Histiocytes
Gout panniculitis
Crystals
Poststeroid panniculitis
Fat necrosis of the newborn
Lipoatrophy
No crystals
Traumatic panniculitis
Subcutaneous sarcoidosis
Without
vasculitis
Neutrophils
Lymphocytes
Facticial panniculitis
Bacteria, fungi, protazoa
Infectious panniculitis
Neutrophils between collagen bundles
1-antitrypsin deficiency
Saponification of adipocytes
Pancreatic panniculitis
Lymphoid follicles and plasma cells
Lupus panniculitis
Superficial & deep perivascular infiltrate
Cold panniculitis
Needle shaped crystals in adipocytes
Sclerema neonatorum
No inflammatory
cells
Vascular calcification
Necrosis at the center of fat lobule
Panniculitis
Oxalosis
Panniculitis
With
vasculitis
Foreign bodies
::
Mostly lobular
Cytophagic panniculitis
Chapter 70
Cytophagocytosis
Calciphylaxis
Sclerosing panniculitis
Neutrophilic lobular panniculitis
Small vessels:
venules
Lucio phenomenon
Erythema nodosum leprosum
Erythemainduratum of
Bazin/Nodular vasculitis
Large vessels:
arteries & veins
Radial granulomas in septa
Erythema nodosum
Cholesterol clefts
Necrobiotic xanthogranuloma
Fibrin
Rheumatoid nodule
Mucin
Subcutaneous granuloma
annulare
Histiocytes
Without
vasculitis
Mostly septal
With
vasculitis
Lymphocytes
and plasma cells
No granulomatous infiltrate
Deep morphea
Granulomatous infiltrate
Necrobiosis lipoidica
Arteries
Cutaneous polyarteritis nodosa
Veins
Superficial thrombophebitis
Venules
Large vessels
Small vessels
Figure 70-1 Approach to the patient with panniculitis.
the adipocyte in protecting the host from infectious

disease and other environmental dangers. The complex interweaving of the adipocytes role in such
numerous and varied spheres may lead to complications should there be a genetic or acquired functional
abnormality and/or molecular perturbations, and this
may in some instances result in the inflammatory process known as panniculitis.
NODULAR LESIONS OF THE LEGS

Nodular lesions of the legs may represent EN, EI, nodular vasculitis (NV), cutaneous polyarteritis nodosa, or
nodules related to vascular disorders. Diagnosis of these
disorders often presents difficulties because their clinical manifestations as well as histopathological findings
733
10
may overlap. In order to diagnose lesions of the leg, one

needs information on the typical as well as unusual
manifestations of each disorder, the associated diseases
and conditions, and the histopathological presentation.
ERYTHEMA NODOSUM
ERYTHEMA NODOSUM AT A GLANCE
Section 10
Clinical
Symmetric, tender, erythematous, warm
nodules, and plaques on the anterior aspects of
the lower extremities. May become confluent.
Acute onset; no ulceration or scarring; more
common in women.
::
Fever, fatigue, arthralgias, arthritis, headache

common.
Lasts from 36 weeks, with new lesions
appearing for up to 6 weeks.
Histopathology
Mostly septal panniculitis without vasculitis.
Thickened septa with inflammatory cells.
Neutrophils in early lesions and histiocytes
and Miescher granulomas in late-stage lesions.
Treatment
Treatment of the associated disorder.
Bed rest, aspirin, nonsteroidal antiinflammatory drugs.
Systemic corticosteroids are rarely indicated.
EPIDEMIOLOGY. EN may occur in both genders, at

any age from childhood to 70 years of age, but is more
common in young women in the second to fourth
decades of life.27 There is no gender difference in childhood cases. Prevalence varies from 2.4 per ten thousand population to 52 per million population, and in
patient population from 0.38% to 0.5% of patients seen
in clinics in Spain and England, respectively.28,29
734
ETIOLOGY AND PATHOGENESIS. EN is a panniculitis that has been reported in association with
infections (bacteria, viruses, fungi, and protozoa),
medications (antibiotics, oral contraceptives, halides),
malignancies (most often leukemias or lymphomas),
autoimmune diseases, and other inflammatory disorders, especially sarcoidosis and inflammatory bowel
disease (see eTables 70-0.1 and 70-0.2 in online edition).
Geographical variations in infectious etiology occur,
but streptococcal upper respiratory infections are the
most common infectious etiologic factors and the most
common causes in childhood.30 Tuberculosis was a

common etiology in the past, and though less frequent
now, must always be excluded. Half of all EN cases are
idiopathic, without specific etiology, even though in
many a viral cause may be suspected.30
EN is considered to be a hypersensitivity reaction to
the various etiologic factors, but the pathophysiological mechanism of the disorder is not yet understood.
Early studies have shown the presence of IFN and
IL-2, activation of leukocytes, 31 and upregulation of
various adhesion molecules,32,33 and genetic polymorphism in TNF- promoter, MIF (macrophage migration inhibitory factor), or RANTES (regulated upon
activation, normal T-cell expressed, and secreted).3436
More recent information identifies AT as an immune
organ and adipocytes as cells of the innate immune
system, with primary responsibilities and capabilities
of activating inflammatory systems and the adaptive
immune system to destroy pathogens37 (see Section
Introduction). Historically, the primary function of
the adipocyte was thought to be protective. However,
excessive adipocyte production and secretion of multiple proinflammatory adipokines and adipocytokines
is associated with obesity, cardiovascular disease,
hypertension, and diabetes.37 In contrast, the inflammatory reaction of EN is associated with a more limited coccidiomycosis infection38 and with a less severe
and shorter duration of sarcoidosis,38 especially in
those carrying the HLA-DRB1*03-positive leukocyte
antigen,39 which belongs to the 8.1 ancestral haplotype genes associated with a wide range of immunopathologic diseases.40 Therefore, it is possible that,
especially in AT, certain genetic mutations associated
with enhanced inflammatory reactions may confer
resistance to certain pathogens, and this may explain
the observation that EN, whether in association with
coccidiomycosis or sarcoidosis, may be protective
against disease dissemination.38,39
CLINICAL FEATURES. EN most commonly presents with an acute onset of tender, painful, erythematous, warm nodules and plaques on the anterior and at
times the lateral aspect of both lower legs and ankles
(Fig. 70-2). Other sites may also be involved, including
forearms, thighs, and rarely the trunk or even the face,
especially in children.41,42 The nodules may persist a
few days or weeks, may become confluent, and evolve
from an erythematous or purple-like hue to a bruiselike pigmentation called erythema contusiforme if
hemorrhage is present in the AT. The eruption usually
lasts from 3 to 6 weeks, with new lesions appearing for
up to 6 weeks, but it may persist longer and may
recur.42 The lesions do not ulcerate, and they resolve
without atrophy or scarring.
Systemic symptoms such as fever, fatigue, malaise,
arthralgia, arthritis, and headache are common.
Abdominal pain, vomiting, diarrhea, and cough are
less frequent.30,42 Ocular manifestations may accompany the cutaneous lesions.42 Tonsillitis/pharyngitis/
upper respiratory infection (URI) preceded the onset in
20%30% in two series29,30 and prodromal symptoms
may appear 13 weeks prior to lesional onset, at which
time symptoms may become exacerbated.43
Panniculitis
HISTOPATHOLOGY. Histopathologically, EN is
considered the prototype of septal panniculitis,
although lobular inflammation may additionally be
present. The composition of the inflammatory infiltrate varies according to lesional age, with the earliest
lesions demonstrating septal edema, extravasated red
::
Laboratory abnormalities may include a high ESR,

positive throat culture, or high ASO titer in those with
a streptococcal etiology and leukocytosis. A positive
PPD must be evaluated in the context of prevalence of
tuberculosis in the geographical area. Chest X-ray will
rule out pulmonary infectious or noninfectious disease
(sarcoidosis), and serology or culture for various infectious diseases as well as other testing may be warranted in the appropriate setting (see eTables 70-0.1
and 70-0.2 in online edition).
10
Chapter 70
Figure 70-2 Erythema nodosum. Erythematous nodules

located mainly on the anterior of the legs.
blood cells, and scattered neutrophils. More fully

developed lesions of EN show widening of the septa
and early fibrosis, along with a septal infiltrate that
includes lymphocytes, histiocytes, neutrophils, and
eosinophils.27,42,44 There may be extension of the infiltrate into adjacent fat lobules, but centrilobular necrosis of adipocytes is not seen.27,41,42 Late-stage lesions
show widened and fibrotic septa, often containing
granulomas (Fig. 70-3A). The fibrosis and inflammation may encroach upon and partially efface fat lobules. Occasionally, predominantly polymorphonuclear
cells may be present in typical EN,45 but this is considered to be part of the early phase of inflammation.27,41,42
Mieschers granuloma, a discrete micronodular
aggregate of small histiocytes around a central stellate
cleft27,42 (Fig. 70-3B), is considered characteristic of
early EN by some, but is not universally found in
EN,41,44 and has been described in other types of panniculitis.41 The picture of Mieschers granuloma also
evolves, as in later-stage lesions, some aggregates of
larger histiocytes and multinucleated giant cells retain
a central cleft. An overlying superficial and deep perivascular dermal infiltrate is frequently present in EN.41
Lipomembranous changes have been described in late
stages of EN.27,42 Although by definition, vasculitis is
characteristically absent in EN, thrombophlebitis has
been emphasized by some as a feature in early EN,1
and medium vessel arteritis may rarely occur.4
DIFFERENTIAL DIAGNOSIS. Differential diagnosis includes cellulitis, infection-induced panniculitis, acute lipodermatosclerosis (LDS), EI/NV, which
tends to appear on the calves and ulcerate, other vasculitides which must be differentiated histopathologically, and pancreatic panniculitis, which may occur
anywhere on the leg, ulcerate and drain, and which
is accompanied by an increase in serum lipase and
amylase.
TREATMENT. Treatment of EN primarily focuses on
treatment or removal of the etiologic factor. Suspected
medications should be discontinued, underlying infections sought and treated if possible, and associated
Figure 70-3 Erythema nodosum. A. Widened septa with inflammatory infiltrate including multinucleated giant cells.
B. High magnification of a Mieschers granulomas shows a discrete micronodular aggregate of small histiocytes around a
central stellate cleft.
735
10
Section 10
inflammatory disorders or malignancies sought and

appropriately treated. The disorder may persist for
months before remission, and recurrence is possible,
especially if the etiology is unknown.46 Additional
management options include bed rest and leg elevation, aspirin, nonsteroidal anti-inflammatory agents
(avoided with IBD). Supersaturated potassium iodide
solution (SSKI), 210 drops (1 drops = 0.03 mL =
30 mg) three times per day in water or orange juice has
been useful, but individuals with thyroid disorders
and on certain medications may be at risk for hypothyroidism and goiter as well as toxicity reactions of high
potassium involving the heart and lungs.47 SSKI is contraindicated in pregnancy. Other medications that have
been used to treat EN include colchicine (especially for
Behcets disease),48 corticosteroids (rarely used, especially
since an underlying infection must be ruled out), etanercept,49 and infliximab for IBD-associated EN.50
::
ERYTHEMA INDURATUM AND

NODULAR VASCULITIS
EPIDEMIOLOGY AND CLINICAL FINDINGS.
EI is an inflammatory panniculitis, most commonly

presenting with ulcerated nodules on the calves, and
frequently associated with MTB infection. A similar
disorder, without ulceration appearing in calves
and other lower extremity sites was subsequently
described without MTB association and was called
NV. However, with patients presenting with different
features in either the same flare or in preceding or
subsequent flares, multiple studies have concluded
that the clinical and pathological features of the two
nodular leg syndromes are so similar that it is impossible to separate them.5154 Therefore, at this time the
terms are most often used interchangeably. But some
still prefer to use EI to denote the MTB-associated
panniculitis, and NV for those without MTB association despite the otherwise identical features, to
emphasize the need for antituberculosis therapy in
the former cases.55
EI/NV is seen most commonly in young to middleaged women, presenting as recurrent erythematous to
violaceous nodules and deep plaques on the lower legs
that may be tender, or only tender to pressure52 (Fig.
70-4). Some lesions may heal without scarring, but
often ulceration leads to scarring.52 Surface changes
include crusting of the ulcers and a surrounding collarette of scale (Fig. 70-5). The histology is shown in
Fig. 70-6. The posterior leg calf region is the most frequent location, but lesions may also appear in the
anterolateral areas of the legs, the feet, thighs, and
rarely the arms and face.51 EI lesions develop more frequently during winter, and EI is commonly associated
with obesity and venous insufficiency of varying
degree and manifestation.52
COURSE. EI/NV can have a protracted course with
736
recurrent episodes over years.52,53 Patients with EI/NV

are for the most part in fairly good health, except for
ERYTHEMA INDURATUM OF BAZIN/

NODULAR VASCULITIS AT A GLANCE
Clinical
Erythematous subcutaneous nodules and
plaques of lower legs; common on calves,
but also on anterolateral legs, feet, and
thighs; rarely elsewhere.
Commonly associated with venous
insufficiency; more frequent in middle-aged
women.
Often, ulceration and scarring, especially on
the calves.
Chronic course.
Infectious etiology including bacterial
[especially Mycobacterium tuberculosis (MTB)],
fungal, protozoal, and viral should be sought.
Histopathology
Mostly lobular or mixed lobular and septal
panniculitis with vasculitis in 90%.
Extensive necrosis of the adipocytes in the
center of the fat lobule.
Variable inflammatory infiltrate in the fat
lobule: neutrophils in early lesions and
epithelioid histiocytes and multinucleated
giant cells in fully developed lesions.
Vasculitis of the small veins and venules of
the fat lobule.
Treatment
With positive MTB microbiological, serological
or Mantoux tests, or when MTB DNA is
demonstrated: a full course of antituberculosis
triple-agent therapy. If other infection proven
or suspect: treat specific infection.
In other cases: potassium iodide, other antiinflammatory drugs, supporting bandages,
support hose, leg elevation, bed rest.
the associated diseases, without the symptoms usually

associated with EN. There has been one case report of
membranous glomerulonephritis associated with EI/
NV72 and one case of painful peripheral neuropathy in
an initially MTB skin test negative patient who was
later found to have MTB-positive culture of cervical
lymph node.73
TREATMENT. In patients with positive MTB cultures, positive skin test or Quantiferon gold test for
MTB, treatment with triple agent antituberculosis therapy is indicated. Patients with hepatitis B or C should
rated potassium iodide (SSKI), nonsteroidal anti-inflammatory agents (NSAIDS), colchicine, antimalarials,
corticosteroids,55 gold74 as well as bed rest or leg elevation, and treatment of venous insufficiency with compression and pentoxifylline. Other treatments that have
been used include tetracycline and mycophenolate
mofetil.75 If immunosuppressive agents are used, continued monitoring for possible infectious etiology is
recommended.
10
LIPODERMATOSCLEROSIS
receive appropriate intervention for that disorder.

Other infectious etiologies including fungi, parasites,
and viruses should be sought and treated, if present.
Medications that may have incited EI should be discontinued.
Anti-inflammatory treatments that have been used in
EI/NV not associated with MBT include super satu-
LDS is the most common form of panniculitis, seen by

clinicians far more frequently than EN, which has the
next highest incidence. LDS occurs in association with
venous insufficiency, mostly in overweight women
over the age of 40.76,77 In a review of 97 patients with
LDS, 87% were female with a mean age at diagnosis of
62 years; 85% of patients were overweight (BMI >30);
and 66% were obese (BMI >34).78 Comorbidities
included hypertension (41% of patients), thyroid disease (29%), diabetes mellitus (21%), prior history of
lower extremity cellulitis (23%), deep vein thrombosis
Panniculitis
Figure 70-4 Erythema induratum. Erythematous to brown

and bluish nodules with ulceration on calves.
::
EPIDEMIOLOGY
Chapter 70
LDS (synonyms: sclerosing panniculitis, hypodermitis

sclerodermiformis, chronic panniculitis with lipomembranous changes, sclerotic atrophic cellulitis, venous
stasis panniculitis) is a form of sclerosing panniculitis
involving the lower legs.
Figure 70-5 A. and B. Erythema induratum with surrounding collarette of scale.
737
10
ignation by various medical names (see list of synonyms for LDS above), precise data for prevalence of
LDS are not available. With increasing rates of obesity
in the United States and the aging of the baby boomer
generation, a corresponding increase in incidence and
prevalence of LDS will likely follow.
LIPODERMATOSCLEROSIS
AT A GLANCE
Clinical
Indurated plaques of wood-like consistency
on the lower legs, acute and chronic changes,
pain frequent.
Chronic venous insufficiency, higher

than normal BMI, female gender, arterial
hypertension, arterial ischemia, episodes of
thrombophlebitis.
Most patients with LDS are female and also have in

common venous hypertension and a higher than normal BMI. Additional associated features that have
been sought as pathogenetic factors in LDS include the
following: elevated hydrostatic pressure-induced
increased vascular permeability secondary to downregulation of tight junctions79,80 with extravascular diffusion of fibrin78; microthrombi81; abnormalities in
protein S and protein C82; hypoxia83; damage to endothelial cells by inflammatory cells84; upregulation of
intercellular adhesion molecule 1 (ICAM-1), vascular
cell adhesion molecule 1 (VCAM-1), leukocyte
function-associated antigen 1 (LFA-1), platelet- and
endothelial-derived factors85; and inflammation with
wound healing and local collagen stimulation leading
to fibrosis and further vascular and lymphatic damage.78 The fibrosis is accompanied by increased transforming growth factor- 1 (TGF-1) gene and protein
expression86 as well as an increase in procollagen type
1 gene expression.87
Hypoxia in AT induces chronic inflammation with
macrophage infiltration and inflammatory cytokine
expression.88 The adipocyte plays a significant role in
extracellular tissue remodeling. For this task, the adipocyte produces multiple matrix metalloproteinases
(MMPs) as well as tissue inhibitors of metalloproteinases (TIMPs) and other tissue proteases needed during
tissue remodeling,89 all of which may significantly contribute to the tissue remodeling seen in LDS. Recent
studies have linked expansion of AT (as seen in obesity) to resultant hypoxia, causing an increase in
hypoxia-inducible factor 1 (HIF1) expression.90 This
stimulates multiple extracellular factors, including
Section 10
Pulmonary hypertension in patients

with systemic sclerosis and sclerosing
panniculitis.
::
Histopathology
Background of stasis changes; mostly lobular
panniculitis without vasculitis.
Ischemic necrosis at the center of fat lobule.

Thickened and fibrotic septa and atrophy of
the subcutaneous fat, with marked fibrosis
and sclerosis in late-stage severe cases.
Frequent membranocystic changes.
Treatment
Compression stockings, ultrasound therapy,
pentoxifylline.
Successful response to anabolic steroids in
some cases.
(19%), psychiatric illness (13%), peripheral neuropathy

(8%), and atherosclerosis obliterans (5%).78 Due in part
to its placement in the ICD9 classification under
Venous insufficiency with inflammation, and its des-
738
Figure 70-6 Erythema induratum-nodular vasculitis. A. Histopathology: scanning power shows a mostly lobular panniculitis. B. Higher magnification: extensive adipocyte necrosis and vascular damage-necrotizing vasculitis of small venules in
the fat lobule.
Panniculitis
LDS has an acute inflammatory stage and a chronic

fibrotic stage with a spectrum of intermediate77 and
overlapping presentations. In patients presenting with
the acute form (Fig. 70-7A), very painful, poorly
demarcated, cellulitis-like erythematous plaques to
purple somewhat edematous indurated plaques or
nodules are seen on the lower legs, most commonly on
10
::
CLINICAL FINDINGS
the lower anteromedial calf area.77,93 Scaling may be

present in some. The pain can be so intense that
patients may not even tolerate a sheet while in bed. In
this stage, patients are frequently diagnosed as having
EN, cellulitis, or thrombophlebitis,77,93 and compression may not be tolerated. The acute form may last a
few months or even a year.93 Although patients in this
acute phase may present without obvious signs of
venous disease,77 vascular studies show venous insufficiency in the majority.93 In the remaining group of
LDS patients with normal venous studies, most have a
high BMI, and given that obesity is usually associated
with inactivity, these patients may not exert enough
calf muscle contraction to maintain normal venous
pressure in the lower extremities78; also, obesity is frequently associated with arterial hypertension.
The chronic form of LDS may or may not be preceded by a clinically obvious acute form.77 Chronic
LDS features indurated to sclerotic, depressed, hyperpigmented skin (Fig. 70-7B). These findings occur on
the lower portion of the lower leg, predominantly but
not limited to the medial aspect, or in a stocking distribution. This is described as having an inverted champagne bottle or a bowling pin appearance.76,77,93
Although some patients may not describe associated
pain or tenderness,93 pain is the most frequent symptom reported by others.78 Most of the patients are obese
or overweight and have hypertension and evidence of
venous abnormalities, but only rarely obstruction.78
Unilateral involvement is seen in 55%, localized plaque
in 51%, and ulceration in 13% of cases78 (Fig. 70-8). Dermatosclerosis in patients with systemic sclerosis has
Chapter 70
collagen I and III, as well as other components involved

in remodeling the extracellular matrix, leading to
fibrosis as the end result.91
A theory regarding an infectious pathogenesis of
LDS was advocated by Cantwell and colleagues, who
reported the presence of unusual acid-fast bacteria
that could not be grown in culture in biopsies of several patients with LDS.92 This 1979 article dealt with
the controversial issue of pleomorphic, nonrodshaped, acid-fast bacteria being responsible for disease. It is widely accepted that other infections
associated with repeated episodes of cellulitis cause
lymphatic damage and subsequent changes in the
AT.77 Particularly in the light of more recent discoveries that adipocytes are cells of the innate immune system and possible reservoirs of infectious organisms of
all types, the role of infection as a contributing factor
to LDS should be reconsidered and explored, perhaps
in an analogous manner to that of the process leading
to evidence of MTB DNA and dormant MTB in AT of
the legs in EI.58,67
Figure 70-7 Chronic lipodermatosclerosis (LDS). A. Sclerotic hyperpigmented skin on medial lower leg. B. Superimposed
acute on chronic lipodermatosclerosis with ulceration.
739
10
Figure 70-8 Chronic lipodermatosclerosis with champagne

bottle/bowling pin deformity.
Section 10
::
740
been associated with pulmonary infarction and hypertension secondary to leg thrombi.94
Diagnostic tests to evaluate peripheral vascular disease should include ankle brachial index for arterial
evaluation. Also indicated are venous tests: Dopplers
to detect thrombi as well as color duplex sonography
to detect direction of flow and presence of venous
reflux.93 If the clinical findings are characteristic, biopsy
of LDS is usually discouraged, due to the high incidence of subsequent development of ulcers at the
biopsy site.77 But if necessary for diagnosis, a thin elliptical excision from the margin of an erythematous and
indurated area, closed primarily with sutures, is recommended.77
DERMATOPATHOLOGY
Histopathologic findings reflect the evolution of the
disease. Dermal stasis changes are present at any stage,
and these include a variable degree of proliferation of
capillaries and venules, small thick-walled blood
vessels, extravasated erythrocytes, hemosiderin-laden
macrophages, lymphohistiocytic inflammation, and
fibrosis.53,95
In the subcutis, early lesions of LDS show a sparse
infiltrate of lymphocytes in the septa, accompanied by
central lobular ischemic fat necrosis; the latter is recognized by the presence of pale-staining, small anucleate
adipocytes. Capillary congestion is also observed within
fat lobules; this may be accompanied by endothelial cell
necrosis, thrombosis, red cell extravasation, and hemosiderin deposition.53,95 Septal fibrosis and small foci of
lipomembranous fat necrosis and fat microcysts have
also been described to occur in acute lesions.95 In lipomembranous or membranocystic change, small pseudocystic spaces are formed within necrotic fat. The spaces
are lined by a hyaline eosinophilic material believed to
be the residue of disintegrated adipocytes and their
interaction with macrophages.96 This distinctive membranous lining is highlighted by periodic acid-Schiff
(PAS) staining and may present an arabesque pattern,
with intricate undulating papillary and crenulated projections into the cystic spaces. However, membranocystic changes are not exclusive to LDS and may be found
in any type of panniculitis.53,97
With progression of LDS, the spectrum of histopathologic changes encompasses increasing degrees of
membranocystic fat necrosis, septal fibrosis, and thick-
ening; an inflammatory infiltrate comprising lymphocytes, histiocytes, and foamy macrophages; and partial
to extensive atrophy of fat lobules.53,77,95 Advanced
lesions show septal sclerosis most prominently, with
marked atrophy of fat lobules secondary to lipophagic
fat necrosis, accompanied by microcystic and lipomembranous change and a marked reduction in
inflammation.53,95 The most severe LDS shows marked
fibrosis and sclerosis in the AT layer with little inflammation.77 In late stages, with fibrous thickening of the
lower dermis and replacement of the subcutis by sclerosis, a punch biopsy of involved skin may not produce any subcutaneous fat.98
TREATMENT
Compression therapy is the major universally recommended treatment for LDS.77,78 Higher compression gradient (3040 mm Hg) may be more effective, but lower
class compression (1520 mm Hg or 2030 mm Hg)
may be associated with higher rate of compliance,
especially in the elderly, and has been shown to be
effective in decreasing edema.99 One mechanism by
which compression improves venous return and
decreases edema is via tightening of vascular tight
junctions, significantly elevating expression of tight
junction proteins and inhibiting permeability of fluid
into the perivascular tissue, thereby preventing progression of venous insufficiency.79,80 Stockings must be
worn all day and not removed until bedtime, since
even a few days without compression may lead to
recurrence of the edema and inflammation.99
Stanazolol has been shown to be effective in LDS,
with decrease in pain, erythema, and induration.77,100
Patients tolerated the treatment well, but potential side
effects of this treatment include hepatotoxicity, and
this may preclude its widespread use. In the United
States, this drug is no longer distributed. Other anabolic steroids such as oxandrolone and danazol have
also been used.101,102 Pentoxifylline has been successfully used in LDS cases with and without associated
ulceration. A Cochrane Database System review of 12
trials involving 864 patients in 2007 concluded the
drug was a useful adjunct to compression for treating
venous ulcers and may be effective in the absence of
compression.103 Other treatments for chronic venous
insufficiency include horse chestnut seed extract,104,105
oxerutin,106,107 and flavonoid fraction.108
Ultrasound therapy was reported in two studies as
being successful in reducing and even resolving hardness, tenderness, and erythema.109,110 Readily available
through physical therapy departments, it is a simple
and safe treatment of a painful and refractory condition and may be used along with Grade-2 compression
therapy.109,110
PREVENTION
Since being overweight and obese are common conditions among affected patients, efforts to reduce weight
are prudent.
INFECTION-INDUCED
PANNICULITIS
INFECTIOUS PANNICULITIS
AT A GLANCE
Clinical
Caused by wide variety of infectious agents,
including bacteria, fungi, parasites, and
viruses.
Due to primary inoculation or hematogenous

spead; patients may be immunosuppressed.
In primary cutaneous infections, epicenter

of inflammation is superficial dermis; in
secondary infections, epicenter is deep
reticular dermis and subcutaneous fat.
Special stains, cultures, and serologic
studies necessary for detection of
microorganisms.
Treatment
Appropriate antimicrobial therapy selected
according to susceptibility tests.
EPIDEMIOLOGY
Infection-induced panniculitis (Infectious panniculitis, infective panniculitis) is panniculitis directly
caused by an infectious agent.62 AT infection can be
due to bacteria, mycobacteria, fungi, protozoa, and
viruses.53,62,111 Primary infections produced by direct
inoculation at a wound site (injury, surgical procedure, catheter, injection, acupuncture) usually result
in a single lesion which may enlarge and spread
locally.53,62,111 Secondary infections caused by sepsis
and hematogenous spread may manifest as single or
multiple lesions.53,62,111 In immunosuppressed patients,
microorganisms may be numerous and identified on
routine histopathology or special stains. In immunocompetent patients, microorganisms may be sparse
and not seen on either routine histopathology or special stains, requiring positive cultures or serological
studies for identification.53,62,111 Recent reports of infectious etiologies in association with various autoimmune disorders include Staphylococcus aureus
panniculitis with juvenile dermatomyositis (DM),112
The clinical appearance of infectious panniculitis

varies from fluctuant- or abscess-type lesions with
purulent discharge and ulcerations to nonspecific
erythematous firm nonfluctuant subcutaneous
plaques and nodules, purpuric plaques, and EN-type
lesions.62,111,129 Deep nodules or plaques may not always
appear fluctuant, and pustules, fluctuant papules, and
ulcers can be superimposed on top of the nodules.111
The most common sites of infection are the legs and
feet, but upper extremities, trunk, and face may also be
involved.62,111 Immunosuppression of varying etiology
is the most frequent, but not universal, association.53,62,111 Immunosuppression is associated with
more widespread abscess-type lesions containing nontuberculous mycobacteria, whereas in immunocompetent patients, granulomas are more commonly
seen.111,130 Fungal infections occur in the following clinical settings: (1) localized environmentally injected
panniculitis of mycetoma, chromoblastomycosis, and
sprorotrichosis; or (2) panniculitis associated with systemic disseminated fungal infection that may be seen
in individuals with normal immune functions, or with
opportunistic fungal infection seen in immune compromised individuals.111,129 Clinical features vary with
the setting, the infective organism and the underlying
state of the individuals immunocompetence or
immunosuppression.111,129
Panniculitis
Histopathology
Suppurative granulomas within fat lobule.
CLINICAL FINDINGS
::
Erythematous plaques, nodules, abscesses,

ulcers with purulent discharge.
10
Chapter 70
AT may serve as reservoir for various

infections.
Mycobacterium- and Histoplasma-associated panniculitis with rheumatoid arthritis,113,114 and diffuse fusariosis with acute lymphobastic leukemia (ALL).115
HISTOPATHOLOGY
Evaluation of panniculitis for infections should include
histopathologic studies with special stains for all types
of organisms as well as culture and sensitivity testing
of biopsy material. In the immunosuppressed patient,
microorganisms may be numerous and more readily
identified, but in immunocompetent patients, microorganisms may not be seen on either routine histopathology or special stains, requiring positive cultures or
serological studies for identification.53,62,111 The antiBacille Calmette-Gurin (BCG) polyclonal antibody
immunostain cross-reacts with many bacteria, mycobacteria, and fungi with minimal background staining
and is advocated as a good screening tool for detection
of microorganisms in paraffin-embedded tissue specimens when conventional stains are negative.53,111,131
Molecular PCR techniques have been utilized with
mycobacterium infections.5658,122 Histopathologic features may vary with the organism and its virulence,
the host immune status, and the duration of the lesion
at time of biopsy.62 Classified by some as a mostly lobular panniculitis,53 infection-induced panniculitis often
presents a mixed septal and lobular pattern, and a predominantly septal, EN-like neutrophilic panniculitis
has also been reported to occur in cases of bacterial as
well as fungal etiology.62 The superficial dermis is the
741
10
Section 10
::
epicenter of inflammation in infections acquired by

direct inoculation or by an indwelling catheter, in contrast to more deeply seated infections secondary to
hematogenous spread involving the deep reticular
dermis and subcutaneous fat.53
Generally, in a typical case, the subcutaneous fat
contains a dense infiltrate of neutrophils and some
admixed lymphocytes and macrophages, often with
extension into the overlying dermis and with abscess
formation a common finding.62,111 Patterson et al
additionally noted distinctive subcutaneous features
in the majority of 15 reported cases of infectioninduced panniculitis of bacterial, atypical mycobacterial and fungal origin, independent of the particular
causative microorganism. These features included
hemorrhage, vascular proliferation, foci of basophilic
necrosis, and sweat gland necrosis. Overlying
changes such as parakeratosis, acanthosis, and spongiosis were seen in all cases in which the epidermis
was available for examination. All 15 cases also had
dermal findings, most commonly upper dermal
edema, a diffuse and perivascular inflammatory
infiltrate, often with prominent neutrophils, proliferation of thick-walled vessels, and focal or diffuse
hemorrhage.62 With observation of any of these enumerated features, special stains for bacteria, mycobacteria, and fungi are imperative, and additional
immunohistochemistry or PCR amplification techniques may be necessary.
Other histopathologic changes may point toward a
more particular etiology. Suppurative granulomas
formed by epithelioid histiocytes surrounding aggregated neutrophils may occur in panniculitis caused
by atypical mycobacteria.53 Caseating granulomas,
though rarely seen, raise suspicion for tuberculous
panniculitis.111 A case of panniculitis secondary to
CMV has been reported as a mostly septal panniculitis
with many CMV inclusions contained within endothelial cells.132
Differential diagnosis includes 1-antitrypsin (1AT)
panniculitis, pancreatic panniculitis, traumatic, and
factitial panniculitis. It is important to recall that
presence of one of the above diagnostic types of panniculitis does not exclude infection, as in the case of
1AT panniculitis associated with lymph node histoplasmosis.133
TREATMENT
742
Treatment will vary and depend on the suspected or

known organisms and their cultures and sensitivities.
In cases involving bacteria such as MTB and parasites
such as T. cruzi, their known capability to remain dormant in AT necessitates the use, for adequate treatment durations, of appropriate antibiotics, selected
for their abilities to affect nonreplicating organisms.67,121
a1-ANTITRYPSIN PANNICULITIS
a1-ANTITRYPSIN-DEFICIENCY
PANNICULITIS AT A GLANCE
Clinical
ZZ-, MZ-, MS-, and SS-phenotypeassociated panniculitis rare, with higher
percentage (>60%) in ZZ cases; low levels
of 1-antitrypsin are associated with
emphysema, hepatitis, cirrhosis, vasculitis,
and angioedema.
Subcutaneous nodules mostly located on
the lower abdomen, buttocks, and proximal
extremities.
Frequent ulceration and isomorphic
phenomenon.
Histopathology
Mostly lobular panniculitis without
vasculitis.
Necrosis of fat lobules with a dense
inflammatory infiltrate of neutrophils.
Splaying of neutrophils between collagen
bundles of deep reticular dermis.
Large areas of normal fat adjacent to necrotic
adipocytes.
Treatment
Dapsone, doxycycline.
Homozygous ZZ patients with severe forms
of the disease: supplemental intravenous
infusion of exogenous 1-proteinase inhibitor
concentrate or 1-antitrypsin produced by
genetic engineering; liver transplantation.

1AT is a glycoprotein that accounts for 90% of the
total serum serine protease inhibitor capacity in
humans.134 It is produced and secreted mainly by hepatocytes, but also in small amounts by monocytes/macrophages and neutrophils,135137 and is known to inhibit
trypsin, chymotrypsin, leukocyte elastase, kallikrein,
collagenase, plasmin, and thrombin among other proteases.134 1AT may also help regulate protease stimulated activation of lymphocytes, phagocytosis by
macrophages and neutrophils, and complement activation.138141 It is an acute phase reactant, increased in
times of stress.
1AT deficiency is inherited as a codominant disorder, and more than 100 alleles have been identified.142,143
The 1AT phenotypes are classified according to gel
10
Chapter 70
::
Figure 70-9 1-Antitrypsin deficiency associated panniculitis. A. Fluctuant abscess type appearance. B. Discharge of oily
material.
electrophoresis migration/mobility as F (fast), M

(medium), S (slow), and Z (very slow), but null variants that do not produce any 1AT and patients may
have dysfunctional 1AT with normal levels.144 Homozygous MM, the most common phenotype, is associated with normal levels of 1AT, whereas those
homozygous for ZZ have low levels at 10%15% of
normal, and those heterozygous for S or Z allele have
levels in between. MS heterozygous individuals may
have low normal serum levels.145 Due to the complex
nature of these proteins, combination protein levels, or
phenotyping and genotyping, have been recommended.144 Estimated prevalence of 1AT deficiency in
Caucasians is 1 per 3,0005,000 in the United States,
with incidence in Caucasian newborns similar to that
of cystic fibrosis.144
Panniculitis
seen between ages 30 and 60.146,148 Patients present

with painful erythematous nodules and plaques, but
early lesions may have a cellulitic or fluctuant abscesstype appearance (Fig. 70-9A). Lesions may ulcerate
and discharge an oily material or serosanguineous discharge9 (Fig. 70-9B) and resolve with atrophic scars.53
The lesions appear most commonly on the lower trunk
(buttocks) (Fig. 70-10) and proximal extremities, but
lower legs and other sites may be affected.53,146,150 As
trauma or excessive activity may precede the onset of
lesions in a third of patients,53,146 debridement is discouraged.53 1AT panniculitis has occurred in patients
with such conditions as hypothyroidism, mixed connective tissue disease, lymphoproliferative disorders,
and infections, including a focus of histoplasmosis in a
lymph node.133,149 Therefore, the presence of 1AT
deficiency in association with panniculitis should not
CLINICAL FINDINGS
1AT deficiency is most commonly associated with
pulmonary and hepatic disease, leading to chronic
obstructive pulmonary disease (COPD), hepatic cirrhosis, or hepatocellular carcinoma144; the ZZ genotype
is at highest risk. There is no association of the null
variant with hepatic disease, as it is the accumulation
of polymerized 1AT in the liver that induces damage,
and accumulation does not occur in this variant.144 The
exact mechanism of injury is still controversial.144
Panniculitis uncommonly occurs in 1AT deficiency.
Less than 50 cases have been reported146,147 in ZZ, MZ,
MS, and SS phenotypes, with higher percentage (>60%)
of ZZ cases as well as higher incidence in women
(65%).146 Presenting in an age range from childhood
(infancy) to the elderly, panniculitis is most frequently
Figure 70-10 1-Antitrypsin deficiency associated panniculitis. Nodular lesion on the buttock.
743
10
Section 10
::
Differential diagnosis of 1AT panniculitis includes other

panniculitides that may ulcerate and drain such as the
spectrum of infections, factitial disease, EI, and pancreatic
panniculitis. Subcutaneous Sweet syndrome, rheumatoid
arthritis, and myelodysplasia-associated neutrophilic
panniculitis do not usually drain and ulcerate.160,161
PATHOLOGY
TREATMENT
Histopathologic findings vary with the age and type of

lesion biopsied. Early in their development, nodular
lesions may reveal edema and degeneration of adipocytes, with ruptured and collapsed cell membranes
and a perivascular mononuclear infiltrate.153 Also
reported at this stage is a mild infiltrate of neutrophils
and macrophages in septa and lobules, with foci of
early necrosis of subcutaneous fat. This may be accompanied by splaying of neutrophils between collagen
bundles throughout the overlying reticular dermis,
considered an early and distinctive diagnostic clue.156
More advanced lesions have masses of neutrophils
and histiocytes associated with necrosis and replacement of fat lobules (Figs. 70-11A and 70-11B). A focal
pattern of involvement is another distinguishing feature that may be appreciated, manifested by large
744
areas of normal fat in immediate proximity to necrotic

septa and fat lobules.157 Liquefactive necrosis and dissolution of dermal collagen may be accompanied by
ulceration, and degeneration of elastic tissue may lead
to septal destruction and the appearance of floating
necrotic fat lobules.149,158 A rare occurrence is an exclusively septal pattern of mixed inflammatory infiltrate
with a predominance of neutrophils.146,158 Neutrophils
and necrotic adipocytes are less prevalent in late stage
lesions, with replacement by lymphocytes, foamy histiocytes, and variable amount of fibrosis within fat
lobules.149,159
preclude a search for infection or other underlying

medical problems such as autoimmune disorders,
malignancies, or infections, since they may coexist.
Cutaneous and subcutaneous necrosis can develop
rapidly. Extensive involvement with 1AT panniculitis
can be life threatening, and fatal cases have been
reported.148,151,152 Erythrophagocytosis was noted in the
biopsy of one of the patients with fatal panniculitis.153
Possible mechanisms leading to the development of
1AT panniculitis include lack of interference with the
various proteases that lead to activation of lymphocytes, macrophages, complement, and lysis and
destruction of connective tissue at sites of inflammation. Trauma to adipocytes may result in their activation, with release of the various adipokines and
cytokines that are chemotactic to inflammatory cells,
whose released proteases are unopposed due to
absence of the 1AT, leading to severe damage in
involved tissue.154,155 Animal models of soft tissue
injury show elevated levels of IL-6 and MCP-1 and
increased systemic inflammatory mediators.154
Many medications have been used in the treatment of

1AT deficiency panniculitis including colchicine, antimalarials, steroids, immunosuppressive agents, cytotoxic agents, dapsone, doxycyline, plasma infusion
and plasma exchange, intravenous 1AT replacement
therapy, and liver transplantation.148,150,162167 Steroids,
immunosuppressives, and cytotoxic agents were the
least successful treatment options. Doxycycline and
especially dapsone were very helpful in mild to moderate cases, but severe panniculitis required A1P
replacement therapy.148,149,159,167 Panniculitis resolved
with liver transplantation,168 and panniculitis acquired
after liver transplantation was successfully treated
with retransplantation.169
Figure 70-11 1-Antitrypsin panniculitis. A. Scanning power shows a mostly lobular panniculitis. B. Dense inflammatory
infiltrate of neutrophils in the fat lobule.
PANCREATIC PANNICULITIS
PANCREATIC PANNICULITIS
AT A GLANCE
Clinical
Erythematous subcutaneous nodules that
often ulcerate spontaneously.
Lower extremities (around ankles and knees)
are most frequent sites of involvement.
Ghost adipocytes with finely granular and

basophilic intracytoplasmic material.
Treatment
Treatment of the underlying pancreatic
disease, ocreotide, plasmapheresis.
EPIDEMIOLOGY
Panniculitis in association with pancreatic disease is a
rare occurrence, developing in 2%3% of all patients
with pancreatic disorders and appearing in the setting
of acute or chronic pancreatitis, pancreatic carcinoma,
or pancreatic pseudocysts.170172 Although pancreatitis
is most commonly due to alcohol abuse, cholelithiasis,
or pancreatic calculi, medications and viral infections
are also known etiologic factors.173,174 The cutaneous
panniculitis may precede the diagnosis of the associated pancreatic disease by weeks to months in up to
45% of patients.170,173 Mono- or oligoarticular arthritis
secondary to periarticular fat necrosis may be present
in over half of patients.170 This triad of pancreatic disease, panniculitis, and polyarthritis may occur with
either pancreatitis or pancreatic carcinoma.175 and is
seen in less than 1% of pancreatitis patients172; joint disease may precede the diagnosis of pancreatic disorder.175 Abdominal symptoms may be mild or absent.175
Pancreatic panniculitis may also be seen in association
with pancreatitis following renal or pancreas renal
transplant,176,177 with SLE,178 and with hemophagocytic
syndrome (HPS).179 Panniculitis associated with pancreatic disease may be fatal,170,172,180 with a mortality
rate of up to 24% in one series175 and mortality rates of
100% in those with pancreatic carcinoma and 42% of 19
patients with pancreatitis in another series.181
CLINICAL FINDINGS
The cutaneous lesions appear most frequently on the
lower legs, especially the periarticular areas,170 but are
also found on the arms, thighs, and trunk.170 Lesions
often appear in crops, although single nodule pancreatic panniculitis also occurs.185 The lesions are illdefined erythematous to redbrown edematous tender
nodules, which in mild cases may involute and resolve
with atrophic hyperpigmented scars,170 may have central softer areas or may become fluctuant, abscesslike, and drain oily material similar to lesions of 1AT
deficiency panniculitis (Fig. 70-12A).170
Extracutaneous manifestations include periarticular
fat necrosis with concomitant arthritis,170 painful medullary fat necrosis in bone,172 and pleural effusions and
serositis.172,181 The presence of pleural effusions, alone
or with arthritis, is associated with a high mortality
rate.181 Eosinophilia may be seen in both pancreatitisand pancreatic malignancy-associated pannicultis,181
and a pancreatic tumor in association with panniculitis, polyarthritis, and eosinophilia (Schmids triad)
imparts a poor prognosis.186
Panniculitis
Intense necrosis of adipocytes at center of fat

lobule.
::
Histopathology
vasculitis.
Pancreatic panniculitis has generally been attributed to

release of pancreatic enzymes such as lipase, amylase,
and trypsin into the circulation, promoting vascular
permeability, leading to release of fatty acids from adipocytes and subsequent fat necrosis.172,182 However,
there are reports of normal serum levels of pancreatic
enzymes in association with typical pancreatic pannicultis.170 Additionally, incubation of normal AT with
amylase and lipase and with pancreatitis patient serum
high in those enzymes failed to induce fat necrosis in
vitro,183 leading to suggestions that other mechanisms
may be involved in the development of pancreatic panniculitis. Since many of the lesions appear on lower legs,
these mechanisms may include venous hypertension,
but likely also involve adipocyte generated cytokines
and adipokines related to effects of high levels of free
fatty acids170; resistin and leptin have been shown to be
potential markers of extrapancreatic fat necrosis.184
10
Chapter 70
Regression of pancreatitis-associated
cutaneous lesions, but those associated with
pancreatic carcinoma tend to persist; may be
fatal.
HISTOPATHOLOGY
Fully developed lesions of pancreatic panniculitis
demonstrate lobular fat necrosis with distinctive qualities (Fig. 70-12B). Adipocytes lose their nuclei but
maintain peripheral outlines, forming characteristic
ghost cells (Fig. 70-12C). With saponification, calcification occurs, producing fine granular basophilic
deposits within and around individual necrotic adipocytes. The ghost cells are frequently aggregated in
small clusters at the center of fat lobules, with a peripheral inflammatory infiltrate of neutrophils.53 In older
lesions, necrosis and ghost cells are less evident,
replaced by foamy histiocytes, multinucleated giant
cells, lymphocytes, and eventually, fibrosis.53,98 Of note,
745
10
Section 10
::
746
pancreatic panniculitis has been reported to originate

as a septal inflammatory process similar to EN in its
earliest manifestation,187 and findings mimicking pancreatic panniculitis have been documented at the site
of subcutaneous interferon injections in the course of
treatment of multiple sclerosis.188
Treatment is supportive and directed at the underlying pancreatic disorder. Since patients may not have
abdominal symptoms, pancreatic panniculitis should
be considered in the differential diagnosis of any panniculitis. Resolution of the lesions occurs with specific
surgical treatment appropriate to the underlying disorder.173,175,189 Ocreotide, a somatostatin analog, and plasmapheresis have also been associated with resolution
of pancreatic panniculitis.190,191
Figure 70-12 Pancreatic panniculitis A. Clinical features: erythematous subcutaneous nodules that ulcerate
and exude an oily material. B. Scanning power shows a
mostly lobular panniculitis with adipocyte necrosis at the
center of the fat lobule. C. Higher magnification shows
ghost adipocytes, necrotic adipocytes without nuclei
and with cytoplasmic fine granular basophilic material
due to calcification.
LUPUS PANNICULITIS [Lupus

Erythematosus Panniculitis
(LEP), Lupus Profundus,
Subcutaneous Lupus
Erythematosus]
EPIDEMIOLOGY
Lupus erythematosus panniculitis (LEP) is a rare variant of lupus erythematosus (LE), which primarily
affects the subcutaneous AT.192,193 LEP may appear as
the sole manifestation of LE or may occur prior to or
LUPUS PANNICULITIS AT A GLANCE

Clinical
Erythematous nodules on face, shoulders,
upper arms, scalp, chest, buttocks; rarely on
lower extremities.
Persistent areas of lipoatrophy in regressed
lesions.
Lobular lymphocytic infiltrate, with plasma

cells in many cases, eosinophils sometimes.
Hyaline necrosis and atrophy of entire fat

lobule in late-stage lesions.
Interface changes of discoid lupus
erythematosus in 20%30% of cases
(changes at the dermalepidermal interface
may also rarely accompany subcutaneous
panniculitis-like T-cell lymphoma).
Treatment
Antimalarials, thalidomide.
If active and severely inflamed, short oral
courses of corticosteroids.
Dapsone, cyclosporine, methotrexate,
intravenous immunoglobulin, and
rituximab.
after the onset of discoid lupus erythematosus (DLE)

or systemic lupus erythematosus (SLE).194,195 The incidence of SLE in patients with LEP has been reported to
range from 10% to 41%, with the highest incidence
seen in a Japanese series of 44 cases193,195,196; LEP occurs
in only 1%5% of patients with SLE.192,193 Although
rare, LEP occurs worldwide, more frequently among
women than men, with a female to male ratio of about
4:1.193,195,197 LEP is most common between the ages of 30
and 60, but may rarely be seen in childhood or even as
neonatal lupus.53,193,194,198 When present in association
with SLE, LEP tends to occur in SLE cases of lesser
severity.195,197 There are a few case reports of LEP in
more than one family member, or of family members
with SLE unaccompanied by LEP.192,193 Patients with
LEP may also have other autoimmune disorders such
as Sjgrens syndrome and rheumatoid arthritis.192,193
Panniculitis
Sclerotic collagen bundles within septa.
::
Lymphoid follicles with germinal centers

often.
While a complete understanding of why LEP develops

is still lacking, the innate immune system has been
recently recognized to play a significant role in the
development of SLE. Adipocytes are important cells of
the innate immune system and function in pathogen
recognition, activation of adaptive immunity, and as a
reservoir for various microbes. All TLRs are expressed
in AT. Adipocytes themselves express TLR1, 2, 3, 4, and
6, whereas TLR5, 7, 8, 9, and 10 are expressed on the
nonadipocyte stromovascular fraction of AT.199 The
reasons for lupus panniculitis may vary from genetic
polymorphism of TLRs leading to inappropriate activation of innate immune systems (especially of the
type 1 interferon system),200 to inappropriate interactions of adipocytes with inflammatory cells, to immune
responsiveness against microbial and nonmicrobial
antigens within AT. The localization of LEP to specific
fat depots may be a clue to the functions of those adipocytes, or to a specific genetic aberration, or to the
type of lymphocytes that are attracted to those AT
depots.
In SLE, TLR7 and TLR9 recognize RNA and DNA
patterns, respectively, and appear to provide a mechanism for recognition of self-DNA or self-RNA, with
subsequent activation of the adaptive immune system and production of autoantibodies to nucleic acids
and proteins bound to nucleic acids.201205 Inhibitors
of TLR7 and TLR9 can prevent disease in mouse models of autoimmunity,203 although deletion of TLR9
may enhance disease in some experimental models.206
Both receptors have been suggested as therapeutic
targets.203,205,206 Genetic variations in TLR9 receptor
has been shown to predispose to SLE in a Japanese
series207 and regression of SLE was seen in a patient
who developed an acquired TLR7 and TLR9 defect
and antibody deficiency.208 SLE occurs much more
commonly in women, and both TLR7 and TLR8 are
encoded on the X chromosome, adding another layer
of disease association.209 In addition, hydroxychloroquine, the most common treatment for all variants of
SLE and LEP, has been shown to block intracellular
TLRs in vitro.210
10
Chapter 70
Histopathology
vasculitis (lymphocytic vasculitis
occasionally).
CLINICAL FINDINGS
LEP lesions may be tender and painful and usually
appear on the upper arms (lateral aspect), shoulders,
face, scalp, hips, buttocks, breasts, and rarely on the
lower extremities (Fig. 70-13).193195 Orbital/ocular
involvement may present with periorbital edema.211,212
The lesions are deep subcutaneous nodules without
any surface changes, or with surface changes including erythema and DLE features such as atrophy, hyperkeratosis, hyper- or hypopigmentation, telangiectasia,
follicular plugging, and focal ulceration and necrosis.193,194 The shoulder and arm sites are frequently
associated with surface DLE lesions.193 Incidence of
ulceration varies from <7% (of 44 Japanese cases).195 to
28% of 40 US cases.197 Individual lesions may enlarge
747
10
Section 10
::
Figure 70-13 Lupus panniculitis. A. Atrophic upper arm lesion with superficial hyperpigmentation. B. With superimposed discoid lupus erythematosus and ulceration.
and/or coalesce to involve large areas with atrophy.193

Areas of ongoing indurated panniculitis may coexist
with DLE, subcutaneous atrophy, and bizarre scar formation.193 LEP resolves with depressed lipoatrophic
areas that may involve much of the upper arms, shoulder, or buttock.193,194 Facial involvement may result in
noticeably atrophic malar areas with severe cosmetic
alterations. LEP is a chronic inflammatory disorder
with yearly or periodic flares or long remissions.193
Lesions may appear at sites of trauma, including injections and surgical sites.193,194 Average disease duration
is 6 years, with a range of less than 1 year to 38 years.197
Serological findings may be normal194 or abnormal.193,195 Patients without associated SLE may have
low positive ANA titers and those with SLE tend to
have higher positive titers.195 C4 deficiency may be
found.194,213 Other laboratory findings in some
patients may include rheumatoid factor, false positive Venereal Disease Research Laboratory (VDRL),
specific ANAs, leucopenia, anemia, or thrombocytopenia.193
HISTOPATHOLOGY
748
Findings may vary, with features of DLE in about

20%30% of cases. These features include vacuolar
alteration of the basal cell layer, thickened basement
membrane,53,193,195 mucin deposition between dermal
collagen bundles,53,193,195 and a superficial and deep
perivascular inflammatory infiltrate of lymphocytes.53

Findings of basement membrane thickening or liquefaction degeneration and/or pigment incontinence
may be noted in significant percentages of LEP
patients without clinical epidermal changes.195 The AT
shows a mostly lobular or mixed lobular and septal
panniculitis, with lymphocytes, often with formation
of lymphoid follicles (some with germinal centers),
variable hyaline fat necrosis,53,195 hyalinized, and sclerotic septal collagen bundles associated with an interstitial infiltrate of lymphocytes and plasma cells53;
occasional lymphocytic vasculitis in small blood vessels of fat lobules, presence of eosinophils in the
inflammatory infiltrate in some cases,53 and membranocystic changes in some late stage lesions.53 Calcification and/or fibrin thrombi may also be noted in 10%
of cases.195
In cases with only AT involvement and without
other features specific for DLE or SLE, differentiation
from subcutaneous T-cell lymphoma, although
essential, can be very difficult. There are reports of a
spectrum of subcutaneous lymphoid dyscrasias,
with lesions originally diagnosed as LEP progressing
to indeterminate lymphocytic lobular panniculitis
and eventuating in a subsequent diagnosis of subcutaneous panniculitis-like T-cell lymphoma (SPTL).214
There may also be epidermal involvement in
SPTL,215217 making the distinction even more difficult; in two cases initially thought to be LEP, one
with subcutaneous leg nodules demonstrating
cigarette smoking on antimalarial treatment in LE still

needs to be better defined, since cigarette smoke may
both attenuate and enhance different aspects of the
immune system and, in the airways, is considered
able to suppress innate immune response to infections.230,231
Corticosteroids are effective and useful if the disease
is active and severe.193,195,232 Corticosteroids may be
used short term during the period of antimalarial initiation, but long-term use is generally avoided due to
the chronic nature of LEP. Intralesional steroids are
not recommended currently since they are traumatic
and may induce atrophy. Other treatments include
dapsone,233 thalidomide,223,234 cyclosporine,235 methotrexate,236 intravenous immunoglobulin (IVIG)236 and
rituximab.237
Panniculitis
PANNICULITIS ASSOCIATED WITH

DERMATOMYOSITIS AT A GLANCE
::
OTHER CONNECTIVE TISSUE

DISEASE-ASSOCIATED
PANNICULITIS
10
Chapter 70
biopsy changes of interface vacuolar alteration and

mucin deposition,218 and the other with vacuolar
interface changes,219 the final diagnosis was fatal
SPTL. Multiple wedge biopsies may be necessary to
differentiate the TCR-SPTL (SPTL-AB) or the
more ominous TCR (SPTL-GD) subcutaneous lymphoma from benign LEP.214,216,217 Hemophagocytocytic syndrome has been reported in SLE with
panniculitis,220 but is more common in patients with
SPTL-AB and SPTL-GD.216
Direct immunofluorescence biopsies are very helpful in the diagnosis of LEP, with positive findings in
almost all SLE-associated LEP, and a high percentage
of positive findings in LEP alone.193,195 Blood vessel
deposition of immunoglobulins and complement varies.193,195 In those cases in which the histopathology
does not provide a specific diagnosis, immunofluorescence biopsies may demonstrate the essential features
for diagnosis.193
Immunhistochemical studies of LEP show a predominance of lymphocytes, with both T helper
(CD4+) and cytotoxic (CD8+) lymphocytes mixed with
(CD20+) B cells and plasma cells.196
Polyclonal findings are seen upon analysis of the
TCR- gene,196 although there are additional reports
that LEP can also show clonality, respond to antimalarials or corticosteroids, and not progress to
clinical lymphoma, suggesting that some cases of
LEP may represent an abortive lymphoid dyscrasia. 221
In one study of biopsies from six patients with active
LEP, high levels of type I interferon marker MxA were
found in the epidermis and infiltrate of inflamed LEP
lesions, along with numerous CD123+ cells with plasmacytoid morphology and expression of interferon
inducible protein (IP10)/CXCL10. Sixty to ninety percent of the infiltrating cells in the lobular infiltrates
comprised cytotoxic CXCR3+ lymphocytes expressing
granzyme B and Tia1, leading to the conclusion that a
type 1 interferon-driven immune response was present
in active LEP lesions.222
In addition to SPTL, the differential diagnosis of LEP
includes panniculitis associated with DM or morphea,
as well as other panniculitides that may occur in
patients with SLE such as pancreatic panniculitis and
EN.
Clinical
Erythematous painful nodules and plaques
on the arms, buttocks, thighs, and abdomen.
Histopathology
Mostly lobular or mixed septal and lobular
panniculitis.
Lobular lymphocytic and plasma cell
infiltrate, hyaline sclerosis of septal collagen
bundles, progressive fibrosis of fat lobules.
Calcification in 25% of cases may have
vacuolar alteration at dermalepidermal
junction; membranocystic change may be
present in late-stage lesions.
Treatment
Same as for dermatomyositis.
TREATMENT
Treatment is challenging and difficult, and there are
no easily verifiable assessment tools to judge response
to therapy other than clinical assessment of erythema,
induration, and tenderness.223 Antimalarials are usually the first-line treatment for LEP193,194,197,224 and may
be the only medications needed.193,224 When monotherapy with hydroxychloroquine is ineffective,
combination with quinacrine has been used successfully.194,225 Antimalarials have a lesser effect in smokers,226228 requiring at least 3 months to show
effectiveness.194 Antimalarials interfere with inflammatory cytokines229 as well as TLRs.210 The effect of
EPIDEMIOLOGY
Clinical signs of panniculitis in association with DM
are very rare, despite histopathological findings of
focal nonspecific panniculitis in 9% (5/55) of biopsy
specimens from patients with Diabetes Mellitus
(DM).193,238 In a 2009 literature review of clinical panniculitis with nodular and plaque lesions in DM
patients, 24 cases were identified, including six in
children.239
749
10
CLINICAL FINDINGS
Panniculitis associated with DM presents as painful
indurated erythematous nodules and plaques on the
arms, buttocks, thighs, and abdomen; these may ulcerate and result in lipoatrophy.240,241 The nodules and
plaques usually present in association with the characteristic cutaneous manifestations of DM. They are
rarely the sole manifestation.53,242 Juvenile DM is also
known to result in lipoatrophy without preceding clinical panniculitis lesions.
Section 10
HISTOPATHOLOGY
::
Histopathological features are similar to those of lupus

panniculitis,53 consisting of a mostly lobular panniculitis, or mixed lobular and septal panniculitis, with lymphocytic and plasma cell infiltrates, hyaline sclerosis
and fibrosis of septal collagen bundles, progressive
replacement of the fat by fibrosis, and calcification in
25% of cases.53,193,239 Lesions may be associated with
vacuolar alteration of the dermalepidermal junction,
and late features may include membranocystic
change.53 Dermal findings include mucin deposition or
edema with perivascular lymphocytic inflammation.243
The main differential diagnoses are cellulitis, infectionassociated panniculitis, and lupus panniculitis, which
can be distinguished by a combination of clinical, laboratory, and histological findings.
CLINICAL COURSE
The panniculitis may precede, occur with, or appear
late in the disease course,240 and subsides and flares
with the overall DM activity.244 Infection can cause
worsening of the panniculitis. Three patients have had
infection associated with the panniculitis, two with
S. aureus [including an immunosuppressed adolescent
with both methicillin-resistant S. aureus (MRSA) and
Acinetobacter baumanii] and one with Mycobacterium
chelonae.239 Membranocystic changes indicated a worse
prognosis.239
TREATMENT
750
As in therapy for DM, treatment for DM-associated

panniculitis consists of corticosteroids alone,239 or
corticosteroids and methotrexate,242,244 or other immunosuppressive therapies such as azathioprine, cyclosporine, or IVIG.240 Response of panniculitis in juvenile
DM to hydroxychloroquine has been variable.245
Patients with cutaneous calcification may benefit from
treatment with IVIG.246 Infection should be aggressively sought and identified prior to increasing immunosuppressive therapy; concurrent infection may
require antibiotic therapy and reduction in immunosuppression.239
Panniculitis may also occur in patients with morphea

(see Chapter 64) or systemic sclerosis (see Chapter 157).
CYTOPHAGIC HISTIOCYTIC
PANNICULITIS
CYTOPHAGIC HISTIOCYTIC
PANNICULITIS AT A GLANCE
Clinical findings
Subcutaneous erythematous to violaceous
plaques and nodules on extremities, trunk,
less frequently elsewhere; lesions ulcerate.
Fever, hepatosplenomegaly, two or more
cytopenias; hemocytophagocytosis in bone
marrow, lymph nodes, liver, or CNS.
Hypertriglyceridemia, ferritin >500 mg/L;
increased soluble CD25, CD163 levels.
Low or absent NK cell activity, fibrinogen
levels.
Rapidly fatal disease course; intermittent
remissions and exacerbations prior to death;
or nonfatal acute or intermittent course.
Histopathological findings
vasculitis.
Histiocytes and mature lymphocytes within
fat lobules.
Bean-bag cells: macrophages that contain
intact or fragmented erythrocytes, leukocytes
or platelets within their cytoplasm; may be
focal, hard to find.
Necrosis of adipocytes.
Treatment
Immunosuppressive therapy:
glucocorticosteroids, in combination with
cyclosporine or etoposide, combined
chemotherapeutic medications, anakinra;
supportive care; search for associated
malignancies and infections.
SUBCUTANEOUS FAT NECROSIS

OF THE NEWBORN
EPIDEMIOLOGY
Subcutaneous fat necrosis of the newborn (SCFN) is a
rare panniculitis that occurs in the first few weeks of
SUBCUTANEOUS FAT NECROSIS OF

THE NEWBORN AT A GLANCE
Clinical
Circumscribed, red to violaceous,
subcutaneous nodules, or plaques with
predilection for buttocks, shoulders, cheeks,
and thighs.
Hypercalcemia in some cases, even
presenting much later than acute episode;
rarely, hypertriglyceridemia, hypoglycemia,
thrombocytopenia, anemia.
Treatment
Nodules and plaques usually resolve
spontaneously.
Monitor for hypercalcemia for 6 months
following onset, treat if hypercalcemia
develops.
life. It presents in full-term newborns with a preceding history of perinatal problems, including meconium aspiration, asphyxia, hypothermia (e.g., for
cardiac surgery or ice pack application for supraventricular tachycardia), hypoxemia, seizures, sepsis, preeclampsia, factors requiring cesarean section, forceps
delivery, severe neonatal anemia, maternal cocaine
use, and/or failure to thrive.279287 SCFN may be complicated by hypercalcemia, and rarely, by hypertriglyceridemia, hypoglycemia, thrombocytopenia, and
anemia.282284

The cause in not known, but hypothermia or hypoxia
is presumed to be involved. Possible explanations
have included a biochemical defect in the composition
or metabolism of neonatal fat, leading to crystallization, fat necrosis, and subsequent inflammation after
cold stress.283,288 The hypercalcemia may be related to
increased levels of 25-hydroxyvitamin D31 hydroxylase within the granulomatous infiltrate of lesions.289
Another explanation takes into account the presence of
BAT in neonates along with its main function, which is
to rapidly convert fat stores to heat under conditions of
Panniculitis
Needle-shaped clefts, often in radial

array, within cytoplasm of histiocytes and
multinucleated giant cells.
Lesions are sharply demarcated, erythematous to violaceous, firm, indurated nodules, or plaques located on
the back, shoulders, arms, buttocks, thighs, or face, but
usually not on the anterior trunk279,283 (Fig. 70-15A). In
one case, MRI findings consistent with fat necrosis
were seen in the abdominal wall as well as in the fat
surrounding the liver, spleen, and a kidney.293 The subcutaneous nodules range in size from several millimeters to up to 11 cm in greatest dimension,280,294 may be
single or multiple, and may be of irregular shape,
although usually well defined.280 Rarely, fluctuant nodules may drain an oily or chalky white material.294
Lesions are not warm to touch280 and may vary from
entirely painless280 to those requiring morphine for
control of pain.284
::
Dense inflammatory infiltrate of

lymphocytes, histiocytes, lipophages, and
multinucleated giant cells.
CLINICAL FINDINGS
10
Chapter 70
Histopathology
vasculitis.
cold stress.290 BAT is widely distributed in the early

years of life. At its maximal size relative to body weight
at birth, when nonshivering heat generation is most
needed, the presence and function of BAT relates to the
immaturity of the heat regulating mechanism, providing the young with a thermogenic jacket.25,290
The BAT cells leak hydrogen ions across the inner
membrane of the mitochondria to generate heat
instead of creating ATP for other metabolic processes.291
The mechanism is complex, and uses uncoupling protein isoform 1 (UCP1), found specifically in BAT, cytosolic fatty acids, and Ca2+ ions.292
HISTOPATHOLOGY
Characteristically, SCFN is a mostly lobular panniculitis (Fig. 70-15B), with focal necrosis of the fat lobule
and a dense inflammatory infiltrate of lymphocytes,
histiocytes, and foreign body giant cells; a few eosinophils may insinuate between the fat cells. Many adipocytes retain their cellular outlines, but contain fine
eosinophilic strands and granules as well as needleshaped clefts in radial array53,98,283,295 (Fig. 70-15C). On
frozen section, these clefts are occupied by doubly
refractile crystals, representing triglycerides. Similar
clefts and crystals may also be seen within the cytoplasm of the multinucleated giant cells.53,98,282,295 Late
stage lesions may demonstrate fibrosis and calcified
areas within fat lobules; the latter may also be seen
radiographically.53,280
Differential diagnoses include cellulitis, erysipelas,
and cold panniculitis (if cold-induced).285,286 In contrast to SCFN, the histopathology of cold panniculitis does not feature the presence of needle-shaped
clefts within the subcutaneous AT.286 Other childhood panniculitides with the histologic finding of
needle-shaped clefts in subcutaneous fat include
sclerema neonatorum, which manifests with diffuse
skin hardening in stressed infants,296 and poststeroid
751
10
Section 10
::
Figure 70-14 Cytophagic histiocytic panniculitis. A. Multiple

erythematous plaques and nodules on lower extremity. B. Lowpower histologic image shows lobular panniculitis. C. Diagnostic cytophagocytic bean bag cells in the adipose tissue.
panniculitis.297299 Only one infant with the clinical

findings of both the diffuse hardening of the skin of
sclerema and the violaceous nodules of SCFN has
been described.300 Poststeroid panniculitis occurs in
children, usually within 10 days (range, 140 days)
after rapid cessation of high-dose systemic corticosteroid therapy.297,298
CLINICAL COURSE
752
SCFN is usually a benign process with an uncomplicated course and excellent prognosis. Lesions regress
in a few weeks to 6 months, with some eventuating in
atrophy.283,284,293 However, there are several metabolic
complications that may occur during and even after

resolution of the panniculitis.283 These include hypercalcemia,280,282,284,293,294 thrombocytopenia,282,283 hypertriglyceridemia, which appears to be related to the fat
necrosis283,284 and anemia.283 Hypercalcemia may be
asymptomatic and uncomplicated,281,284 or may become
symptomatic, with failure to thrive, irritability, fever,
vomiting, hypotonia, seizures, polyuria and polydypsia, and even death.280,294 Soft tissue calcification may
occur and resolve without evidence of hypercalcemia,280 or calcium may deposit in the kidneys and cardiovascular system.282284 The hypercalcemia may have
a delayed onset up to 6 months after appearance of the
skin lesions; therefore, serial monitoring of serum calcium levels is necessary.283,284
10
Chapter 70
::
Panniculitis
Figure 70-15 Subcutaneous fat necrosis of the newborn. A. Circumscribed indurated subcutaneous nodules on the back.
B. Scanning power shows mostly lobular pannicultis. C. Higher magnification shows narrow needle-shaped clefts of adipocytes, histiocytes, and multinucleated giant cells.
TREATMENT
SCFN nodules resolve spontaneously, and treatment
should be conservative in most cases, except for fluctuant lesions that may benefit from aspiration to prevent
rupture, infections, necrosis, and scarring.282,283 Serum
calcium should be monitored with serial calcium determinations. If hypercalcemia is present, management by a
pediatric endocrinologist will include hydration, use of
the calcium wasting diuretic furosemide, and a low calcium and vitamin D diet.283,294 The diuretics that increase
calcium excretion may also induce dehydration, requiring careful monitoring. If these measures are insufficient
to control hypercalcemia, systemic glucocorticoids are
used, as they interfere with vitamin D metabolism and
inhibit active vitamin D production by the macrophages
in the inflamed AT279,283,294; however, nephrocalcinosis
may still develop in spite of response to systemic steroids.301 First and second generation bisphosphonates,
including etidronate,302,303 clodronate,304 and pamidronate,305 have been used to treat hypercalcemia in SCFN.
However, nephrocalcinosis may develop, despite a rapid
response to pamidronate.306 The degree and duration of
hypercalcemia and hypercalciuria may be the important
factor in development of nephrocalcinosis; this calls for
close early monitoring and recognition of hypercalcemia, since rapid therapeutic intervention to lower serum
and urine calcium may be the best treatment modality
for prevention of dystrophic calcification.306
COLD PANNICULITIS
COLD PANNICULITIS AT A GLANCE
Clinical
Circumscribed, red to violaceous, subcutaneous
nodules or plaques on the face and thighs, and
rarely of the scrotal fat in prepubertal boys.
Follows exposure to cold weather, popsicles,
ice packs, and swimming in cold ocean water.
Histopathology
Mostly lobular panniculitis (lymphohistiocytic
or mixed infiltrate) without vasculitis.
Perivascular lymphohistiocytic infiltrate
involving blood vessels at dermosubcutaneous
junction and within overlying dermis.
Findings similar to those seen in perniosis.
Treatment
Avoid direct ice placement on skin, mucous
membranes.
Spontaneous resolution within 3 months.
753
10
FACTITIAL PANNICULITIS
FACTITIAL PANNICULITIS
AT A GLANCE
Clinical
Erythematous nodules with disparate
location or appearance in patients with
personality aberrations.
Section 10
Subcutaneous implantation range from

medications, cosmetic fillers, oils, food to
human waste.
Histopathology
vasculitis.
::
Suppurative granuloma involving the

fat lobule; requires cultures for various
organisms.
Polarization of the slide may identify the
refractile foreign material.
Panniculitis morphology, such as histiocyte
characteristic inclusions, or cystic spaces
with foreign substances may vary with type
of injected material.
Treatment
Psychiatric treatment for self-inflicted
factitial panniculitis.
Supportive care and interference with
injection of responsible agents.
In panniculitis induced by cosmetic
fillers, intralesional steroids, and often
the implanted material must be surgically
excised.
754
Factitial panniculitis is a reaction in AT induced by

external factors, usually injection of foreign materials.
This may be iatrogenic due to injection of medications
or cosmetic fillers, or secondary to cupping and acupuncture,320 or other means of trauma (accidental or
deliberate). Factitial panniculitis is also associated with
self-induced injections of various substances due to
psychiatric disorder. History obtained from patients of
injections of therapeutic agents or cosmetic fillers aids
the diagnosis. Self-inflicted factitial panniculitis due to
substances that may not necessarily leave a recognizable clinical or histopathologic footprint may be difficult to diagnose and requires a high index of
suspicion.53,320322 Factitial lesions present a spectrum of
clinical findings, from papules and nodules to erosions
or ulcerations with perfect round or angulated appearance322 (Fig. 70-16). Lesions due to blunt trauma will
Figure 70-16 Factitial panniculitis. Self-induced round

and angulated ulceration on the leg at sites of injections
and trauma.
often be ecchymotic, show organized hematomas and
hemosiderin deposits.322 Injections of various oily substances will lead to foreign body reactions with foamy
histiocytes and pseudocystic spaces.53,322 Injection of
medication and various other substances such as acids,
milk, mustard, acids, alkalis, infected/contaminated
materials, urine, and feces have been reported.53,322
Early lesional histopathology is usually predominantly
neutrophilic, and later may show a granulomatous
infiltrate.53,234 Due to the presence of macrophages and
lymphocytes in AT, as well as the adipocytes role as an
innate immune cell producing multiple cytokines,
materials injected into AT are treated as a foreign agent,
with an inflammatory immune response with or without associated fat necrosis.53,234 Patients with selfinduced factitial panniculitis suffer from mental illness
and require psychiatric care.53,234 If iatrogenic, the causative action must cease. Surgical excision of the injected
materials may be necessary.320,322
KEY REFERENCES
5. Fantuzzi G: Adipose tissue, adipokines and inflammation. J Allergy Clin Immunol 115:911, 2005
27. Requena L, Sanchez Yus E: Panniculitis. Part I. Mostly
septal panniculitis. J Am Acad Dematol 45:163, 2001
52. Segura S et al: Vasculitis in erythema induratum of Bazin:
A histopathologic study of 101 biopsy specimens from 86
patients. J Am Acad Dermatol 59:839, 2008
53. Requena L, Sanchez Yus E: Panniculitis. Part II. Mostly

lobular panniculitis. J Am Acad Dermatol 45:325, 2001
78. Bruce AJ et al: Lipodermatosclerosis: Review of cases
evaluated at Mayo Clinic. J Am Acad Dermatol 46:187,
2002
129. Morrison LK et al: Infections and panniculitis. Dermatol
Ther 23(4):328-340, 2010
193. Winkelmann RK: Panniculitis in connective tissue diseases. Arch Dermatol 119:336, 1983
223. Hansen C, Callen J: Connective tissue panniculitis. Dermatol Ther 23(4):341-349, 2010
251. Crotty CP, Winkelmann RK: Cytophagic histiocytic panniculitis with fever, cytopenia, liver failure and terminal
hemorrhagic diathesis. J Am Acad Dermatol 4:181, 1981
LIPODYSTROPHY AT A GLANCE
Four loci have been identified for autosomal

dominant familial partial lipodystrophy
(FPL), namely, (1) LMNA, (2) PPARG, (3)
AKT2, and (4) PLIN1.
CIDEC is the locus for autosomal recessive
FPL, and LMNA and ZMPSTE24 are loci
for autosomal recessive mandibuloacral
dysplasia-associated lipodystrophy.
Molecular basis of many rare forms of
genetic lipodystrophies remains to be
elucidated.
The most prevalent variety of lipodystrophy
develops after prolonged duration of protease
inhibitor containing highly active antiretroviral
therapy in HIV-infected patients.
The acquired generalized lipodystrophy and
acquired partial lipodystrophy are mainly
autoimmune in origin.
Localized lipodystrophies occur due to drug
or vaccine injections, pressure, panniculitis,
and other unknown reasons.
The current management includes cosmetic

surgery and early identification and treatment
of metabolic and other complications.
Lipodystrophy
Four loci have been identified for the

autosomal recessive congenital generalized
lipodystrophy (CGL), namely, (1) AGPAT2,
(2) BSCL2, (3) CAV1, and (4) PTRF.
::
Lipodystrophies are genetic or acquired

disorders characterized by selective loss of
body fat. The extent of fat loss determines
the severity of associated metabolic
complications such as diabetes mellitus,
hypertriglyceridemia, hepatic steatosis, and
acanthosis nigricans.
Lipodystrophies are a heterogeneous group of disorders characterized by selective loss of adipose tissue.1
The extent of fat loss varies, with some patients losing
fat from small areas (localized lipodystrophy),
whereas others may have more extensive fat loss, for
example, involving the extremities (partial lipodystrophy) or the entire body (generalized lipodystrophy). Depending upon the extent of fat loss, patients
may be predisposed to develop complications associated with insulin resistance such as, diabetes mellitus, dyslipidemia, hepatic steatosis, acanthosis
nigricans, polycystic ovarian disease, and coronary
heart disease.2,3 There are two main types of lipodystrophies: (1) genetic and (2) acquired. A detailed classification of various types of lipodystrophies is given
in Table 71-1.
Chapter 71
Chapter 71 :: Lipodystrophy

:: Abhimanyu Garg
10
GENETIC LIPODYSTROPHIES
In the last decade or so, considerable progress has
been made in elucidation of the molecular basis of
many types of genetic lipodystrophies. In general,
mutations in genes involved in adipocyte differentiation, triglyceride synthesis, lipid droplet formation,
and adipocyte survival have been reported to cause
lipodystrophies.
EPIDEMIOLOGY
Although the genetic lipodystrophies are rare, recent
advances such as improved definition of the phenotypes and elucidation of the molecular defects, have
led to increased recognition of these syndromes. Overall, based on literature reports of less than 1,000
patients, the estimated prevalence of genetic lipodystrophies may be less than 1 in a million. The autosomal recessive, congenital generalized lipodystrophy
(CGL) has been reported in fewer than 300 patients,
with clustering of patients reported from Lebanon and
Brazil where there is increased prevalence of consanguinity. The autosomal dominant, familial partial
lipodystrophy (FPL) of the Dunnigan variety due to
LMNA mutations is the most common with 500
patients being reported; autosomal dominant, FPL
due to PPARG mutations with 30 patients; autosomal
755
10
TABLE 71-1
Classification of Lipodystrophies
Section 10
::
756
A. Genetic Lipodystrophies
1.Autosomal recessive, congenital generalized
lipodystrophy (CGL)
a. Type 1: AGPAT2 mutations
b. Type 2: BSCL2 mutations
c. Type 3: CAV1 mutation
d. Type 4: PTRF mutations
e. Others
2.Autosomal dominant, familial partial lipodystrophy
(FPL)
a. Dunnigan variety: LMNA mutations
b. PPARG mutations
c. AKT2 mutation
d. PLIN1 mutations
e. Others
3. Autosomal recessive, familial partial lipodystrophy
a. CIDEC mutation
4.Autosomal recessive, mandibuloacral dysplasia (MAD)associated lipodystrophy
a. LMNA mutations
b. ZMPSTE24 mutations
c. Others
5. Other lipodystrophies associated with LMNA mutations
a. Atypical progeroid syndrome
b. HutchinsonGilford progeria syndrome
6. SHORT syndrome
a. Autosomal recessive
b. Autosomal dominant
7.Neonatal progeroid (WeidemannRautenstrauch)
syndrome
8.Mandibular hypoplasia, deafness, progeroid (MDP)
syndrome
9.Joint contractures, microcytic anemia, panniculitisassociated (JMP) lipodystrophy syndrome spectrum
a. PSMB8 mutations
9a.Chronic atypical neutrophilic dermatosis with
ipodystrophy and elevated temperature (CANDLE)
syndrome
B. Acquired Lipodystrophies
1.Highly active antiretroviral therapy-induced
lipodystrophy in HIV-infected patients
2. Acquired generalized lipodystrophy
a. Panniculitis-induced
b. Autoimmune diseases-associated
c. Idiopathic
3. Acquired partial (BarraquerSimons) lipodystrophy
a. Autoimmune diseases-associated
b.Membranoproliferative glomerulonephritisassociated
c. Idiopathic
4. Localized lipodystrophies
a. Panniculitis-induced
b. Pressure-induced
c. Drug-induced
d. Centrifugal
e. Idiopathic
recessive, mandibuloacral dysplasia (MAD) due to

LMNA mutations in 30 patients and due to ZMPSTE24 mutations in eight patients. Affected females
are recognized easily and thus are reported more often
than males.
CONGENITAL GENERALIZED
LIPODYSTROPHY (CGL,
BERARDINELLISEIP SYNDROME)
ETIOLOGY AND PATHOGENESIS. This autosomal recessive disorder can be recognized at birth or
soon thereafter due to near total lack of body fat.
Genome-wide linkage analysis with positional cloning
strategy and candidate gene approach have led to
the identification of four genetic loci for CGL: (1)
1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2)
gene on chromosome 9q34,4,5 (2) BerardinelliSeip congenital lipodystrophy 2 (BSCL2) gene on chromosome
11q13,6 (3) caveolin 1 (CAV1) gene on chromosome
7q31,7 and (4) polymerase I and transcript release factor
(PTRF) on chromosome 17q21.8 AGPAT2 is a critical
enzyme involved in the biosynthesis of triglycerides
and phospholipids from glycerol-3-phosphate and is
expressed highly in the adipose tissue.9 The BSCL2encoded protein, seipin, plays a role in lipid droplet formation and may also be involved in adipocyte
differentiation.1012 Caveolin 1 is an integral component
of caveolae, specialized microdomains seen in abundance on adipocyte membranes. Caveolin 1 binds fatty
acids and translocates them to lipid droplets. PTRF is
involved in biogenesis of caveolae and regulates expression of caveolins 1 and 3.8
CLINICAL FINDINGS. Patients with CGL present
with near total loss of body fat, marked muscularity,
prominent subcutaneous veins, acromegaloid features,
acanthosis nigricans, hepatomegaly, and umbilical prominence or hernia (Fig. 71-1A, Table 71-2). During childhood, they have a voracious appetite, and accelerated
linear growth. Females usually have hirsutism, clitoromegaly, oligoamenorrhea, and polycystic ovaries. Only a
few women have had successful pregnancies. Fertility is
normal in men. Some of them develop hypertrophic cardiomyopathy, mild mental retardation, and focal lytic
lesions in the appendicular bones after puberty.1315 Metabolic abnormalities related to insulin resistance, such as
diabetes mellitus, hyperlipidemia, and hepatic steatosis,
may manifest at a young age and are often difficult to
control. Patients with BSCL2 mutations lack mechanical
fat located in the retro-orbital region, palm, sole, and in
periarticular regions as well as metabolically active
adipose tissue located in the subcutaneous (sc), intraabdominal, intrathoracic, and other areas as compared to
those with AGPAT2, CAV1, and PTRF mutations where
mechanical fat is preserved.7,16 The only reported patient
with CAV1 mutation also had short stature and presumed
vitamin D resistance.7 Only 21 patients with PTRF mutations have been reported and they have congenital
myopathy, increased creatine kinase levels, percussioninduced myoedema, pyloric stenosis, cardiac rhythm
disturbances including prolonged QT interval, exerciseinduced ventricular tachycardia, and atlantoaxial instability.8,17,18 Patients of Lebanese origin harbor homozygous
c.659delGTATC mutation in BSCL2, whereas those of
African origin nearly always have either homozygous or
compound heterozygous c.IVS42A>G mutation in
AGPAT2 gene.5,6,13
10
Chapter 71
::
Figure 71-1 Clinical features of patients with various types of lipodystrophies. A. Anterior view of a 33-year-old Hispanic
female with congenital generalized lipodystrophy (also known as BerardinelliSeip congenital lipodystrophy), type 1 due
to homozygous c.IVS42A>G mutation in AGPAT2 gene. The patient had generalized loss of sc fat with acanthosis nigricans
in the axillae and neck. She has umbilical prominence and acromegaloid features (enlarged mandible, hands, and feet).
B. Anterior view of a 27-year-old Native American Hispanic female with familial partial lipodystrophy of the Dunnigan
variety due to heterozygous p.Arg482Trp mutation in LMNA gene. She had marked loss of sc fat from the limbs and anterior truncal region. The breasts were atrophic. She had increased sc fat deposits in the face, anterior neck, and vulvar
regions. C. Anterior view of an 8-year-old German boy with acquired generalized lipodystrophy. He had severe generalized
loss of sc fat with marked acanthosis nigricans in the neck, axillae, and groin. D. Anterior view of a 39-year-old Caucasian
female with acquired partial lipodystrophy (BarraquerSimons syndrome). She had marked loss of sc fat from the face,
neck, upper extremities, and chest, but had lipodystrophy on localized regions on anterior thighs. She had increased sc
fat deposition in the lower extremities. E. Lateral view of a 53-year-old Caucasian male infected with human immunodeficiency (HIV) virus with highly active antiretroviral therapy-induced lipodystrophy. He had marked loss of sc fat from the
face and limbs, but had increased sc fat deposition in the neck region anteriorly and posteriorly showing buffalo hump.
Abdomen was protuberant due to excess intra-abdominal fat. He had been on protease inhibitor-containing antiretroviral
therapy for more than 8 years.
FAMILIAL PARTIAL
LIPODYSTROPHY (FPL)
ETIOLOGY AND PATHOGENESIS. FPL is an
autosomal dominant disorder characterized by fat loss
from the limbs with variable fat loss from the trunk
and increased sc fat deposition in nonlipodystrophic
regions (Fig. 71-1B). It results from heterozygous missense mutations in one of the four genes: (1) lamin
A/C (LMNA) on chromosome 1q2122,1922 an integral
component of nuclear lamina; (2) peroxisome proliferator-activated receptor (PPARG) on chromosome
3p25,2325 a key transcription factor involved in adipocyte differentiation; (3) v-AKT murine thymoma oncogene homolog 2 (AKT2) on chromosome 19q13,26
involved in downstream insulin signaling; and (4) perilipin 1 (PLIN1) on chromosome 15q26, a key component of lipid droplets.27 Adipocyte loss in patients with
Lipodystrophy
LMNA mutations may be due to disruption of nuclear

envelope function and integrity resulting in premature
cell death.
CLINICAL FINDINGS. Patients with FPL have normal body fat distribution during early childhood, but
around the time of puberty, sc fat from the extremities
and trunk is progressively lost (Fig. 71-1B). The face,
neck, and intra-abdominal region are spared, and often
excess fat accumulates there.28,29 Affected men are often
more difficult to diagnose clinically, as many normal
men are also quite muscular. Women are more severely
affected metabolically.30 Some patients with mutations
in amino-terminal region of lamin A/C also develop
myopathy, cardiomyopathy, and conduction system
abnormalities indicative of a multisystem dystrophy.31
On the other hand, others with mutations in the
extreme C-terminal region of lamin A may have mild
lipodystrophy.32
757
10
TABLE 71-2
Clinical Features of Various Types of Congenital Generalized Lipodystrophy (CGL)

Subtype of CGL
Section 10
::
Characteristic
CGL1
CGL2
CGL3
CGL4
Gene
AGPAT2
BSCL2
CAV1
PTRF
Loss of metabolically active adipose

tissue
+++
+++
++
++
Loss of mechanical adipose tissue
Bone marrow fat
Lytic bone lesions
++
Mild mental retardation
Cardiomyopathy
Echocardiogram
Normal
Abnormal
Normal
Normal
Catecholaminergic polymorphic
ventricular tachycardia (CPVT)
Prolonged QT interval
Sudden death
Congenital pyloric stenosis
Atlantoaxial instability
Acanthosis nigricans
+++
+++
++
+/
Hepatomegaly
Congenital myopathy
Diabetes mellitus
Hypertriglyceridemia
Hypocalcemia
Hyperinsulinemia
Nearly 30 patients with FPL due to heterozygous

mutations in PPARG gene have been reported so far.
They have more marked fat loss from the extremities,
especially from distal regions, but the fat from the face,
neck, and truncal area is spared. There is increased
prevalence of hypertension among the affected subjects. Four subjects from a single family with diabetes
and insulin resistance were reported to harbor a heterozygous mutation in AKT2 gene. The female proband had lipodystrophy of the limbs although detailed
studies of body fat distribution were not performed.
Recently, five FPL patients were reported to harbor
PLIN1 mutations.27
MANDIBULOACRAL DYSPLASIA (MAD)

ASSOCIATED LIPODYSTROPHY
ETIOLOGY AND PATHOGENESIS. Mutations in
758
LMNA and zinc metalloproteinase (ZMPSTE24) on

chromosome 1p34 also result in autosomal recessive,
MAD-associated lipodystrophies.33,34 ZMPSTE24 is
involved in posttranslational proteolytic processing of
prelamin A to mature lamin A and its deficiency can

result in accumulation of prelamin A in cells which is
supposed to cause toxicity.
CLINICAL FINDINGS. Patients with MAD have

characteristic skeletal abnormalities including hypoplasia of the mandible and clavicles, acroosteolysis,
cutaneous atrophy, progeroid features such as thin
beaked nose, hair loss, thin skin with prominent superficial vasculature and mottled hyperpigmentation,
delayed dentition and closure of cranial sutures, joint
stiffness, and lipodystrophy.35,36 Those with ZMPSTE24
mutations develop clinical manifestations earlier in life,
are premature at birth, and can develop focal segmental
glomerulosclerosis and calcified skin nodules.37,38
OTHER TYPES
ETIOLOGY AND PATHOGENESIS. Recently, a
single patient with autosomal recessive, FPL phenotype was found to harbor a homozygous missense
mutation in cell death-inducing DNA fragmentation
10
Despite recognition of acquired lipodystrophies for

more than a century, progress in understanding underlying pathogenetic mechanisms has been slow.
EPIDEMIOLOGY
ACQUIRED PARTIAL LIPODYSTROPHY

(APL, BARRAQUERSIMONS
SYNDROME)
Lipodystrophy
Acquired partial lipodystrophy was recognized

approximately 125 years ago and only 250 cases of
various ethnicities with male-to-female ratio of 1:4
have been reported.51 Acquired generalized lipodystrophy has been reported in less than 100 cases, mostly
Caucasians with a male-to-female ratio of 1:3.52 The
most common type at present is highly active antiretroviral therapy [containing protease inhibitors (PIs)]induced lipodystrophy in human immunodeficiency
virus (HIV)-infected patients, which is estimated to be
affecting more than 100,000 patients in the United
States and many more in other countries.53
::
CLINICAL FINDINGS. We recently reported a

novel autosomal recessive syndrome with mandibular
hypoplasia, deafness, progeroid features (MDP)associated lipodystrophy.45 All males with MDP had
undescended testes and were hypogonadal. One
adult female showed lack of breast development. The
molecular basis of this syndrome remains unclear.
PSMB8 mutations present as a spectrum of clinical
manifestations ranging from onset during the first
months of life46 to later during childhood.47 Early features are recurrent fevers, annular violaceous plaques,
poor weight and height gain, persistent violaceous
eyelid swelling, hepatomegaly, arthralgias variable
muscle atrophy, and progressive lipodystrophy.46 Histopathologic examination of lesional skin shows atypical mononuclear infiltrates of myeloid lineage and
mature neutrophils, and laboratory abnormalities
include chronic anemia, elevated acute-phase reactants, and raised liver enzymes with a cytokine profile
showing high levels of IP-1, MCP-1, IL-6, and IL-1Ra,
consistent with an IFN signaling signature.43 This presentation has been called CANDLE syndrome (Chronic
Atypical Neutrophilic Dermatosis with Lipodystrophy
and Elevated temperature).46 Older individuals with
PSMB8 mutations show joint contractures, muscle
atrophy, microcytic anemia, and panniculitis-induced
(JMP) childhood-onset lipodystrophy.47 Other features
of JMP syndrome include hypergammaglobulinemia,
elevated erythrocyte sedimentation rate, hepatosplenomegaly, and calcification of basal ganglia.42,44a,44b,47
Other rare syndromes of lipodystrophy include
SHORT syndrome, which is characterized by the constellation of Short stature, Hyperextensibility or inguinal hernia, Ocular depression, Rieger anomaly,
and Teething delay.48,49 This syndrome is reported to
have autosomal recessive as well as dominant
inheritance patterns and fat loss is usually confined
to the face, upper extremities, and trunk, and
sometimes the buttocks.48,49 The autosomal recessive,
neonatal progeroid (WeidemannRautenstrauch)
syndrome presents with generalized loss of body
fat and muscle mass and progeroid appearance at
birth.50
ACQUIRED LIPODYSTROPHIES
Chapter 71
factor a-like effector c (CIDEC) gene on chromosome

3p25, involved in lipid droplet formation.39 The histopathology of the sc adipose tissue of the patient
revealed multilocular, small lipid droplets in adipocytes. Heterozygous LMNA mutations can also cause
variable amount of fat loss in patients with atypical
progeroid syndrome40 and generalized loss of sc fat in
HutchinsonGilford progeria syndrome.41 Another distinct autosomal recessive autoinflammatory lipodystrophy syndrome with a spectrum of disease
manifestations (see JMP and CANDLE syndromes
below) results from mutations in proteasome subunit,
beta-type, 8 (PSMB8).42,43,44a,44b PSMB8 encodes the
b5i subunit of the immunoproteasome involved in
proteolytic cleavage of immunogenic epitopes presented by major histocompatibility complex, class I
molecules.44c The molecular genetic basis of many other
genetic lipodystrophy syndromes remains unclear
(Table 71-1).
ETIOLOGY AND PATHOGENESIS. The exact

pathogenesis of sc fat loss remains unclear but there is
strong evidence of autoimmune-mediated adipocyte
loss as more than 80% of the patients have low levels of
complement 3 (C3) and presence of a circulating
immunoglobulin (Ig) G, C3-nephritic factor that blocks
degradation of the enzyme C3 convertase.51 Loss of fat
could be due to C3-nephritic factor-induced lysis of
adipocytes expressing factor D.54
CLINICAL FINDINGS. Acquired partial lipodystrophy develops in most patients before age 15.
Patients lose sc fat gradually in a symmetric fashion
starting with the face and then spreading downwards.
Most of them present with fat loss from the face, neck,
upper extremities, and trunk with sparing of sc abdominal fat and lower extremities (Fig. 71-1C). Approximately, 20% of the patients develop mesangiocapillary
(membranoproliferative) glomerulonephritis, and
some develop drusen.51 Usually, patients do not
develop metabolic complications.
ACQUIRED GENERALIZED
LIPODYSTROPHY (AGL, LAWRENCE
SYNDROME)
ETIOLOGY AND PATHOGENESIS. The exact
mechanisms of fat loss are not known. In approximately
25% of patients, sc fat loss occurs following development of sc inflammatory nodules that on biopsy reveal
panniculitis.52 These lesions initially result in localized
fat loss followed by generalized loss of fat. Another
25% of the patients have associated autoimmune
diseases such as juvenile dermatomyositis.52 In the
759
10
remaining patients with the idiopathic variety, multiple

unknown mechanisms are likely involved.52 Patients
with the panniculitis-associated variety have less
severe fat loss and metabolic complications than seen
in other types.
Section 10
CLINICAL FINDINGS. Acquired generalized lipodystrophies present with variable amount of sc fat loss
usually during childhood. Although many patients
have generalized loss of fat, some areas are spared in
some of them (Fig. 71-1D). Usually, intra-abdominal or
bone marrow fat is spared.52 However, patients
develop extremely severe hepatic steatosis and fibrosis, diabetes, and hypertriglyceridemia, which are difficult to manage.
::
HIGHLY ACTIVE ANTIRETROVIRAL

THERAPY (HAART)-INDUCED
LIPODYSTROPHY IN HIV-INFECTED
PATIENTS
ETIOLOGY AND PATHOGENESIS. Drugs such
as HIV-1 PIs and nucleoside analogs are implicated in
causing lipodystrophy in HIV-infected patients. Many,
but not all, PIs may induce lipodystrophy by inhibiting
ZMPSTE24, resulting in accumulation of prelamin A.55
Other mechanisms may include PI-induced alteration
of expression of key transcription factors involved in
lipogenesis and adipocyte differentiation, such as,
sterol regulatory element-binding protein 1c, and
PPARG.56 PIs also reduce glucose transporter 4 expression, which may be a mechanism for inducing insulin
resistance.57 Nucleoside analogs, especially zidovudine
and stavudine, may induce fat loss by inhibiting
polymerase-, a mitochondrial enzyme involved in replication of mitochondrial DNA.58 Since most patients
receive multiple antiretroviral drugs together, the individual effects of PIs or nucleoside reverse transcriptase
inhibitors (NRTIs) on the phenotype are not clear.
CLINICAL FINDINGS. Patients infected with HIV
usually lose sc fat from the face, trunk, and extremities
2 years or more after receiving PI-containing HAART
(Fig. 71-1E; Figs. 71-2A and 71-2B). Fat loss from the
face can be so severe as to result in an emaciated
appearance. Some of them develop buffalo hump,
double chin, and also gain intra-abdominal fat. The fat
loss progressively gets worse with ongoing HAART
therapy and does not reverse on discontinuation of
PIs. Some cases develop diabetes mellitus and many
develop combined hyperlipidemia that can predispose
the patients to coronary heart disease.59
LOCALIZED LIPODYSTROPHY
ETIOLOGY AND PATHOGENESIS. This can
occur due to sc injection of various drugs, panniculitis,
pressure, and other mechanisms.2
760
CLINICAL FINDINGS. Localized lipodystrophies

present with sc fat loss from a focal region resulting in
a dimple or a crater with overlying skin usually unaffected. In some patients, large contiguous or anatomically distinct areas on any region of the body may be
involved.2
APPROACH TO PATIENT
ALGORITHM
Lipodystrophies should be strongly suspected in lean
or nonobese patients who present with premature
onset of diabetes, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and polycystic ovarian syndrome. These patients should be examined carefully
for evidence of loss of sc fat especially from the hips
and thighs, as well as excess sc fat deposition in various anatomic regions. For those presenting with generalized lipodystrophy during childhood, pictures at
birth should be evaluated for evidence of fat loss. If
lipodystrophy phenotype is discovered at or shortly
after birth, CGL should be considered; otherwise, the
patient may have acquired lipodystrophy.
HISTORY
Patients should be asked about the age of onset and
progression of lipodystrophy and other associated
manifestations. Taking a detailed family history,
including the history of consanguinity, is very important to understand the mode of inheritance of genetic
lipodystrophies. Associated autoimmune diseases,
especially juvenile dermatomyositis, should be considered in patients with acquired lipodystrophies. Those
with localized lipodystrophies should be asked about
local injections, trauma, pressure, or other insults. A
detailed history of duration and type of antiretroviral
therapy should be obtained from HIV-infected patients
with lipodystrophy.
CUTANEOUS LESIONS
The most common cutaneous lesion seen in patients
with lipodystrophies is acanthosis nigricans in the axillae, groins, neck, and sometimes even on the knuckles,
Achilles tendons, and trunk (Figs. 71-3A and 71-3B).
Many patients develop clitoromegaly and hirsutism
due to associated polycystic ovarian syndrome. Freckles have been noted in a patient with atypical progeroid
syndrome (Fig. 71-3C). Thin beaked nose with loss of
the scalp, eyebrow, and axillary hair with cutaneous
atrophy and mottled hyperpigmentation can be seen in
patients with progeroid syndromes and MAD (Fig.
71-3D) along with acroosteolysis (Fig. 71-3E).35,40,41 Rare
patients with MAD develop shiny, taut, atrophic skin
with a tendency to breakdown. Eruptive, tuberous, and
planar xanthomas are also commonly seen in patients
with extreme hypertriglyceridemia (Figs. 71-3F and
71-3G). Loss of sc fat from the soles can result in plantar
calluses. Subcutaneous nodules with overlying erythema may be seen in patients with panniculitis.
10
Chapter 71
::
Lipodystrophy
Figure 71-2 A. Highly active antiretroviral therapy-induced lipodystrophy in a patient with human immunodeficiency
virus (HIV) infection-associated lipodystrophy in a patient receiving highly active antiretroviral therapy. Loss of buccal
fat results in prominence of the zygomatic arch B. Highly active antiretroviral therapy-induced lipodystrophy with loss of
subcutaneous fat from the lateral buttock and deposit in the trunk, causing an increased waisthip ratio.
LABORATORY TESTS
Laboratory testing depends upon the type of lipodystrophy. Except for patients with localized lipodystrophies, a serum chemistry profile for glucose, lipids,
liver enzymes, and uric acid should be obtained. Measurement of fasting and postprandial serum glucose
and insulin during an oral glucose tolerance test can
provide some estimate of insulin resistance. Serum
leptin measurements are not diagnostic, but can help
guide treatment decisions as far as investigational
human recombinant leptin replacement therapy is concerned. Serum leptin and adiponectin levels are very
low in patients with generalized lipodystrophies.60
Patients with acquired partial lipodystrophy should be
tested for serum C3 and C3-nephritic factor and annually checked for proteinuria. Radiographs can show
presence of lytic lesions in appendicular bones in
patients with CGL and skeletal defects in those with
MAD. Skin biopsy is useful for patients with localized
lipodystrophy or panniculitis-associated varieties.
SPECIAL TESTS (INCLUDING

IMAGING STUDIES)
Distinction between various types of lipodystrophies
can be made by physical examination and supported
by anthropometry, including measurement of skinfold
thickness with calipers at various sites. For in-depth

phenotyping of body fat distribution, dual energy
X-ray absorptiometry, and a whole body T-1 weighted
magnetic resonance imaging can be conducted. For
those genetic lipodystrophies whose molecular basis is
known, various commercial and research laboratories
offer genetic testing. Prenatal genetic testing is also feasible. FPL patients and CGL, type 4 patients who are
predisposed to cardiomyopathy should undergo electrocardiography and Holter monitoring to detect
arrhythmias and echocardiography to assess cardiac
function.
The most important differential diagnosis of generalized lipodystrophies is with conditions presenting
with severe weight loss, such as, malnutrition, famine,
starvation, anorexia nervosa, uncontrolled diabetes
mellitus, thyrotoxicosis, adrenocortical insufficiency,
cancer cachexia, HIV-associated wasting, diencephalic
syndrome and chronic infections. For partial lipodystrophies, distinction should be made with Cushing syndrome, generalized and truncal obesity, and multiple
symmetric lipomatosis (Madelung disease). Patients
with MAD and progeroid syndromes-associated
lipodystrophies should be differentiated from those
with Werner syndrome and leprechaunism (Donahue
syndrome).
761
10
Section 10
::
Figure 71-3 Dermatologic manifestations seen in patients with lipodystrophies. A. Acanthosis nigricans (brownish discoloration with thickening of the skin) in the axilla and anterior neck in an 8-year-old Caucasian boy with acquired generalized lipodystrophy. B. Acanthosis nigricans in the perineum and medial parts of the proximal thighs in a 37-year-old
female with familial partial lipodystrophy (FPL). Multiple, small skin tags accompany increased pigmentation and thick
skin. C. Multiple, slightly hyperpigmented flat plaques (freckles) in a 7-year-old boy with atypical progeroid syndrome due
to heterozygous p.Cys588Arg mutation in LMNA gene. D. Loss of hair from the posterior scalp region in a 5-year-old girl
with severe mandibuloacral dysplasia (MAD) due to homozygous p.Arg527Cys mutation in LMNA gene. She had narrow
shoulders due to clavicular hypoplasia. E. Acroosteolysis in a 20-year-old Hispanic woman with MAD due to homozygous
p.Arg527His mutation in LMNA gene. The terminal digits appear short and bulbous due to resorption of the terminal
phalanges. The skin on the dorsum of the hand is atrophic, especially over the proximal interphalangeal and metacarpophalangeal joints. F. Tuberous xanthomas over the middle finger of a 45-year-old Caucasian patient with severe hyperlipidemia associated with FPL of the Dunnigan variety due to heterozygous p.Arg482Gln mutation in LMNA gene. G. Planar
xanthomas on the sole of the patient described in F. (Panel C reproduced with permission from Garg A et al: Atypical
progeroid syndrome due to heterozygous missense LMNA mutations. J Clin Endocrinol Metab 94:4971-4983, 2009. Copyright 2009, The Endocrine Society. Panel G reproduced with permission from Simha V, Garg A: Lipodystrophy: lessons in
lipid and energy metabolism. Current Opin Lipidol 17:162-169, 2006. Wolters Kluwer/Lippincott Williams & Wilkins.)
COMPLICATIONS
762
Some patients develop extreme hypertriglyceridemia

and chylomicronemia, which result in acute pancreatitis
and even death. Long-term complications of diabetes
such as nephropathy, neuropathy, and retinopathy are
frequently seen. Many patients develop coronary heart
disease and other atherosclerotic vascular complications.30,61 Hepatic steatosis can lead to cirrhosis, necessitating liver transplantation. Sudden death has been
reported during childhood in CGL, type 4, likely due to
arrhythmias.17 Some patients with APL and membranoproliferative glomerulonephritis may require kidney
transplantation.51 Patients with HutchinsonGilford
progeria syndrome die of acute myocardial infarction or
cerebrovascular accidents during teenage years.62 Some

patients with atypical progeroid syndrome and FPL,
Dunnigan develop cardiomyopathy with valvular dysfunction, congestive heart failure, and arrhythmias
requiring pacemaker implantation.31,40 Two adult
patients with MAD due to ZMPSTE24 mutations have
died of renal failure due to focal segmental glomerulosclerosis.37
The prognosis is dependent upon the type of lipodystrophy. Most of the published cases of CGL have been
children and thus there is lack of data about their prog-
With the discovery of the molecular genetic basis of

many types of inherited lipodystrophies, prenatal
diagnosis can be offered for those families with an
affected child. Premarital genetic counseling can be
provided to those with high prevalence of consanguinity and CGL such as those from Lebanon and certain
regions of Brazil. If the newer HAART regimen (not
including PIs) are proven not to be associated with
lipodystrophy and are deemed to be efficacious and
safe, we may be able to prevent development of lipodystrophy in HIV-infected patients.
Lipodystrophy
Treatment of various types of lipodystrophies is quite

challenging. There is no specific treatment available to
reverse the loss of body fat. The mainstay of treatment
includes cosmetic surgery and management of complications. Patients with partial lipodystrophies can
undergo autologous adipose tissue transplantation or
implantation of dermal fillers such as hyaluronic acid,
calcium hydroxylapatite, silicone, polyacrylamide
gels, or poly-L-lactic acid.64 Unwanted excess adipose
tissue can be surgically excised or removed by liposuction. Those with CGL can undergo reconstructive facial
surgery including fascial grafts from thighs, free flaps
from anterolateral thigh, anterior abdomen, or temporalis muscle.1 Support of the parents is critical for preventing unwanted stress and psychological sequelae
in children affected with lipodystrophies.
All patients are advised to consume low-fat diets.
These diets can improve chylomicronemia in patients
with extreme hypertriglyceridemia. However, high
carbohydrate intake may also raise very low-density
lipoprotein triglyceride concentrations. Increased
physical activity should be encouraged to mitigate
insulin resistance and its complications except in those
with FPL who have cardiomyopathy. Lytic bone lesions
in appendicular bones in patients with CGL usually do
not pose an increased risk of fractures.
There are no well-controlled trials available to guide
treatment decisions about how to manage metabolic
complications. For severe hypertriglyceridemia, an
extremely low-fat diet along with fibrates and n-3
polyunsaturated fatty acids should be used. Statins
can be added if required. Any form of estrogen therapy
should be avoided, as it can pose the risk of severe
hypertriglyceridemia-induced acute pancreatitis. Diabetes should be managed initially with metformin.
Thiazolidinediones should be used with caution in
patients with partial lipodystrophies as they can potentially increase unwanted fat deposition in nonlipodystrophic regions.65 Although thiazolidinediones can be
useful in FPL patients with PPARG mutations, the data
on their efficacy are equivocal.66 If hyperglycemia persists despite using various combinations of oral anti-
PREVENTION
10
::
TREATMENT
diabetic drugs, insulin therapy should be initiated. For

those with extreme insulin resistance, U-500 insulin
should be used. No specific therapy is available at this
time for hepatic steatosis. Although, subcutaneous
metreleptin replacement therapy has been shown to
improve diabetes control, hepatic steatosis, and hypertriglyceridemia in markedly hypoleptinemic patients
with generalized lipodystrophies,67,68 its effects in
patients with FPL so far have been equivocal.69
Metreleptin therapy is investigational and not
approved by the Food and Drug Administration of US.
Switching PIs and NRTIs strongly associated with
lipodystrophy to other regimen may improve dyslipidemia and insulin resistance in HIV-infected patients
with lipodystrophy; however, loss of sc fat may not
improve.70
Chapter 71
nosis. In our experience, some have died of complications of acute pancreatitis, cirrhosis, or developed
end-stage renal disease, requiring renal transplantation, and blindness due to diabetic retinopathy. Patients
with FPL are also predisposed to metabolic complications and die of atherosclerotic vascular and coronary
heart disease or cardiomyopathy and rhythm disturbances. Some patients with MAD have reportedly died
during childhood and some died later in the 3rd and
4th decades of complications of renal failure.37,63
Patients with AGL suffer severe metabolic complications. Patients with APL and membranoproliferative
glomerulonephritis develop renal failure, but others
have normal life span as do those with localized lipodystrophy. HIV-infected patients with lipodystrophy
are predisposed to developing coronary heart disease.
KEY REFERENCES
1. Garg A: Acquired and inherited lipodystrophies. N Engl J
Med 350:1220-1234, 2004
2. Garg A: Lipodystrophies. Am J Med 108:143-152, 2000
5. Agarwal AK et al: AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat
Genet 31:21-23, 2002
6. Magre J et al: Identification of the gene altered in
Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365-370, 2001
7. Kim CA et al: Association of a homozygous nonsense
caveolin-1 mutation with Berardinelli-Seip congenital
lipodystrophy. J Clin Endocrinol Metab 93:1129-1134, 2008
8. Hayashi YK et al: Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular
dystrophy with generalized lipodystrophy. J Clin Invest
119:2623-2633, 2009
19. Cao H, Hegele RA: Nuclear lamin A/C R482Q mutation
in Canadian kindreds with Dunnigan-type familial partial
lipodystrophy. Hum Mol Genet 9:109-112, 2000
23. Agarwal AK, Garg A: A novel heterozygous mutation in
peroxisome proliferator-activated receptor-g gene in a
patient with familial partial lipodystrophy. J Clin Endocrinol Metab 87:408-411, 2002
33. Novelli G et al: Mandibuloacral dysplasia is caused by a
mutation in LMNA-encoding lamin A/C. Am J Hum Genet
71:426-431, 2002
34. Agarwal AK et al: Zinc metalloproteinase, ZMPSTE24,
is mutated in mandibuloacral dysplasia. Hum Mol Genet
12:1995-2001, 2003
763
10
Section 10
::
764
51. Misra A, Peethambaram A, Garg A: Clinical features and

metabolic and autoimmune derangements in acquired
partial lipodystrophy: Report of 35 cases and review of
the literature. Medicine (Baltimore) 83:18-34, 2004
52. Misra A, Garg A: Clinical features and metabolic derangements in acquired generalized lipodystrophy: Case
reports and review of the literature. Medicine 82:129-146,
2003
53. Chen D, Misra A, Garg A: Lipodystrophy in human

immunodeficiency virus-infected patients. J Clin Endocrinol Metab 87:4845-4856, 2002
59. Grinspoon S, Carr A: Cardiovascular risk and body-fat
abnormalities in HIV-infected adults. N Engl J Med 352:4862, 2005
67. Oral EA et al: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570-578, 2002
Disorders of Melanocytes
Chapter 72 :: Biology of Melanocytes

:: Hee-Young Park & Mina Yaar
BIOLOGY OF MELANOCYTES
AT A GLANCE
Melanoblasts
derive from the neural crest. Their
migration/survival in the epidermis is
influenced by numerous factors.
Melanocytes
populate the epidermis, hair follicle, eye,
cochlea, and meninges.
synthesize melanin, an indole derivative
of 3,4 di-hydroxy-phenylalanine (DOPA)
that is stored in melanosomes.
are influenced by endocrine, paracrine,
and autocrine factors and by ultraviolet
(UV) irradiation.
Melanosomes
display four maturation stages.
contain structural matrix proteins,
melanogenic enzymes, pH-maintaining
proteins, and free-radical scavengers.
are transported to melanocyte dendrite
tips and transferred to epidermal
keratinocytes.
in skin, absorb UV radiation and protect
against photodamage.
EMBRYONIC DEVELOPMENT
Melanocytes are pigment-producing cells that originate
from the dorsal portions of the closing neural tube in
vertebrate embryos1 (eFig. 72-0.1 in online edition). They
derive from pluripotent neural crest cells that differentiate into numerous cell lineages including neurons, glia,
smooth muscle, craniofacial bone, cartiledge, and melanocytes.2,3 Progenitor melanoblasts migrate dorsolaterally between the mesodermal and ectodermal layers to
reach their final destinations in the hair follicles and the
skin as well as inner ear cochlea, choroids, ciliary body,
and iris.2,4 Pigment-producing cells can be found in fetal
epidermis as early as the 50th day of gestation.
Melanoblast migration and differentiation into
melanocytes are influenced by a number of signaling molecules produced by neighboring cells. These
include Wnt, endothelin (ET)-3, bone morphogenetic
proteins (BMPs), steel factor (SF) (stem cell factor, c-Kit
ligand), and hepatocyte growth factor (HGF/scatter
factor).510 By interacting with their specific cell surface
receptors, these molecules induce intracellular and
intranuclear signaling to influence gene transcription
and protein synthesis. Genetic defects in some of these
molecules are associated with human genetic diseases: ETs (Waardenburg syndrome and Hirschsprung
disease) and c-Kit and stell factor with piebaldism.
Detailed discussion of each signaling molecule is available online.
SITE-SPECIFIC MELANOCYTES
MELANOCYTE STEM CELLS
Generally, stem cells are defined by their undifferentiated state and their capacity to develop into several
differentiated cell types. They are quiescent, slowcycling cells that frequently are found in niches where
they are surrounded by differentiated cells that affect
their behavior through the secretion of cytokines and
growth factors.29,30
Melanocyte stem cells reside in the hair follicle bulge
(Fig. 72-1). They express TRP-2 as well as the neural
crest stem cell intermediate filament nestin in addition
to other neural crest stem cell markers including the
transcription factors Sox10 and Pax5 that participate
in the regulation of microphthalmia-associated transcription factor (MITF) and TRP-2. Melanocyte stem
cells can leave the bulge region and migrate/differentiate in the epidermis or the hair follicle.
11
Section 11
::
766
Figure 72-1 Melanocyte stem cells in the hair follicle

bulge. A stem cell melanocyte is shown in the hair follicle
bulge, indicated by an arrow in the high-power insert.
These cells stain positive for TRP-2 (green fluorescence), an
early marker of commitment to the melanocyte lineage,
but are negative for the proliferation marker Ki-67 (red
fluorescence) that characterizes melanocytes migrating
down the follicle to the dermal papilla during the anagen
phase of the hair cycle. (From Botchkareva NV et al: SCF/ckit signaling is required for cyclic regeneration of the hair
pigmentation unit. FASEB J 15:645, 2001, with permission.)
CUTANEOUS MELANOCYTES
The largest number of melanocytes are present in the
skin and hair follicles. While in most furred mammals melanocytes are found only in the hair follicle,
in humans, melanocytes are also present in interfollicular epidermis, specifically in the basal layer.28 There
is approximately one melanocyte per five or six basal
keratinocytes. Melanocytes synthesize melanin, a pigmented polymer that is stored in cytosolic organelles
called melanosomes that are transferred to keratinocytes through melanocyte dendritic processes (Fig.
72-2). As keratinocytes are continuously being desquamated, there is a constant need for synthesis and transfer of melanosomes from melanocytes to keratinocytes
in order to maintain cutaneous pigmentation.
The term epidermal melanin unit describes a single epidermal melanocyte surrounded by several epidermal keratinocytes31 (Fig. 72-3). Interestingly, signals
from keratinocytes substantially regulate epidermal
melanocyte survival, dendricity, melanogenesis and
the expression of cell surface receptors32 (see below).
Most keratinocyte-derived signals are induced by
ultraviolet (UV) irradiation.
Melanocyte density/mm2 ranges from approximately 550 to >1,200 with the highest concentrations
found in the genitalia and face.33,34 Melanocyte density is the same in individuals of different racial backgrounds,34 and thus cutaneous pigmentation does not
depend on melanocyte number, but rather upon melanogenic activity within the melanocyte, the proportion
of mature melanosomes, and/or their transfer and distribution within the keratinocytes.35 Indeed, in lightskinned individuals, melanosomes are smaller and are
Figure 72-2 Melanosomes are organized into supranuclear caps within keratinocytes. Note melanized dendritic
melanocytes and adjacent keratinocytes with the supranuclear caps. Melanin silver-stained (Fontana-Masson)
section of a heavily melanized human epidermis. (Bar =
50 m.) (From Byers HR et al: Role of cytoplasmic dynein in
perinuclear aggregation of phagocytosed melanosomes
and supranuclear melanin cap formation in human keratinocytes. J Invest Dermatol 121:813, 2003, with permission.)
present in clusters within the keratinocytes, while in

ethnic groups with darker complexion, melanosomes
are larger, darker, and are individually dispersed
within the keratinocytes.36
HAIR FOLLICLE MELANOCYTES

In contrast with interfollicular epidermal melanocytes,
the follicular melanin unit undergoes cyclic modifications in coordination with the hair cycle (Fig. 72-4).
Melanocytes are located in the proximal hair bulb during anagen and there is a ratio of 1:5 between melanocytes and keratinocytes and 1:1 between melanocytes
and basal layer keratinocytes.37 Melanocytes proliferate, migrate, and undergo maturation during early
to mid anagen. Melanogenesis and melanin transfer
to keratinocytes occurs throughout anagen. Melanocytes eventually apoptose during late catagen. In mice,
melanocyte proliferation and differentiation during
anagen depends on c-Kit expression by melanocytes
and SF synthesis by keratinocytes.38
Similar to their role in the epidermis, in hair, melanocytes transfer melanin to differentiated keratinocytes
that ultimately form the hair shaft. They thus determine hair color by the amount of melanin transferred,
as well as by the ratio of eumelanin (blackbrown) to
pheomelanin (redyellow) (see below).39
In hair, melanin does not appear to have a protective
effect, since UV irradiation does not reach the hair follicle. Still, in furry animals hair color plays an important
role in camouflage, mimicry, and social communication.40 It is also speculated that melanocytes restrain
keratinocyte proliferation, affect calcium homeostasis,
and protect against reactive oxygen species (ROS) during the rapid proliferation and differentiation of the
hair follicle.37
11
Chapter 72
::
Biology of Melanocytes
Figure 72-3 The epidermal melanin unit. A. Representation showing the relationship between basal melanocytes, keratinocytes, and Langerhans cells, shown at the upper layer of the epidermis. (From Quevedo WC Jr.: The control of color in
mammals. Am Zoology 9:531, 1969, with permission.) B. Electron micrograph of the dermalepidermal junction of human
skin showing a dendritic melanocyte (M) among the basal keratinocytes (K). k represents a basal keratinocyte undergoing mitosis with condensed chromatin (arrows). (Bar = 10.0 m.) (Illustration used with permission from Raymond E.
Boissy, Department of Dermatology, University of Cincinnati, Cincinnati, Ohio.) C. Human epidermis immunostained for
fibroblast growth factor-2 (FGF2). The figure shows basal keratinocytes with peroxidase reaction indicating the presence
of immunore-active FGF2. Arrows point to melanocytes. (Used with permission from Glynis Scott, MD, Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY.) D and E. Distribution of melanosomes
within keratinocytes in lightly pigmented Caucasian and darkly pigmented African-American skin. Melanosomes in lightly
pigmented Caucasian skin (D) are distributed in membrane-bound clusters. In contrast, in darkly pigmented AfricanAmerican skin (E) the melanosomes are individually distributed throughout the cytoplasm of epidermal keratinocytes.
Melanosomes in both skin types are frequently concentrated over the apical pole of the nucleus (arrows). L = Langerhans cell.
(Bar = 3.0 m.) (Used with permission from Minwalla L et al: Keratinocytes play a role in regulating distribution patterns of
recipient melanosomes in vitro. J Invest Dermatol 117:341, 2001.)
767
11
Melanocytes in the hair
Epidermal
Infundibular
Section 11
Outer root
sheath
Amelanotic
::
Bulbar melanogenic
Apoptotic
A
Figure 72-4 Melanocytes in the hair. A. Pigmented human scalp hair follicle in full anagen with high levels of hair bulb
melanogenesis. Mature melanin granules are transferred into cortical keratinocyte. B. Scalp hair bulb. Representation of
early catagen hair follicle showing loss of some bulbar melanotic melanocytes via apoptosis. Arrows point at melanocytes located in epidermal, infundibular, and outer root sheath regions. C. Transmission electron micrograph of section
of an early catagen hair bulb showing apoptosis of melanotic melanocytes. Inset, high-power view of premelanosomes.
D. Primary culture of human scalp hair follicle melanocytes. Mature, fully differentiated (Diff; large arrow), and less differentiated (small arrows) are indicated. DP = dermal papilla. (From Tobin DJ, Paus R: Graying: Gerontobiology of the hair follicle
pigmentary unit. Exp Gerontol 36:29, 2001, with permission.)
MELANIZATION
The major differentiated function of melanocytes is to
synthesize melanin in specialized organelles within
the melanocytes, the melanosomes, and to transfer
melanosomes to neighboring keratinocytes in order
to provide protection from UV irradiation (Fig. 72-5).
Melanogenesis, the synthesis and distribution of
melanin in the epidermis, involves several steps: transcription of proteins required for melanogenesis; melanosome biogenesis; sorting of melanogenic proteins
into the melanosomes; transport of melanosomes to
the tips of melanocyte dendrites and transfer of melanosomes to keratinocytes. Disruption in any of these
events results in hypopigmentation.
MELANOSOMES
MELANOSOME BIOGENESIS
768
The melanosome is a unique membrane-bound organelle in which melanin biosynthesis takes place. Because
melanosomes contain enzymes and other proteins also
Figure 72-5 Melanocytes cultured on keratinocytes.

Light micrograph showing dendritic melanocytes from a
black donor loaded with melanin and adjacent pigmented
keratinocytes due to transfer of melanosomes.
11
E
A
C
F
Chapter 72
::
Figure 72-6 Melanosome biogenesis. Electron microscopy of eumelanosome (AF) and of pheomelanosome (GJ) development. I, II, III, and IV in AJ represent the different maturation stages of melanosomes. [Scale bars are as follows (in
m): a = 0.20; b = 0.23; c = 0.24; d = 0.22; e = 0.20; f = 0.35; h = 0.26; i = 0.26; j = 0.30; k = 0.5.] (From Slominski A et al: Melanin
pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 84:1155, 2004, with permission from the American Physiological Society.)
present in lysosomes, they are thought to represent
a modified version of the latter. Proteins common to
both organelles include the lysosome-associated membrane proteins (LAMPs) that participate in autophagy
and regulation of intravesicular pH,56 as well as acid
phophatase, a marker enzyme for lysosomes.56 Also
like lysosomes, melanosomes can endocytose receptors that are targeted for degradation.56
Depending on the type of melanin synthesized,
melanosomes can be divided into eumelanosomes
and pheomelanosomes (Fig. 72-6). Eumelanosomes
are large (0.9 0.3 mm), elliptical in shape and contain a highly structured fibrillar glycoprotein matrix
required for eumelanin synthesis.40 Pheomelanosomes
are smaller (0.7 mm in diameter), spherical in shape
and their glycoprotein matrix appears disorganized
and loose40 Although both eumelanosomes and pheomelanosomes may be present within a single melanocyte,57 once committed, they do not change.58
Melanosomes display four maturation stages (Fig.
72-6). Stage I melanosomes or premelanosomes likely
develop from the endoplasmic reticulum (ER).40 They
have an amorphous matrix and display internal vesicles that form as a result of membrane invagination.
Premelanosomes already contain the glycoprotein
Pmel17 (gp100) but it requires further processing to
become a component of the final fibrillar matrix.59 Stage

II eumelanosomes have organized structured fibrillar
matrix, but no active melanin synthesis, whereas in
stage II pheomelanosomes melanin synthesis already
takes place. Although no active melanogenesis takes
place in stage II eumelanosomes, they already contain
the enzyme tyrosinase. Deposition of melanin on the
fibrillar matrix is found in stage III eumelanosomes,
while stage IV eumelanosomes are fully melanized and
their internal matrix is masked by melanin deposits.60,61
MELANOGENIC PROTEINS
The timely and organized sorting of melanogenic
enzymes and structural proteins to melanosomes is an
integral part of melanosomal maturation. Melanosome
proteins express sorting signals at their amino-terminus
and these direct them into the ER and eventually into
the melanosomes.40,60,61
Enzymes
Tyrosinase. Tyrosinase is present in plants, insects,
amphibians, and mammals. It was initially identified

in the early 1900s in mushroom extracts and was subsequently isolated and purified in 1949 from murine
769
11
Sorting of melanosomal proteins into melanosomes
Plasma membrane
Stage II
Endosome
Stage III
AP-3
Tyrosinase/
Tyrosine/
TRP-1
TRP-1
Stage II
Stage I
TRP-2
PMEL17/
MART-1
Trans-Golgi network
Section 11
Golgi
ER
::
770
Tyrosinase/
TRP-1
TRP-2
Figure 72-7 Sorting of melanosomal proteins into melanosomes. Tyrosinase and tyrosinase-related protein-1
(TRP-1) are initially synthesized in the endoplasmic reticulum (ER) and, after additional maturation steps (*)
in the Golgi and trans-Golgi network, are packaged in
endosomes as a complex. TRP-2 follows similar maturation steps. Melanosomes originate in the ER as stage I
already containing the melanosomal proteins PMEL17 and
MART-1. They then mature to stage II melanosomes and
fuse with tyrosinase/TRP-1 in a process directed by the
adaptor protein 3 (AP-3). Melanosomes become progressively darker as melanin biosynthesis takes place.
melanoma cells.62 Mouse and human tyrosinase genes

are 6070 kb, and 50 kb long, respectively. The murine
tyrosinase gene maps to chromosome 7, whereas
human tyrosinase gene maps to chromosome 11. The
human tyrosinase gene is composed of five exons and
four introns,63 and tyrosinase mRNA is approximately
2 kb long (genebank access number NM_000372).
Tyrosinase is synthesized in the ER as a precursor
protein whose nascent chain is processed in the Golgi
complex where sialic acid and neutral sugars are
added to the peptide via N- and O-glycosidic linkages
through a process called glycosylation64 (Fig. 72-7).
At least four forms of tyrosinase, all differing with
regards to their degree of glycosylation, have been
identified. The glycolsylation steps have been shown
to be important for proper association of tyrosinase
with melanosomes, as well as for its activity.64 Following the glycosylation steps, mature tyrosinase is folded
in the ER, a step required for appropriate trafficking/
sorting of tyrosinase into the Golgi apparatus and ultimately into endosomes and finally into melanosomes.
A strict control mechanism guarantees the elimination
of defective tyrosinase.
Within the melanosome, tyrosinase spans melanosomal outer membrane (eFig. 72-7.1 in online edition).
It has three domains: (1) an inner melanosomal domain,
(2) a melanosomal transmembrane domain, (3) and a
cytoplasmic domain. The inner domain that contains

the catalytic region is approximately 90% of the protein. It is followed by a short transmembrane domain,
and a cytoplasmic domain composed of approximately
30 amino acids.65 Histidine residues present in the
inner (catalytic) portion of tyrosinase bind copper (Cu)
ions and the latter are required for tyrosinase activity.
The biological function of the tyrosinase cytoplasmic
domain was not known for a long time. In a mouse
model where the entire cytoplasmic domain is missing,
tyrosinase protein is inserted into the cellular plasma
membrane instead of into the melanosomal membrane,
suggesting that tyrosinase cytoplasmic domain is
required for proper trafficking of tyrosinase into melanosomes. Indeed, it was found that the motifEXXQPLL
(glutamic acid-X-X-glutamine-proline-leucine-leucine,
where X stands for any amino acid) in the cytoplasmic domain is responsible for tyrosinase trafficking
into the melanosomes.66 In addition, protein kinase C-
(PKC-) (see below) must phosphorylate two serine
residues on this cytoplasmic domain to activate tyrosinase,65 and in the absence of those phosphorylation
events pigmentation does not occur.
Tyrosinase mutations including missense, nonsense
frameshift, and deletion mutations that lead to inactivation of the enzyme are found in oculocutaneous
albinism type I (see Chapter 73 and Albinism database: http://albinism-db.med.unm.edu/). Such mutations may affect tyrosinase glycosylation interfering
with enzyme maturation, or may involve Cu-binding
sites disrupting tyrosinase activity or premature termination of tyrosinase protein that causes truncation of
cytoplasmic domain.64
Tyrosinase-Related Proteins. Two tyrosinaserelated proteins, (1) TRP-1 and (2) TRP-2, play important roles in melanogenesis.6769 They are structurally
related to tyrosinase and share 40% amino acid homology. Also, similar to tyrosinase, TRP-1 and TRP-2 are
glycoproteins located within the melanosomes and
span the melanosomal membrane.70 The conserved
nucleotide and amino acid sequences among these
three melanogenic enzymes suggest that they originated from a common ancestral gene.71,72 Mutations
of TRP-1 and TRP-2 in mice after coat color (brown
and slaty mice, respectively) and polymorphisms of
these gene products are implicated in lighter hair and
skin color in European population studies. Their functions are incompletely understood, but the proteins
complex with tyrosinase and may stablilize it.
Protein Kinase C-.
PKC constitutes a family

of at least 12 isoforms86 among that PKC- has been
shown to be involved in regulating tyrosinase activity.87 The mechanisms through which PKC mediates a
wide range of membrane generated signals and their
relevance to melanocyte biology are further discussed
below (see Section Signaling Pathways Regulating
Melanocyte Functions). PKC- phosphorylates serine
residues on the cytoplasmic domain of tyrosinase, thus
activating tyrosinase.88 Still, the means by which PKC-mediated phosphorylation of tyrosinase leads to the
enzyme activation is not well elucidated. It has been
suggested that phosphorylation of tyrosinase causes a
However, there are no known hypopigmentary disorders in humans linked to mutations of Pmel17.
Activation of tyrosinase by protein kinase
Plasma membrane
MART-1/Melan A. MART-1, also known as Melan
A, is a membrane-associated protein98 that is present in

stage I and stage II melanosomes and forms a complex
with Pmel17 (Fig. 72-7). MART-1 affects the expression, stability, trafficking, and processing of Pmel17
within the melanosomes.98 To date, no hypopigmented
phenotypes associated with nonfunctional MART-1
have been identified.
PKC-
PKC-
Rack-1
Rack-1
TYR
TYR
Melanin
Inactive
11
Active
Pmel17. Pmel17, also known as gp100 and the silver locus product, is a glycoprotein recognized by the
antibodies HMB45, HMB50, and NKI-.94 It plays a
critical role in fibril matrix formation within eumelanosomes.59,95 Pmel17 transcription is induced by -MSH
through MITF and it is synthesized as a precursor protein in the ER and the protein undergoes glycosylation
and eventual cleavage (Fig. 72-7). After its synthesis,
Pmel17 is transported to stage I melanosomes to form
a fibrillar structure that is the backbone of eumelanosome matrix,94 contributes to melanosome ellipsoid
shape and promotes melanin polymerization.94 Melanosomes lacking Pmel17 cannot transit to stage II and
have no active melanogenesis.96 It has been suggested
that loss of functional Pmel17 results in melanin cytotoxicity, perhaps through leakage of melanin intermediates from abnormal melanosomes into the cytosol.94,97
STRUCTURAL PROTEINS. Fibrillar matrix proteins within the melanosomes are required for proper
deposition of melanin. Pmel17 and MART-1 are two
such melanosomal structural matrix proteins.
::
complex to form between tyrosinase and TRP-1,89 an

event known to stabilize tyrosinase and increase its
enzymatic activity.79
In melanocytes, activated PKC- is associated with
melanosomes and the enzyme is found in close proximity to the melanosomal membrane.88 While structural differences among PKC isoforms may contribute
to their associations with particular subcellular fractions, receptors for activated C-kinase (RACK), unique
for each PKC isoform, primarily determine the translocation of specific PKC isoforms to specific cellular compartments to activate its target on the membrane9092
(Fig. 72-8). RACK-I is the PKC- partner,90 and in
human melanocytes, the activated PKC-/RACK-I
complex translocates to the melanosome membrane to
allow tyrosinase phosphorylation (Fig. 72-8)93
including tyrosinase, TRP-1, TRP-2, and Pmel17 and

directing them to the appropriate cytosolic organelles is
facilitated by heterodimeric adapter protein complexes
(APs).99,100 AP-3 and possibly also AP-1 facilitate tyrosinase transport from endosomes to melanosomes101 (Fig.
72-7). Patients with HermanskyPudlak syndromean
autosomal recessive disorder of oculocutaneous albinism, platelet dysfunction, and pulmonary disease (see
Chapter 73)have defects in specific subunits of the
AP-3 adaptor protein complex and as a result display
several anomalies associated with cellular transport
of molecules.102 Studies suggest that a molecule of the
kinesin family, microtubule-associated motor proteins,
is involved in endosomal sorting and positioning of
melanosomal proteins via interaction with AP-1.103,104
Chapter 72
Figure 72-8 Activation of tyrosinase by protein kinase

C- (PKC-). Under baseline conditions, there is no activation of PKC-, and tyrosinase (TYR) is not phosphorylated.
Activated PKC- binds receptors for activated C-kinase-I
(RACK-I), the complex translocates to the melanosome,
and phosphorylates serine residues on the cytoplasmic
tail of tyrosinase. Tyrosinase phosphorylation activates the
enzyme to catalyze melanin biosynthesis.
TRANSPORT PROTEINS
Heterotetrameric Adaptor Protein Complexes. Sorting of membrane-associated proteins
P-Protein. The P-protein (pink-eyed dilution) is a

transmembrane protein with 12 membrane-spanning
domains whose sequence is homologous to that of
other transmembrane transport proteins, including
anion transporters97,105,106 thought to function as a
transport protein.107 Studies have identified the protein as an ATP-associated proton pump responsible
for maintaining acidic environment within the melanosomes.108 Other proposed functions of P-protein
include stabilizing the tyrosinase/TRP-1/TRP-2
complex and/or transporting tyrosine into the melanosomes.105 Individuals lacking functional P-protein
display occulocutaneous albinism type 2, largely due
to improper melanosomal pH.108110 Also, Angelman
and PraderWilli syndromes display deletion mutations that include the P-locus on chromosome 15.
SLC24A5. SLC24A5 is a melanosomal protein whose
structure and homology to cation exchange proteins
suggests that it is a melanosome-associated cation
exchanger.111 Mutations in slc24a5 in zebrafish lead to
hypopigmentation of the organism.111 The ancestral
human homolog is expressed by darker complexioned
individuals including Africans and Asians, while
lighter complexioned Europeans tend to express a
variant allele.111
SCAVENGER PROTEIN
Lysosome-Associated Membrane Proteins.
LAMPs are linked to melanosome membranes and/

or matrix. They are thought to protect melanosomal
integrity by acting as scavengers of free radicals that
771
11
are produced during melanin biosynthesis.112 Because

LAMPs are also present in lysosomes, it is thought that
melanosomes and lysosomes share a common ancestral origin.112
Regulatory proteins
Microphthalmia-Associated
Transcription Factor
Section 11
::
Gene and Protein. MITF, a basic-helix-loop-helix

(bHLH) and leucine zipper transcription factor, has
been termed the master gene for melanocyte survival and is a key factor regulating the transcription
of the major melanogenic proteins, tyrosinase, TRP-1,
TRP-2,12 PKC-113 and MART-1.114 In melanocytes, it is
the MITF-M isoform that stimulates transcription of
tyrosinase and PKC-b.114 MITF binds to conserved consensus elements in gene promoters, specifically the M(AGTCATGTGCT) and E- (CATGTG) boxes.115 It can bind
as a homodimer or a heterodimer with another related
family member.116 MITF appears to be a key regulator
determining cell fate, as transfection of human MITF
cDNA into mouse fibroblasts converts these cells into
dendritic cells expressing melanocyte-specific genes.117
MITF comprises a family of nine isoforms: (1) MITFM, (2) -A, (3) -B, (4) -H, (5) -C, (6) -D, (7) -E, (8) -J, and
(9) -Mc.118,119 MITF-M expression is highly specific for
melanocytic cells.120 Melanocytes express in addition
other MITF isoforms specifically, MITF-A, -B, and,
-E114The biologic role of other MITF isoforms in normal
melanocytes is not known.
MITF Role in Melanocyte Proliferation and Survival. MITF promotes melanoycte survival by
upregulating the expression of a major antiapoptotic protein BCl2.127 It is frequently overexpressed
or amplified in melanomas, contributing to their
increased survival.128131 Mutations in MITF are found
in the pigmentary disorder Waardenburg syndrome
type 2132(see Chapter 73).
A role for MITF in melanocyte proliferation has
also been proposed, as under certain conditions,
MITF induces the expression of the cell cycle-associated kinase Cdk2 that is involved in the progression of cells from G1 into S phase of the cell cycle.133
MITF also suppresses the expression of p21, a protein
that inhibits Cdk2 activation.133,134 Conversely, under
The melanocortin receptor and ligands

ACTH
H2N-SYSMEHFRWGKPVGKKRRPV
KVYPNGAEDESAEAFPLEF-OH
138-176
77-88
-endorphin
YGGFMTSEKSQTPLV
TLFKNAIIKNAYKKGE
237-267
217-234
H2N-YVMGHFRWDRFG-OH
H2N-DEGPYRMEHFRWGSPPKD-OH
-MSH
-MSH
138-152
Ac-SYSMEHFRWGKPVGK-NH2
-MSH
Extracellular
D84E
772
Regulation of MITF Activity and Expression. The

activity and stability of MITF are modulated by phosphorylation of the protein. MITF activity is increased
upon its phosphorylation by the mitogen-activated
protein kinase-2 (MAP kinase-2), whose activity is in
turn induced by binding of SF/kit/stem cell factor
to c-Kit receptor121 (Fig. 72-8). Phosphorylated MITF
binds to another protein, p300/CBP, which belongs
to a coactivator family of proteins and acts to enhance
MITF transcriptional activity.121,122 Another kinase that
is activated by SF/c-Kit interaction is p90RSK that also
phosphorylates MITF but at a different site from that
phosphorylated by MAP kinase-2.123 These phosphorylation events both activate MITF and at the same time
decrease the stability of the protein, as phosphorylated MITF is targeted for degradation by proteosomes
(eFig. 72-8.1A in online edition).123,124
The expression of MITF is under the control of several transcription factors, including Sox10 (mutated in
Waardenburgs syndrome type 4, see Chapter 73) and
Pax3. MITF expression is also controlled by the cAMPresponse element binding protein (CREB) and Lef1
transcription factor that participates in Wnt-signaling.
These transcription factors bind to specific sites within
MITF promoter regions to induce MITF transcription.116
The promoter region of the MITF gene contains a cAMPresponse element (CRE) that interacts with CREB when
the cAMP-dependent pathway is activated.125,126 Therefore, cAMP-elevating agents like -MSH induce the
expression of MITF (eFig. 72-8.1B in online edition).
D294H
V6OL
TM
R160W
R151C
R160W
Intracellular
Loss of function mutants associated with red hair

and melanoma
Common in red head or blond light skin
Figure 72-9 The melanocortin receptor (MCR) and its

ligands. A. Structure of the proopiomelanocortin precursor. Standard abbreviations for amino acids are used. The
synthetic superactive -melanocyte-stimulating hormone
(-MSH) analogue [Nle4 D-Phe7]--MSH is modified by
the exchange of methionine (M) with norleucine and Lphenylalanine (F) with D-phenylalanine. In red are critical
amino acids required for binding to the MCR. B. Schematic
representation of the human MC1R receptor. Each of the
318 amino acid residues in the polypeptide chain of the
receptor is represented by an empty circle. Branched
structures represent N-linked glycosylation sites. Reduced
function mutants (red circles), variants common in red- or
blond-haired and fair skinned individuals (orange circles),
and the conserved C-terminal cysteine (green circle), the
possible site for fatty acid acylation and anchoring to
the plasma membrane, are indicated. Ac = acetylated;
ACTH = adrenocorticotropic hormone; NH2 = amidated;
TM = transmembrane domain.
Eumelanin
11
Pheomelanin
Chapter 72
ifferent conditions, MITF can induce p21 expression

d
and it can also stimulate the expression of p16INK4a,
a protein that inhibits the activation of kinases
required for progression through the cell cycle, thus
promoting cell cycle arrest.135,136 Because MITF cooperates with other transcription factors to induce its
effects, it is to be expected that these transcription
factors would influence MITF activity, resulting
in either stimulation or inhibition of melanocyte
proliferation.
Mice bearing null mutations of MITF display loss of
melanocytes, deafness and failure of differentiation of
retinal pigment epithelium.12
Melanocortin 1 Receptor. Melanocortin recep-
tors (MCRs) comprise a family of five related receptors

(MC1R, MC2R, MC3R, MC4R, and MC5R). Each has
seven transmembrane domains and they belong to the
G-protein-coupled receptor superfamily.137 MC3R and
MC4R are mainly found in the central nervous system,
are absent in melanocytes,138 and are thought to control
energy intake. MC2R is expressed in the adrenal cortex and MC5R is expressed in peripheral adipocytes.139
MC1R is expressed in a number of cells such as endothelial cells, fibroblasts,140 and keratinocytes,140 but the
highest expression is found in melanocytes.140
-MSH and adrenocorticotropic hormone (ACTH),
a 39 amino acid proopiomelanocortin-derived
peptide that contains the -MSH sequence (Fig.
72-9A),141143 activate MC1R (Fig. 72-9B) Receptor
ligand interaction leads to G-protein-dependent activation of the enzyme adenylate cyclase followed by
increased intracellular cAMP level141 inducing MITF
transcription and upregulating the level of melanogenic proteins including tyrosinase40 promoting the
synthesis of brown/black eumelanin.141 Agouti, a
protein expressed in both humans and mice, whose

expression in mice leads to yellow coat color, antagonizes -MSH by competitive binding to MC1R. It thus
blocks adenylate cyclase activation144146 and favors
pheomelanin over eumelanin synthesis (Fig. 72-10).
However, the role of agouti in human pigmentation is
poorly documented.
Polymorphisms within the MC1R gene are largely
responsible for the different skin/hair color among different racial groups.147 At least 30 MC1R variants have
been identified and nine of them display loss of function148,149 (Fig. 72-9B), not being able to induce intracellular cAMP production in response to -MSH despite
adequate receptor/ligand binding. Other MC1R variants have reduced affinity for -MSH.148,149 Three
MC1R variants, each with only a single amino acid
substitution, have been associated with red/yellow
hair and fair skin150 of Northern Europeans and Australians.151156 Mice expressing a loss-of-function MC1R
variant receptor also fail to respond to UV irradiation
with increased pigmentation despite an increased
level of epidermal -MSH,157 but do tan if provided
forskolin, a chemical enhancer of pigmentation that
bypasses the receptor to directly increase cAMP, demonstrating that the intracellular melanogenic pathway
is functional in such individuals.155
Figure 72-10 Eumelanin and pheomelanin presentation in mice. A. Two mice with different coat colors are shown. The
one on the left displays brown/black coat color due to eumelanin, and the one on the right displays red/yellow coat color
due to pheomelanin. B. Representative hair shafts of these mice. (From Sharov et al: Bone morphogenic protein (BMP)
signaling controls hair pigmentation by means of cross-talk with the melanocortin receptor 1 pathway. PNAS 102:93, 2004,
with permission.)
::
MELANIN BIOSYNTHESIS
Two types of melanins are synthesized within melanosomes: (1) eumelanin and (2) pheomelanin.158 Eumelanin is dark, brownblack, and insoluble, whereas
pheomelanin is light, redyellow sulfur-containing,
and soluble.158 Melanins are indole derivatives of
3,4 di-hydroxy-phenylalanine (DOPA) and they are
773
11
Melanin biosynthesis
Tyrosine
Tyrosinase
DOPA
Tyrosinase
DOPAquinone
Section 11
DHI
Tyrosinase
Indole 5,6-quinone
CysteinylDOPA
TRIP-2
Indole 5,6-quinone
carboxylic acid
Alanyl-hydroxybenzothiazine
Tyrosinase
or TRIP-2
::
774
DOPAchrome
DHI melanin
black
insoluble
high MW
DHICA melanin
brown
poorly soluble
intermediate MW
Pheomelanin
red/yellow
soluble
low MW
Figure 72-11 Melanin biosynthesis. Melanin biosynthesis

begins with the amino acid tyrosine that is converted to
DOPA (3,4-dihydroxyphenylalanine) in the rate-limiting
step of melanin biosynthesis catalyzed by tyrosinase.
DOPA is subsequently converted to DOPAquinone by
the same enzyme. DHI (5,6-dihydroxyindole) and DHICA
(5,6-dihydroxyindole-2-carboxylic acid) are then formed
to produce either black or brown eumelanin. Alternatively,
through incorporation of glutathione or cysteine, DOPAquinone can form pheomelanin. MW = molecular weight;
TRP = tyrosinase-related protein.
formed in melanosomes through a series of oxidative

steps159 (Fig. 72-11). Melanosomal pH affects the activity of the melanogenic enzymes and influences melanin polymerization.
The synthesis of both types of melanin involves the
rate-limiting catalytic step in which the amino acid
tyrosine is oxidized by the enzyme tyrosinase (also
called tyrosine oxidase, DOPA oxidase, monophenol,
DOPA: oxygen oxidoreductase) to DOPA, a first step
in a reaction known as the RaperMason pathway160
(Fig. 72-11). Conversion of tyrosine to DOPA is thought
to be the critical rate-limiting step in melanogenesis, as
inhibition of this reaction blocks melanin synthesis.161
In both reactions, DOPA acts as a cofactor and also as a
substrate for tyrosinase. Although the exact interaction
between tyrosinase and its substrates is not completely
understood, in vitro kinetic studies suggest that distinct sites mediate tyrosinase binding to tyrosine and
to DOPA, and that binding to DOPA causes a conformational change in tyrosinase, resulting in increased
affinity for both tyrosine and DOPA.
DOPA is oxidized into DOPAquinone,162 DOPAquinone is further converted to DOPAchrome and DOPAchrome can be converted to 5,6-dihydroxyindole (DHI)
or to 5,6-dihydroxyindole-2-carboxylic acid (DHICA).
The latter reaction is catalyzed by the enzyme DOPAchrome tautomeras or TRP-2. The level of brown versus black eumelanin appears to correlate with DHI/
DHICA ratio, with a higher ratio leading to the formation of black eumelanin and a lower ratio to brown
eumelanin.163 DOPAquinone can also combine with
glutathione or cyteine to form cysteinylDOPA, which
then becomes the yellow/red, soluble, low-molecularweight pheomelanin.163 Interestingly, tyrosinase also
catalyzes a more distant step in melanin biosynthesis, namely DHI conversion to indole-5,6-quinone. In
mice, the enzyme TRP-1 (also called DHICA oxidase)
converts DHICA to indole-5,6-quinone carboxylic acid.
However, the TRP-1 role in human melanin biosynthesis is not well established.
The main function of melanin is to provide protection against UV-induced DNA damage by absorbing
and scattering UV radiation (280400 nm). Accordingly, energy absorption by melanin is maximal in
this portion of the electromagnetic spectrum, and
decreases gradually across the visible light spectrum.
UV absorbed by melanin is converted into heat, a less
toxic form of energy.164 Still, in vitro studies conducted
by several investigators suggest that melanins capacity to act as a sunscreen is limited and that melanin,
when incorporated into a cream and spread over the
skin, absorbs only 50%75% of incident sunlight. Naturally, it is possible that in vivo, by virtue of localizing
above the nucleus, melanin in melanosomes achieves a
higher level of protection.
Melanin intermediates as well as melanin itself
can also be harmful to the cell because, depending on their molecular weight and polymerization
state, they can promote UVA (320400 nm)-induced
DNA damage, most likely through the generation
of ROS.165 It has been suggested that the increased
incidence of UV-induced melanomas in lightskinned, red-hair individuals is not only due to
decreased ability of pheomelanin to protect against
UV-induced DNA damage, but may also be due to
mutagenic capacity of pheomelanin and possibly
other melanin intermediates as a result of their prooxidant capacity.166
MELANOCYTE DENDRITES
Melanocyte dendrites are branching protoplasmic
processes that interact with keratinocytes. Actin is a
major structural component of melanocyte dendrites,
and actin filament disruption leads to dendrite loss.167
Cocultures of keratinocytes and melanocytes demonstrate that keratinocyte-derived factors play a role in
melanocyte dendricity.168 These factors include ET-1,
nerve growth factor (NGF), -MSH, ACTH, prostaglandins (PGs) E2 and F2168 and -endorphin.169 Integrins, receptors that mediate actin-extracellular matrix
contact are likely to play a role in dendrite formation
as well.170
Another group of proteins, the Rho family, also

plays a role in melanocyte dendrite formation. Rho
proteins become active when they bind GTP and inactive when binding GDP.171,172 It appears that when Rho
is activated, dendrites retract; while when its family
member Rac is activated, dendrites form.172 Indeed,
it is currently assumed that by increasing cAMP levels, -MSH inhibits Rho, enhancing melanocyte dendricity. Thus, the equilibrium between Rho and Rac
appears to be an important factor influencing melanocyte dendricity.
MELANOSOME TRANSPORT
Melanocyte
dendrite tip
Melanosomes
Rab27
MIph
Dynein
Kinesin
MyoVa
Actin
Figure 72-12 Schematic diagram of melanosome transport across melanocyte dendrites. Melanosomes move
bidirectionally along melanocyte dendrites. They are
attached to microtubules through the motor proteins
kinesin (anterograde) and dynein (retrograde). At the tip
of the dendrite, melanosomes are captured in the actinrich periphery. Myosin-Va (MyoVa) mediates melanosome
binding to actin through the linker proteins Rab27a and
melanophilin (Mlph).
Transfer of melanosomes from melanocytes to neighboring keratinocytes is a critical step in normal

pigmentation. Studies suggest several ways for melanosomal transfer, including exocytosis, cytophagocytosis, fusion of plasma membranes, and transfer by
membrane vesicles.187
The exocytosis pathway of melanosomal transfer involves fusion of the melanosomal membrane
with the melanocyte plasma membrane, melanosome
release into the intercellular space and phagocytosis by
surrounding keratinocytes. Cytophagocytosis is a term
indicating the phagocytosis of a live cell or a portion of
it. With regard to keratinocytes, they cytophagocytose
the tip of a melanocyte dendrite, which then fuses with
lysosomes inside the keratinocyte, is transported to a
supranuclear location where the phagolysosome membranes break up releasing the melanosomes. Fusion of
keratinocyte and melanocyte plasma membranes creates a space through which melanosomes are transferred from the melanocyte to the keratinocyte. Indeed,
high-resolution photography shows the presence of
filopodiaslender, filliform, pointed cytoplasmic projections at the tip of melanocyte dendrites.188 These
filopodia adhere and fuse with keratinocyte plasma
membrane prior to melanosome transfer. Another
way of melanosomal transfer involves shedding of
melanosome-filled vesicles followed by phagocytosis
of these vesicles by keratinocytes, or their fusion with
keratinocyte plasma membrane.
The molecular and cellular mechanisms involved
in melanosome phagocytosis have been partially
elucidated. It appears that keratinocytes express a
Melanosome transport across melanocyte dendrites
TO KERATINOCYTES
::
Melanosomes are transferred from their site of origin

in melanocyte perikaryon to the tips of melanocyte
dendrites. Melanosome transport takes place on microtubules that are arranged parallel to the long axis of the
dendrite and is controlled by two classes of microtubule-associated motor proteins: (1) kinesins173175 and
(2) cytoplasmic dyneins176180 (Fig. 72-12). Both motor
proteins act as short cross-bridge structures connecting
the organelle to the microtubules.
Centrifugal, anterograde organelle movement is
mediated primarily by kinesin, whereas centripetal
movement is controlled by cytoplasmic dynein. Studies examining melanosomal transport suggest that
their microtubule-dependent movement is bidirec-
11
Chapter 72
WITHIN MELANOCYTES
tional,181 consistent with a cooperative forward and

backward pull of kinesin173 and dynein,176 respectively.
For melanosomes with net centrifugal movement, the
bidirectional movement appears to terminate with
myosin-Va (encoded by dilute locus)-dependent melanosomal capture in the actin-rich periphery of the dendrite (Fig. 72-12).181
Additional proteins that participate in melanosome
transport include Rab27a (encoded by ashen locus) that
mediates myosin-Va binding to melanosomes through
another linker protein-melanophilin (encoded by
leaden locus) (Fig. 72-12).182 In the absence of myosinVa, melanosomes do not collect in dendrite tips.
Mutations in any of the above gene products results
in decreased cutaneous pigmentation. Griscelli syndrome, a rare autosomal recessive disorder in which
individuals display dilute skin and hair color, is the
result of mutations of myosin-Va, Rab27a, or melanophilin182 (see Chapter 73). Myosin-Va and Rab27a
are closely located on chromosome 15.183186 Because
myosin-Va is also expressed in the brain, mutations
of this gene may also cause neurological abnormalities. Rab27a also plays a role in immuno-regulation
and individuals with mutations of this gene display
abnormalities of the immune system. Mutations of
melanophilin result only in the distinctive hypopigmentation that characterizes the syndrome.186
775
11
Section 11
seven-transmembrane G-protein coupled receptor

called protease activated receptor-2 (PAR-2). PAR-2
is activated when serine proteases cleave the extracellular portion of the receptor, exposing a new segment that acts as a tethered (attached) ligand.189,190
Activation of PAR-2 increases keratinocyte phagocytic activity.189,190
Interestingly, and consistent with its role in melanosome phagocytosis, UV induces the activity and
expression of PAR-2.191 UV effect on PAR-2 activity
and expression is more pronounced in individuals
with skin phototypes II and III than in those with skin
phototype I.191 Keratinocyte growth factor receptor
has also been implicated in enhancing phagocytosis of
melanosmes by keratinocytes.192
::
REGULATION OF MELANOCYTE
FUNCTION
Melanocyte behavior in skin is largely influenced by

signals from neighboring keratinocytes as well as autocrine signals and environmental factors such as UV
irradiation (also see Section UV Irradiation and Melanocytes). The synthesis and secretion of most keratinocyte-derived factors is increased by UV irradiation,
but it is also evident that UV can directly stimulate
melanocyte dendricity and melanin production.171,193
Melanocytes receive both positive and negative paracrine signals that modulate their proliferation and differentiated function.
MELANOGENIC STIMULATORS
PROOPIOMELANOCORTIN AND DERIVED
PEPTIDES. It is well documented that MSH and
776
ACTH are potent stimulators of melanogenesis.

They belong to a family of peptides derived from
the precursor proopiomelanocortin (POMC) that is
synthesized, in addition to the pituitary gland, also
by epidermal keratinocytes. Interestingly, POMC
expression in keratinocytes is induced by UV, phorbol esters, and interleukins.194,195 In rodents, -MSH
stimulates melanogenesis and favors eumelanin
over pheomelanin production, but systemic administration of -MSH, -MSH, and ACTH to people
increases skin pigmentation predominantly in sunexposed areas.196,197 However, in certain disease conditions characterized by abnormally high levels of
ACTH, such as Addison disease198 or Nelsons syndrome199 (ACTH secreting pituitary adenoma), more
generalized hyperpigmentation of the skin has been
observed.200
Aside from its effect on melanogenic proteins and
eumelanin synthesis, -MSH was also reported to
enhance the repair of UV-induced DNA damage in
melanocytes, specifically the repair of pyrimidine
dimers, and also to reduce the level of UV-induced
hydrogen peroxide in the cell.201 In addition, -MSH
was shown to regulate melanosomal pH.202 These data
suggest a role for POMC-derived peptides beyond
merely stimulating melanogenesis.
ENDOTHELIN-1. ET-1 appears to play a role in

mature melanocytes, inducing melanogenesis by activating tyrosinase and increasing TRP-1 levels.203,204
ET-1 also leads to melanocyte proliferation203,204 and
promotes dendrite formation.205 Cultured keratinocytes synthesize and secrete ET-1,204206 and UV irradiation stimulates ET-1 production by keratinocytes.204,205
ET-1 can also cooperate synergistically with other
growth factors/cytokines to further influence melanocyte function.
ET-1 upregulates MC1R level and increases MC1R
affinity for -MSH.207,208 Similar to -MSH, ET-1 displays photoprotective effects on melanocytes, enhancing thymine dimer repair, decreasing the level of
UV-induced hydrogen peroxide, and inducing the
level of antiapoptotic proteins.201,209
STEEL FACTOR (SF). Like other keratinocytederived factors, SF is induced by UV-irradiation, and
in guinea pigs, anti-Kit antibodies block UV-induced
tanning. SF can also act synergistically with other
cytokines such as IL-3, IL-6, IL-7, IL-9, and granulocyte-macrophage-colony stimulating factor to regulate UV-induced melanogenesis and melanocyte
survival.210,211
INFLAMMATORY MEDIATORS. Several inflammatory mediators can affect skin pigmentation.
PGsarachidonic acid-derived metabolites, and
leukotrieneslipid compounds related to PGs, both
mediators of inflammatory responses, affect melanocyte function. Their level is elevated in sunburned
skin212 and in a variety of inflammatory dermatoses,
including atopic dermatitis213 (see Chapter 14) and
psoriasis214 (see Chapter 18).
Human melanocytes express several PG receptors including the receptors for PGE2 and PGF2.215,216
Indeed, PGF2 stimulates melanocyte dendrite formation and activates tyrosinase,215,216 and UV irradiation
upregulates the level of PG receptors on melanocytes.215,216 Similarly, leukotrienes B4 and C4 increase
melanin synthesis and stimulate melanocyte proliferation and motility.217 Interestingly, melanocytes also
contribute to cutaneous inflammatory responses, as
they synthesize and release IL-8 when stimulated by
the proinflammatory cytokines IL-1 and TNF-.218
Melanocytes also respond to histamine released
by mast cells during cutaneous inflammation. Histamine binds H1 and H2 receptors to induce melanocyte
dendricity and upregulate tyrosinase level.219,220 These
effects are decreased when melanocytes are pretreated
with the H2 receptor antagonist famotidine.220
NEUROTROPHINS. Neurotrophins (NTs) are
a family of molecules that enhance neuronal survival in the central and peripheral nervous systems. They include NGF,221 NT-3,222224 NT-4,225 and
brain-derived neurotrophic factor.226,227 Melanocytes
express the low-affinity receptor common to all
NTs, p75NTR,228 as well as the high-affinity receptors
for NGF (TrkA) and NT3 (TrkC).229 Keratinocytederived NGF, whose expression is upregulated by
UV irradiation, is chemotactic for melanocytes and
induces their dendricity.230 Both NGF and NT-3,

the latter expressed by dermal fibroblasts, increase
melanocyte survival. Specifically, after UV irradiation, NGF supplementation increases the level of the
antiapoptotic Bcl-2 protein, reducing melanocyte
apoptotic cell death.231,232 Thus, in addition to other
keratinocyte-derived cytokines, NGF may help preserve the population of cutaneous melanocytes that
would otherwise be depleted by UV damage.
MELANOGENIC INHIBITORS
Numerous reports have suggested the existence of
endogenous melanogenic inhibitors,245,246 but only
few specific molecules have been identified. One
group of inhibitors includes sphingolipids, a class of
membrane-associated lipids247 that act as signal transducers. Sphingolipids were shown to decrease melanogenesis, at least in part by enhancing MITF degradation
via ubiquitin-meditated pathways.248,249 Another melanogenic inhibitor, BMP-4, downregulates tyrosinase
expression in melanocytes,250 also in part via its effects
on MITF.251 Interestingly, physiologic doses of UV irradiation, a potent melanogenic stimulator, decrease the
expression of BMP receptors on melanocytes,250 presumably eliminating its inhibition during UV-induced
tanning. Mice that transgenically overexpress the
physiologic BMP antagonist noggin have a darker coat
color than wild-type mice and their hairs have a higher
eumelanin to pheomelanin ratio.252
cAMP/PKA-DEPENDENT PATHWAY
cAMP, one of the first identified intracellular second
messengers, plays a key role in diverse biological functions such as cellular metabolism, growth, and differentiation.253,254 It also mediates -MSH effect255 and
was one of the first recognized regulators of mammalian pigmentation256 The intracellular level of cAMP
is upregulated by a membrane-associate enzyme
called adenylate cyclase that is activated upon receptorligand interaction in receptors that are coupled
to GTP-binding proteins like MC1R257 (eFigs. 72-8.1
and 72-12.1 in online edition). cAMP is also elevated
by reagents such as choleragen or isobutylmethylxanthine. Providing melanocytes with dibutyryl cAMP, a
cAMP analog, increases the intracellular level of cAMP
and induces signaling that leads to melanogenesis.258
cAMP-dependent protein kinase (PKA) mediates
most of the biologic actions of cAMP.257 PKA is a serine/
threonine kinase consisting of two regulatory subunits
and two catalytic subunits.257 It exists in the cytosol in
an inactive form and binding of cAMP to its regulatory
subunits releases the catalytic subunits, activating the
enzyme.257 PKA phosphorylates the cAMP responsive
element-binding protein (CREB) that binds its DNA consensus sequence CRE in the MITF promoter to induce
MITF transcription (eFig. 72-8.1 in online edition). cAMP
elevation also affects other target genes by increasing or
decreasing their transcription259 (eFig. 72-12.1 in online
edition). In vitro, PKA effect can be antagonized by the
inhibitor PKI that acts as a pseudosubstrate for the catalytic subunit of PKA and thus prevents it from phosphorylating its endogenous substrates.260
CATECHOLAMINES. Catecholamines are a group

of signaling molecules, primarily functioning as neurotransmitters and as endocrine hormones.243 Catecholamines bind either 1-adrenergic receptors (AR) or
2-AR and can induce melanogenesis through PKC-
or cAMP-dependent pathways.169,244
::
NITRIC OXIDE. Nitric oxide (NO) is a diffusible free

radical displaying pleiotropic bioregulatory effects in
diverse cells and tissues.236,237 Melanocytes and keratinocytes produce NO in response to inflammatory
cytokines,238241 and NO production in keratinocytes is
induced by UV irradiation.242 NO increases tyrosinase
activity and melanogenesis242 and is thus an autocrine
as well as paracrine molecule that affects melanocyte
behavior in skin.
Growth factors, cytokines, hormones, and other

ligands for receptors expressed on melanocytes exert
their biologic effect by interacting with their specific
cell surface receptors, generating a signaling cascade
involving activation or inhibition of protein kinases
and leading to distinct patterns of protein phosphorylation. Two types of kinases participate in cellular signaling: (1) serine/threonine kinases and (2) tyrosine
kinases that by definition phosphorylate serine and/or
threonine residues and tyrosine residues, respectively,
on their specific target proteins. This section reviews
the major signaling pathways that affect melanocyte
behavior in skin.
11
Chapter 72
BASIC FIBROBLAST GROWTH FACTOR. Basic

fibroblast growth factor (bFGF), named for its ability to
stimulate the growth of fibroblasts, was one of the first
identified melanocyte mitogens.233,234 It is produced by
keratinocytes, but lacks a secretory signal and hence is
presumed to affect melanocytes through cellcell contact. It binds tyrosine kinase transmembrane receptors
to induce its mitogenic effect in the presence of cAMP
elevating factors. Like other keratinocyte-derived
cytokines, it is upregulated in response to UV irradiation.234,235 Keratinocyte growth factor, another member
of the FGF family of proteins, has been shown to promote melanosome transfer from melanocytes to keratinocytes.192
SIGNALING PATHWAYS
REGULATING MELANOCYTE
FUNCTION
PKC-DEPENDENT PATHWAY
PKC is a serine/threonine kinase involved in diverse
cellular functions, including growth, transformation, and differentiation.261 PKC resides as an inactive
enzyme in the cytoplasm, and it is activated by diacylglycerol (DAG), a component cleaved from the plasma
membrane when cell surface receptors interact with
777
11
Section 11
::
their ligands. DAG can also be released from the membrane by UV irradiation (eFig. 72-12.1 in online edition). DAG induces PKC translocation to membranes
where the latter is activated261 to induce phosphorylation of serine/theonine residues on target proteins
like tyrosinase. Phorbol esters mimic DAG action and
initially activate PKC.261 However, within 24 hours the
entire cellular reserves of PKC are depleted, and when
melanocytes are treated with phorbol esters they can
no longer signal through PKC.87
The critical role of PKC in melanogenesis was first
suggested by the observation that addition of DAG,
the endogenous activator of PKC, to cultured human
melanocytes rapidly increased total melanin content,262
and this increase was blocked by a PKC inhibitor.262
Moreover, topical application of DAG to guinea pig
skin increased epidermal melanin content.263
The expression of the 12 PKC isoforms varies among
different tissues.86 Each isoform is thought to carry
out a distinct biological function. Human melanocytes
express PKC-, -, -, -, and -264,265 and the PKC- isoform is specifically involved in regulating tyrosinase
activity (see above). ET-1 and histamine also utilize
the PKC-dependent pathway (in addition to cAMPdependent pathway) to exert their regulatory effects
on melanocyte function.266,267
RECEPTOR TYROSINE KINASES

Melanocytes express several distinct tyrosine kinase
receptors that bind BMP, bFGF, HGF, and c-Kit ligand.
Receptorligand interaction activates an intracellular
tyrosine kinase domain on the receptor, phosphorylating the receptor and subsequently activating a series of
kinases called mitogen-activated protein (MAP) kinases,
or other intracellular signaling molecules (eFig. 72-12.1
in online edition). Through a chain reaction involving
phosphorylation of proteins like MITF, the signals are
transferred to the nucleus to activate or suppress the
transcription of genes that participate in melanocyte
proliferation, melanogenesis, and/or survival.
b2- AND 1-ADRENERGIC RECEPTORS
778
Studies suggest that pathways that increase intracellular cAMP are also involved in regulation of melanogenesis. POMC-deficient mice (POMC -/) that lack
melanocortin ligands still display normal black coat
color.269 Histological and electron paramagnetic resonance spectrometry of the hair follicles showed normal structure and eumelanin pigmentation.269 This
study suggests that either MC1R has adequate basal
activity to induce pigmentation or that pathways that
do not involve melanocortin can also induce melanogenesis. Indeed, melanocytes express both 2-AR and
1-AR, respectively.270,244 a1-AR interacts with melanocyte derived-norepinephrine and increases the
level of DAG169,244 inducing melanogenesis in a PKC-dependent pathway. Also, keratinocytes produce
epinephrine, which then binds to 2-AR expressed on
melanocytes and increases the level of cAMP, leading
to melanin synthesis.244 Therefore, numerous pathways may act in tandem to regulate melanogenesis.
UV IRRADIATION AND
MELANOCYTES
TANNING RESPONSE
Melanocyte survival, proliferation, and differentiated
function are influenced by environmental factors, the
most important of which is UV irradiation. UV irradiation induces tanning, the so-called facultative skin
color, an increase above baseline or constitutive skin
pigmentation that provides protection against future
UV irradiation.271 Tanning is divided into immediate
tanning and delayed tanning.
IMMEDIATE TANNING. Immediate tanning or

immediate pigment darkening occurs within 510
minutes of exposure and fades within minutes to days
depending on the UV dose and the complexion of the
individual (Fig. 72-13B). As summarized in Table 72-1,
immediate tanning does not provide photoprotection
and does not increase epidermal melanin level.272 It is
primarily produced by UVA irradiation, although visible light can also induce immediate tanning.273 Immediate tanning is only visible in darker individuals, and
it is thought to represent melanosomal relocation from
the perikaryon to melanocyte dendrites.274
DELAYED TANNING. Delayed tanning, summarized in Table 72-1 and shown in Figure 72-13A, occurs
within 34 days after UV exposure.271,272 UV is arbitrarily divided into UVC (100280 nm), UVB (280320
nm), and UVA (320400 nm). The UVC portion of the
spectrum is generally not present in terrestrial sunlight
because it is absorbed by the atmospheric ozone layer.
Delayed tanning is affected by both UVB and UVA.
The action spectrum that produces delayed tanning
is the same as for UV-induced erythema (sunburn),
with UVB wavelengths far more effective than UVA.264
Especially in darker skinned individuals, suberythemogemic UV doses may be effective as well. Delayed
tanning peaks between 10 days and 34 weeks depending on the absorbed UV dose and the individuals skin
type, then fades gradually over a few weeks. Histologically, there are increased epidermal melanocytes,
melanocyte dendriticity, and melanosome transfer to
keratinocytes with greater melanization of individual
melanosomes.272,274 Overall, total epidermal melanin is
increased, providing additional photoprotection from
UV irradiation.
DIRECT AND INDIRECT EFFECTS OF
UV IRRADIATION
UV irradiation affects melanization, melanocyte proliferation and survival both directly and indirectly
through its effect on keratinocytes, inducing the synthesis and secretion of paracrine keratinocyte factors.
11
Chapter 72
::
Figure 72-13 A. Delayed tanning. Four template test sites in a phototype III individual were exposed to repeated erythemogenic doses of ultraviolet B (UVB) (+UVA) delivered in 24-hour intervals, and the photograph was taken 10 days
after the last exposure. The tan in the more heavily pigmented test sites persisted for 2 months. B. Immediate tanning in a
phototype III individual. Four template test sites were exposed to various doses of UVA, and the photograph was taken 2
hours after the end of exposure. After 48 hours, the tan had almost completely faded.
DIRECT EFFECTS. UV irradiation triggers several

biological reactions through its interaction with cellular chromophores that absorb photons. Photochemical
reactions affect proliferation, survival, and the differentiated function of melanocytes. Most UVA effects are
assumed to be the result of oxidative damage mediated

through UVA absorption by cellular chromophores like
melanin precursors that act as photosensitizers leading
to the generation of ROS and free radicals.275 UVB irradiation is directly absorbed by cellular DNA, leading
TABLE 72-1
Immediate Tanning versus Delayed Tanning

Immediate
Delayed
Onset
Minutes
34 days
Peak intensity
Minutes to few hours
1028 days
Fading
Within 24 hours
Weeks
Mechanism
Redistribution of melanosomes
Keratinocyte-derived melanogenic cytokines

Tyrosinase level and activity
Melanin synthesis
Melanocyte dendriticity
Melanosome number
Melanosome transfer
Melanocyte proliferation
Photoprotection
Unchanged
Increased
Change in skin color
Undetectable in fair skin

Subtle in darker skin
Obvious in most light-skinned and all dark-skinned

individuals
From Dillman AM: Photobiology of skin pigmentation. In: Pigmentation and Pigmentary Disorders, edited by N Levine. Boca Raton, CRC Press,
1993, pp. 61-94; Gilchrest BA et al: Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 63(1):1-10, 1996; Ortonne JP: The
effects of ultraviolet exposure on skin melanin pigmentation. J Int Med Res 18(Suppl. 3):8C-17C, 1990; and Sturm RA: Human pigmentation genes
and their response to solar UV radiation. Mutat Res 422(1):69-76, 1998.
779
11
to the formation of DNA lesions, mainly cyclobutane

dimers and pyrimidine (64) pyrimidone photoproducts.276 DNA damage repair systems are activated, at
least in part through the tumor suppressor p53 protein. It has been shown that plasma membrane lipids
are also affected by UV irradiation to release DAG,277
which then activates PKC- to stimulate melanogenesis by activating tyrosinase (see above).
Section 11
INDIRECT EFFECTS. Key keratinocyte paracrine factors induced by UV irradiation and their effects on melanocytes are summarized in eTable 72-1.1 in online edition.
These factors can act alone and/or synergistically to modulate melanocyte function. Interestingly, UV irradiation
also induces the level of TNF- and IL-1, cytokines that
inhibit melanogenesis, suggesting a fine-tuned epidermal equilibrium between melanogenic stimulators and
inhibitors after UV irradiation, with the final outcome of
increased melanogenesis and melanocyte proliferation.
::
THE ROLE OF DNA DAMAGE IN

MELANOGENESIS
Interestingly, the action spectrum for tanning is virtually the same as that for the formation of thymine
dimers,278,279 and UV-induced melanogenesis can be
augmented in pigment cells by treatment with T4 endonuclease V,276 an enzyme that acts exclusively to enhance
the repair of UV-induced DNA damage. Moreover,
treatment of melanocytes with agents that act exclusively by damaging DNA, unlike UV that has multiple
cellular targets, also stimulates melanogenesis.280
A central role for DNA damage and/or its repair
in stimulating melanogenesis is further suggested
by the fact that p53, a tumor-suppressor protein
and transcription factor termed the Guardian of the
Genome, when activated, upregulates the level of
tyrosinase mRNA and protein, enhancing melanogenesis.281284 Thus, tanning may be viewed as part of
a p53-mediated DNA damage adaptive response that
protects the skin during subsequent exposure to UV
irradiation.
p53 IN UV-INDUCED MELANOGENESIS.
780
A
central role for DNA damage and/or its repair in stimulating melanogenesis is further supported by the fact
that the tumor-suppressor protein p53, when activated,
upregulates the level of tyrosinase mRNA and protein,
enhancing melanogenesis.281285 In p53 knockout mice,
it was observed that UV irradiation of the ears (that
contain interfollicular melanocytes) minimally stimulates melanogenesis, compared to the far greater tanning response in p53 wild-type mice.282 These findings
were expanded by Cui et al,286 who found a p53 consensus sequence in the POMC gene promoter, thus
establishing a continuous signaling pathway from UVinduced DNA damage to the final tanning response.
It was shown in mice keratinocytes that following UV
irradiation p53 activation stimulates POMC transcription, thereby increasing the release of POMC-derived
-MSH, a key physiologic inducer of melanogenesis.
Keratinocyte-derived -MSH then stimulates MC1R
on melanocytes, resulting in increased production of

eumelanin.286
It has also been shown that p53 transcriptionally
upregulates the hepatocyte nuclear factor-1 (HNF1) that is a transcription factor for tyrosinase.287 Thus,
even in keratinocyte absence, UV directly activates
p53 and HNF-1 in melanocytes to increase tyrosinase
transcription. Furthermore, UV is known to increase
H2O2 that activates p53.288 Thus, tanning may be
viewed as part of a p53-mediated DNA damage adaptive response aimed at protecting the skin from subsequent UV irradiation.282,283,289
MELANOCYTE AGING AND

PHOTOAGING
Epidermal melanocyte aging is affected by both
genetic and environmental factors. With aging, there
is a decrease in the density of epidermal melanocytes
(number per unit area of skin surface), approximately
10% per decade.290 However, the number of DOPApositive melanocytes is greater in chronically sunexposed skin than in sun-protected skin,290 possibly
due to melanocyte proliferation after sun exposure
and/or UV-induced keratinocyte-derived paracrine
factors. Melanocyte loss is especially notable in hair
follicles with age, with total loss of melanocytes in
approximately half of all scalp follicles by middle
age.37 Hair graying (depigmentation) occurs over the
entire body but is usually first noted on the scalp, perhaps because of the long anagen (growth) cycle and
resulting requirement for melanocyte proliferation and
sustained high level of melanogenesis.
In vitro melanocytes derived from older individuals show decreased proliferative capacity compared to those derived from younger individuals.
Also, with aging in vitro, there is a general increase
in the levels of total melanin as well as in the level
differentiation-associated proteins such as MITF,
TRP-1, and TRP-2291,292 and decrease in the level of
proliferation-associated proteins such as cyclin D1
and E.291,292
KEY REFERENCES
3. Westerhof W: The discovery of the human melanocyte.
Pigment Cell Res 19(3):183-193, 2006
23. Mizoguchi M: Melanocyte development: With a message
of encouragement to young women scientists. Pigment
Cell Res 17(5):533-544, 2004
39. Ito S: Biochemistry and physiology of melanin. In: Pigmentation and Pigmentary Disorders, edited by N Levine.
Boca Raton, FL, CRC Press, 1993, pp. 34-59
40. Slominski A et al: Melanin pigmentation in mammalian
skin and its hormonal regulation. Physiol Rev 84(4):11551228, 2004
65. Park HY, Gilchrest BA: Signaling pathways mediating
melanogenesis. Cell Mol Biol 45(7):919-930, 1999
171. Scott G. Rac and rho: The story behind melanocyte dendrite formation. Pigment Cell Res 15(5):322-330, 2002
182. Matesic LA, Copeland, NG, Jenkins, NA: A genetic

approach to the study of vesicle transport in the mouse.
In: Mechanisms of Suntanning, edited by JP Ortonne, R
Ballotti. Nice, Martin Dunitz, 2002:199-208
187. Van Den Bossche K, Naeyaert JM, Lambert J: The quest
for the mechanism of melanin transfer. Traffic 7(7):769778, 2006
256. Lerner AB: My 60 years in pigmentation. Pigment Cell Res

12(2):131-144, 1999
271. Gilchrest BA et al: The photobiology of the tanning
response. In: The Pigmentary System: Physiology and Pathophysiology, edited by JJ Nordlund, RE Boissy, VJ Hearing, RA King, JP Ortonne. New York, Oxford University
Press, 1998, pp. 359-372
Albinism is usually inherited as a recessive

trait, but other congenital disorders of
pigmentation are usually inherited as
dominant traits. There can be marked
differences in penetrance.
Clinical features of albinism may include
lightly pigmented or nonpigmented skin and
silvery-white or light hair color.
Ocular nystagmus and reduced visual acuity
are important features of albinism that
distinguish albinism from other congenital
disorders of pigmentation.
Clinical features of congenital disorders
of pigmentation include patches of white
hair (poliosis), variations in iris color, and
depigmented patches of white skin.
The presence of ocular nystagmus is useful
for distinguishing albinism from congenital
disorders of pigmentation.
Albino skin contains melanocytes with
reduced or absent DOPA-positivity.
Depigmented patches in congenital
disorders of pigmentation lack melanocytes.
EPIDEMIOLOGY
EPIDEMIOLOGY OF ALBINISM
Oculocutaneous albinism (OCA) is the most common inherited disorder of generalized hypopigmen-
Albinism and Other Genetic Disorders of Pigmentation
Worldwide occurrence
tation, with an estimated frequency of 1 in 20,000 in

most populations. Four different types of OCA have
been described. OCA1 and OCA2 are the most frequent types and account for approximately 40% and
50%, respectively, of OCA worldwide. OCA2 occurs
in approximately 1 in 30,000 to 1 in 36,000 Caucasians
and 1 in 10,000 to 1 in 17,000 blacks in the United
States,13 but is reported at higher frequencies ranging
from 1 in 1,400 to 1 in 7,000 in Sub-Saharan Africa4,5
and even as high as 1 in 170 individuals in the Kuna
population of the Panama coast.6 OCA3 and OCA4 are
far less frequent, although the rufous OCA phenotype,
described later, associated with OCA3 in South African
blacks has been reported at an incidence of approximately 1/8,500,7 while OCA4 accounts for 27% of all
cases of OCA in Japan.8
HermanskyPudlak syndrome (HPS) is rare except
in the Caribbean island of Puerto Rico, particularly in
the northwestern region where the majority of patients
are found, with an incidence of 1 in 1,800.9 Chediak
Higashi syndrome is also quite rare.
::
ALBINISM AND CONGENITAL

DISORDERS OF PIGMENTATION
AT A GLANCE
Chapter 73
Chapter 73 :: A
lbinism and Other Genetic
Disorders of Pigmentation

:: Thomas J. Hornyak
11

of Albinism
OCA types 14
HermanskyPudlak syndrome
Griscelli syndrome
ChediakHigashi syndrome
Ocular albinism
Currently unclassified types of albinism
Tietz syndrome
Vitiligo (extensive)
ZiprkowskiMargolis syndrome (X-linked albinism
deafness syndrome)
Cross (CrossMcCusickBreen) syndrome (oculocerebral syndrome with hypopigmentation)
781
11
TABLE 73-1
Characteristics of Albinism
Section 11
Chromosome
Gene Locus
Oculocutaneous
albinism type 1
11q21
TYR
Tyrosinase/TYR
Type 1Ano pigment

Type 1Bsome pigment
Oculocutaneous
albinism type 2
15q11.2-q12
Pink protein/P
Some pigmentation apparent;

nevi and freckles possible
Oculocutaneous
albinism type 3
9p23
TYRP1
Tyrosinase-related protein-1/
TYRP1
Similar to OCA2 phenotype.

Includes rufous (red) albinism
phenotype.
Oculocutaneous
albinism type 4
5p
MATP
Membrane-associated
transporter protein/MATP
Similar to OCA2 phenotype.

Most common in individuals
with Asian biogeographic
ancestry.
Type 1
10q24
HPS1
HPS1 (BLOC-3)
Pulmonary fibrosis associated;

absent platelet dense granules
is a hallmark of all types of HPS
Type 2
15q15
AP3B1
-3 subunit of adaptor protein

3 complex/AP3B1
Type 3
3q24
HPS3
HPS3 (BLOC-2)
Type 4
22q11.2-q12.2
HPS4
HPS4; distant homology with

yeast CCZ1 (BLOC-3)
Type 5
11p14
HPS5
HPS5 (BLOC-2)
Type 6
10q24.32
HPS6
HPS6 (BLOC-2)
Type 7
6p22.3
DTNBP1
Dysbindin (BLOC-1)
Type 8
BLOC1S3
BLOC1S3 (BLOC-1)
ChediakHigashi
syndrome
1q43
LYST
Lysosome trafficking/LYST
::
Disease
Protein [Biogenesis
of Lysosome-Related
Organelles Complex
(BLOC)]
HermanskyPudlak
syndromes
EPIDEMIOLOGY OF CONGENITAL
Waardenburg syndrome (WS) is probably less frequent
than OCA. The highest reported incidence is 1/20,000
in Kenya, although most estimates of its incidence in
the Netherlands where it was originally reported are in
the range of 1/40,000. The incidence of WS with deafness is lower, ranging between 1/50,000 and 1/212,000.
WS has been described occurring in a range of frequencies in the congenitally deaf, ranging from 0.9%2.8%
to 2%5% in different reports. The incidence of piebaldism is estimated to be less than 1/20,000.10,11
ETIOLOGY, PATHOGENESIS, AND

CLINICAL FEATURES
782
Distinguishing Signs
Awareness of the biologic basis of the distinction

between congenital disorders of pigmentation, which
Pulmonary fibrosis associated
Giant peroxidase-positive
lysosomal granules in
neutrophils
are disorders of melanocyte development, and the varieties of albinism, which are disorders of melanocyte
differentiation, is important for fully understanding
their clinical manifestations. Albinism results from the
dysfunction of a normal complement of pigment cells,
which results in complete or partial loss of cutaneous
pigmentation. The forms of albinism, including the
subtypes of OCA as well as albinism syndromes with
systemic manifestations, result either from enzymatic
defects in the biosynthesis of melanin, from melanosomal defects that interfere with melanin formation, or
from problems in the intracellular transport and localization of proteins essential for melanin biosynthesis
(Table 73-1; see Chapter 72). Congenital disorders of
pigmentation usually result from mutations in genes
critical for melanocyte development during embryogenesis. These disorders can also be associated with
other systemic problems because of the requirement
for these gene products in the development of cell
types other than melanocytes. More accurate descriptors of these disorders could be congenital (or genetic)
11
Melanocyte life cycle
Differentiated adult
skin-Disorders of
melanin biosynthesis
Melanocyte embryonic
development-Congenital
disorders of pigmentation
PAX3
Melanosome formation,
transport, and transferDisorders of vesicle
formation and trafficking
KIT
MITF
Chapter 73
SOX10
SLUG/SNA12
EDN3
EDNRB
Enzymatic defects
(OCA1, OCA3)
Melanosome function
(OCA2-4)
Figure 73-1 Schematic diagram illustrating the steps of the melanocyte life cycle, from development through differentiation, where key genes, altered in the indicated genetic diseases, act to control the function of the melanocyte.
disorders of melanocyte differentiation and congenital (or
genetic) disorders of melanocyte development, to reflecting the fact that both categories of conditions, albinism
and developmental pigmentary syndromes, are generally inherited but result from different mechanisms of
disease (Fig. 73-1).

CLINICAL FEATURES OF ALBINISM
Although the pigmentary abnormalities associated
with types of albinism can vary widely, common to
all types of albinism is reduced visual acuity and
ocular nystagmus, a result of misrouting of the optic
nerve at the optic chiasm and foveal hypoplasia.
This has been described not only in humans12 but
also in other albino mammals.13 Experiments using
the tyrosinase promoter to express both tyrosinase
and tyrosine hydroxylase in albino transgenic mice
suggest that the tyrosine hydroxylase activity of
tyrosinase is particularly important for ensuring
the proper routing of retinal projections at the optic
chiasm during development.14,15 The ocular manifestations of albinism can vary greatly, ranging from
severe (20/400) to nearly undetectable, but is often
close to 20/80.16 They also include a reduction in iris
pigment, a reduction in retinal pigment, and alternating strabismus.
OCULOCUTANEOUS
ALBINISM
1. OCA1 [Online Mendelian Inheritance
TYPE
in Man
(OMIM) #203100] is caused by loss of function of the
melanocytic enzyme tyrosinase resulting from mutations of the TYR gene.1719 Null mutations are associated with a total loss of function and no pigment
formation (OCA1A), whereas leaky mutations result
in an enzyme that retains some function and is associated with some pigment formation (OCA1B). OCA1
appears to be the most common type of albinism in
non-Hispanic Caucasian patients.20
Analyses of DNA from individuals with OCA1A
have shown a large number of different mutations
in the TYR gene. These mutations include missense,
nonsense, frameshift, splice site, and deletion mutations. Most individuals with OCA1 are compound
heterozygotes with different mutant maternal and
paternal alleles.7 Missense mutations in the TYR gene
are distributed among distinct regions of the coding
sequence, which suggests that the encoded protein has
multiple functional domains. Two of the clusters are
in the copper-binding regions, with a third near the
amino-terminus of the mature protein, in the extramelanosomal domain of tyrosinase shown to require
phosphorylation for enzyme activation.21,22 Clustering
of mutations in discrete regions of the coding sequence
is consistent with these regions importance either
for the melanogenic activity of tyrosinase or for functions related to its maturation or processing.7,22 Missense mutations at the signal peptide cleavage site23,24
implicate this cleavage event as an important step in
the development of tyrosinase activity. Frameshift
mutations near the C-terminus of the coding region25,26
indicate that the cytoplasmic domain of tyrosinase
is also important for full activity, possibly because
of the presence of protein kinase C--dependent
TYR
TYRP1
P
MATP
::
WS1-4
Tietz syndrome
Piebaldism
AP3B-HPS2
DTNBP1-HPS7
BLOC1S3-HPS8
other HPS gene products
LYST- Chdiak-Higashi
MY05A, MLPH, RAB27AGriscelli syndrome
(See Chap. 75)
783
11
Section 11
::
784
Figure 73-3 OCA1B with golden blond scalp hair and tan.
Figure 73-2 OCA1A with no hair or skin pigment, demonstrating iris translucency.
phosphorylation sites that have been identified at its

extreme C-terminus.22
All nonsense and frameshift mutations are associated with a complete loss of tyrosinase activity, presumably because of the subsequent production of a
truncated protein. With missense mutations the picture is more complicated. A set of missense mutations
that were associated with OCA1 patients accumulating pigment with age in either OCA1B or temperaturesensitive OCA (OCA1TS) patients27 were shown to
have residual enzymatic activity. Hence, it is likely that
a subset of TYR missense mutations are responsible for
the OCA1B and OCA1TS phenotypes because of the
reduced, rather than absent, tyrosinase activity in their
melanocytes.7 However, other missense mutations
resulting in the OCA1A and OCA1TS phenotypes
result in defective intracellular processing of tyrosinase and retention of the mutant tyrosinase proteins in
the endoplasmic reticulum, which suggests that some
molecular variants of OCA1 represent an endoplasmic reticulum retention disease.2830 Thus, the residual
enzymatic activity of a missense tyrosinase mutant
cannot fully predict its phenotype, because other,
presumably conformational, determinants of nascent
mutant proteins may lead to their retention in the
endoplasmic reticulum, block transport to the melanosome, and cause a more severe pigmentary phenotype.
In OCA1A, or the classic tyrosinase-negative OCA,
there is a complete inability to synthesize melanin
in skin, hair, and eyes, resulting in the characteristic
albino phenotype. Affected individuals are born
with white hair and skin and blue eyes, and there are
no changes as they mature. The phenotype is the same
in all ethnic groups and at all ages (Fig. 73-2). The hair
may develop a slight yellow tint due to denaturing of
the hair protein due to sun exposure and/or shampoo
use. The irides are translucent, appear pink early in
life, and often turn a grayblue color with time. No

pigmented lesions develop in the skin, although amelanotic nevi can be present. The architecture of skin and
hair bulb melanocytes is normal. The melanosomes
show a normal melanosomal membrane, and normal
internal matrix formation is observed in stage 1 and 2
melanosomes.
The phenotype of OCA1B can range from minimal
hair pigment to skin and hair pigmentation approaching the normal pigmentary phenotype for the individuals genetic composition and continental ancestry.
Most individuals with OCA1B have very little or no
pigment at birth and develop varying amounts of melanin in the hair and skin in the first or second decade
of life (Fig. 73-3). In some cases the melanin develops
within the first year. The hair color changes to light
yellow, light blond, or golden blond first, as a result
of residual pheomelanin synthesis, and eventually can
turn dark blond or brown in adolescents and adults.
The irides can develop light-tan or brown pigment,
sometimes limited to the inner third of the iris, and
iris pigment can be present on globe transillumination.
However, some degree of iris translucency, as demonstrated by slit lamp examination, is usually present. Many individuals with OCA1B will tan with sun
exposure, although it is more common to burn without
tanning. Pigmented lesions (nevi, freckles, lentigines)
develop in the skin of individuals who have developed
pigmented hair and skin. In some patients, the moderate amount of residual tyrosinase activity can lead
to near-normal cutaneous pigmentation, so that the
clinician may overlook subtle cutaneous pigmentary
abnormalities and render instead the mistaken diagnosis of ocular albinism (OA).
One variation of OCA1B is the temperature-sensitive phenotype. In this variation, scalp and axillary
hair remain white or slightly yellow, but arm and leg
hair pigments. The skin remains white and does not
tan. The retention of melanin synthesis in the cooler
areas of the body, such as the arms and legs, but not
11
the warmer areas, such as the trunk and the scalp, is

associated with a temperature-sensitive mutation in
tyrosinase, which loses activity above 35C.27 Similar tyrosinase mutations have been described in the
Himalayan mouse31 and in the Siamese cat with dark
points at the tips of the ears and on the paws.32
OCULOCUTANEOUS ALBINISM TYPE 2.
Chapter 73
::
Figure 73-4 OCA2 with yellow hair, white skin, and freckles in an African individual (classic tyrosinase-positive OCA
phenotype).
the Navajo population.48 On the other hand, OCA2 in
the Kuna population is caused by a splice site mutation
in intron 17 of OCA2.49 Unlike the mutations in TYR,
the missense mutations described to date in OCA2 do
not seem to cluster in any specific region.
Regarding OCA2 gene product function, it has been
shown that melanosomes from P protein-deficient
melanocytes have an abnormal pH. Melanosomes in
cultured melanocytes derived from wild-type mice
are typically acidic, whereas melanosomes from P
protein-deficient mice are nonacidic.50 Hence, it is
likely that the P protein regulates the pH of melanosomes, perhaps by functioning as an anion cotransporter in conjunction with a distinct proton pump on
the melanosomal membrane. An alternate possibility
is that the acidic conditions mediated by the P protein
favor the normal biogenesis of melanosomes, including the correct targeting of other melanosomal proteins
such as tyrosinase.51 Single nucleotide polymorphisms
in the first intron of OCA2 are the major determinant
of brown versus blue iris color,52 and a germ line polymorphism of the OCA2 gene is associated with favorable survival of estrogen receptor-negative breast
cancer.53 Conceivably this finding may be related to the
previously reported enhanced sensitivity of cells overexpressing P protein to cytotoxic agents.54
In African and African-American individuals, there
is a distinct OCA2 phenotype (Fig. 73-4). Hair is yellow at birth and remains so throughout life, although
the color may turn darker. Hair color can turn lighter
in older individuals, and this probably represents the
normal graying with age. The skin is creamy white at
birth and changes little with time. No generalized skin
pigment is present, and no tan develops with sun exposure, but pigmented nevi, lentigines, and freckles often
develop, since the cutaneous melanocytes in these individuals both remain susceptible to ultraviolet (UV)induced changes early in life and retain some ability
Mutations of the OCA2 (P) gene, which maps to

chromosome arm 15q, are responsible for OCA2
(OMIM #203200).33 OCA2 occurs worldwide, though
somewhat more frequently in the African, AfricanAmerican, and certain Native American populations.
Historically, affected individuals have benefited from
limiting their sun exposure, especially in desert and
equatorial climates. Interesting anthropological studies have described how various societies have differed in their treatment of members with OCA2. For
example, the Cuna Indians of Panama actively forbade
marriage between female and male albinos, and infanticide against albino infants was common in the early
twentieth century. In contrast, no marriage discrimination was practiced in Hopi tribes, whose albinos were
not expected to participate in farming activities requiring substantial exposure to sunlight.34 From the standpoint of melanin synthesis, the defect in OCA2 appears
to involve a reduction in eumelanin synthesis primarily, with less effect on pheomelanin synthesis. The
predicted structure of the OCA2 gene, a melanosomal
protein, includes 12 transmembrane domains.35,36 As
expected, a number of mutations of the human OCA2
gene are associated with human OCA2.37,38
In Sub-Saharan Africa, a single 2.7-kb deletion allele
accounts for 60%90% of mutant OCA2 alleles and is
associated with a common haplotype, suggesting a
common founder.5,3840 It has been estimated that this
single mutation is associated with 25%50% of all
mutant OCA2 alleles in African-Americans.5,3844 However, other diverse mutant alleles have been described
in this population and in Africans. The Brandywine,
Maryland, isolate affects an inbred American population, originally located in a rural area east of Washington, DC, that has been studied extensively for its
prevalence of albinism, dentinogenesis imperfecta, and
other inherited recessive and dominant conditions,
with mixed Caucasian, African, and possibly Native
American ancestry.45 In this population, 1 in 85 individuals has OCA245,46 and is homozygous for the 2.7kb deletion allele of OCA2.38 Thus, it is likely that this
2.7-kb deletion allele accounts for the distinct OCA2
phenotype in Africans and African-Americans.47
OCA2 also has been reported at relatively high frequencies ranging from 1 in 28 to 1 in 6,500 in specific
Native American groups, including those populations
in the southwest United States (Hopi population),
southern Mexico, eastern Panama (Kuna population),
and southwest Brazil.34 In the Navajo population, a
homozygous 122.5-kb deletion has been described
in members with OCA2. This mutations results in
the loss of exons 10 to 20 of OCA2, corresponding
to a region containing seven of the transmembrane
domains, and appears to be specific for OCA2 within
785
11
Section 11
::
to synthesize melanin later. The irides are bluegray or

light tan or brown. The development of lentigines or
ephelides, well-demarcated pigmented patches usually
on sun-exposed areas of the skin, may be evidence of
a separate genetic susceptibility because these lesions
only develop in some OCA2 families and not in others.
The presence versus absence of ephelides is associated
with a lower risk of skin cancer in South African albinos,55 probably because the ability to produce ephelides
by albinos in that environment also signifies a greater
ability to produce pigment and thus demonstrate
increased protection from UV radiation.
In Caucasian individuals with OCA2, the amount of
hair pigment present at birth or developing with time
varies from minimal in northern Europeans (particularly Scandinavians) to moderate in southern European
or Mediterranean individuals. The hair can be very
lightly pigmented at birth, having a light yellow or
blond color, or more pigmented with a definite blond,
golden blond, or even red color. The skin is creamy
white and does not tan. The iris color is bluegray or
lightly pigmented, and the amount of translucency
correlates with the development of iris pigment. With
time, pigmented nevi and lentigines may develop, and
freckles are seen in areas with repeated sun exposure.
The hair in Caucasian individuals may slowly turn
darker through the first two or more decades of life.
The normal delayed maturation of the pigment system and sparse hair early in life can make it difficult
to recognize albinism early in northern European individuals. For all types of OCA in northern European
families, the cutaneous hypopigmentation at birth
or early in life is often similar to that of the parents
and relatives, and the first concern is raised when it
appears that the child is not tracking well or has developed nystagmus.
PRADERWILLI AND ANGELMAN SYNDROMES. PraderWilli and Angelman syndromes
often are associated with hypopigmentation.57,58 The

intragenic deletion encompassing one P allele in these
patients59,60 suggests that the observed pigmentary phenotype is related to OCA2 and the P gene, even if the
details of this association are not fully understood.47
PraderWilli and Angelman

syndromes
OCULOCUTANEOUS ALBINISM TYPE 3.
786
Mutations in the TYRP1 gene result in OCA3 (OMIM

#203290). The first described mutation was in an
African-American newborn twin initially classified
clinically as brown OCA. Mutation analysis revealed
a single-base deletion at codon 368 producing a frameshift and premature stop codon in exon 6 and a slightly
truncated TYRP1 molecule.63 This mutation is shared
by a substantial proportion of the rufous (red)
OCA population in southern Africa.64 Rufous OCA
is a distinct OCA phenotype in which the skin color
is a mahogany brown with a slight reddish hue, and
the hair color varies from deep mahogany to sandy
red.2,64 Additional OCA3-associated TYRP1 mutations

include a single-base substitution at codon 166, resulting in the alteration of a serine to a premature stop
codon in exon 3 and a truncated TYRP1 molecule,64
also identified in the rufous OCA population; and, in
a Pakistani kindred, individuals homozygous for a
distinct premature termination mutation.65 A Caucasian male was compound heterozygous for a missense
mutation in TYRP1 located in the second copper-binding domain, inherited from the patients mother, and
a stop codon, which apparently occurred spontaneously.66 Interestingly, the p.S166X mutation in TYRP1
previously associated with rufous OCA64 was found to
modify an OCA2 phenotype to a red-haired variant.67
OCA3 has presented with both the brown OCA and
the rufous OCA phenotypes in the African and AfricanAmerican populations. In the two cases of individuals
with OCA3 mutations only, not of African descent, the
phenotype has been that of a tyrosinase-positive albinism, such as OCA1B or OCA2. As additional examples of OCA3 are characterized, genotypephenotype
correlation should become clearer.
PATHOGENESIS OF OCA3
HERMANSKYPUDLAK SYNDROME. Mutations in eight different genes to date have been associated with types of HPS.70 Currently, our understanding
about the function of their gene products varies greatly.
However, a common theme is their functional involvement in trafficking cell type-specific products in
cells containing lysosome-related organelles (LROs),
including melanosomes in melanocytes.
HPS patients have OCA, with variable hypopigmentation of the skin, hair, and irides, and ocular abnormalities (see Fig. 73-5 and eFigs. 73-4.1, 73-5.173-5.3 in
online edition). In addition, they lack platelet dense bodies and demonstrate a prolonged bleeding time, mucous
membrane bleeding, a predisposition to epistaxis, easy
bruising, and metromenorrhagia.75 Whole-mount electron microscopy is used to provide a definitive determination of the absence of platelet dense bodies.76
The greatest clinical experience exists with patients
with HPS1 (OMIM #604982), HPS3 (OMIM #606118),
and HPS4 (OMIM #606118). Pulmonary fibrosis is
a common and severe manifestation of HPS1 and
HPS4, generally causing death between the fourth and
sixth decades of life.70,77 However, pulmonary fibrosis
appears not to be associated with HPS3, which also features less severe pigmentary abnormalities.7880 Among
HPS1 and HPS4 patients, a granulomatous colitis is
associated, occurring in approximately 15%.81,77 Ceroid
lipofuscin, a complex lipid-protein material, has been
reported to accumulate in the cells of HPS patients,
predominantly those with HPS1.75
Mutations in distinct genes, rather than clinical
phenotypes, define the various types of HPS. For
example, more than two dozen distinct mutations
have been found in HPS1 that cause disease.7678 The
most common, found in over 400 Puerto Rican individuals, is a 16-base pair (bp) frameshift duplication in
exon 15.79,80 Although the precise function of HPS1
protein is not yet known, HPS1 associates with HPS4

in the 200 kDa BLOC-3 (biogenesis of LROs complex-3)
complex81 and has also been found in association with
HPS4 in a larger, 500-kDa complex in melanoma cells
and fibroblasts.8284 In melanocytes cultured from the
skin of HPS1 patients, the melanogenic enzymes TYR,
TYRP1, and DCT/TYRP2 are found in large vesicular
structures in the cell body and dendrites, instead of in
the granular pattern typically associated with melanosomal localization,85,86 suggesting a role in the control
of protein trafficking to the melanosome. Mutations in
HPS4 have been described in 15 patients,76 although
its exact cellular role is not yet known. Functionally,
the ATP-dependent pump MRP4 (ABCC4), normally
localized to platelet granules and the plasma membrane, was found to be greatly reduced in HPS4
platelets.87
Mutations or deficiencies in the AP3B1 gene, encoding the 3A subunit of adaptor complex 3 (AP-3), one of
the four known APs, cause HPS2 disease.88 AP-3 interacts with tyrosinase, which is not targeted properly to
melanosomes in AP3B1-deficient melanocytes. Hence,
AP-3 protein is required for the trafficking of tyrosinase, and possibly other melanosomal proteins, from
an intracellular site to melanosomes. Interestingly,
the subcellular distribution of TYRP1 is unchanged in
HPS2 melanocytes, suggesting that TYRP1 transport,
in contrast to tyrosinase, is not entirely dependent
upon the AP-3 mechanism.89 The respiratory infections
associated with HPS2 may be due to the abnormal
movement of lytic granules in cytotoxic T lymphocytes
(CTLs) to the immunologic synapse, leading to impairment of microbial killing.90
CHEDIAKHIGASHI
SYNDROME
CHS
(OMIM #214500). CHS is a rare autosomal reces-
sive disorder characterized by severe immunologic

defects, hypopigmentation, bleeding tendency due
to absent or reduced platelet dense bodies,94 progressive neurologic dysfunction, and the presence of giant
peroxidase-positive lysosomal granules in peripheral
blood granulocytes.95,96 Mutations in the LYST (lysosomal regulator trafficking) gene have been associated with ChediakHigashi syndrome.97 Although the
precise role of the LYST product is not known, structural comparisons and inferences from the cell biology
of LYST mutant cells suggest it may be important for
membrane fusion during vesicular transport from the
trans-Golgi network to late endosomes and multivesicular structures.96,97
Most patients with CHS have a severe form of the
disease, childhood CHS,98 with early onset of the socalled accelerated phase, characterized by fever, anemia,
and neutropenia, including a lymphoproliferative
syndrome with hemophagocytosis and benign infiltration of most tissues by activated T lymphocytes. This
form of the disease is uniformly fatal unless patients
undergo allogenic bone marrow transplantation. However, this treatment does not prevent future neurologic
complications.69 Ten percent to 15% of patients exhibit
a much milder clinical disease, adult CHS,98 surviving
to adulthood but developing progressive and often
fatal neurologic dysfunction in middle age. Very rare
patients exhibit the intermediate adolescent CHS phenotype,98 which presents with severe infections in early
childhood but has a milder course by adolescence and
no accelerated phase. Interestingly, mutation analysis
of patients with the childhood, adolescent, and adult
forms of CHS showed that patients with severe childhood CHS had only functionally null mutant LYST
alleles, whereas patients with the adolescent and
adult forms of CHS tended to exhibit missense mutant
Figure 73-5 Puerto Rican HPS1 patient. The patient died

of pulmonary fibrosis.
Griscelli syndrome is
::
GRISCELLI SYNDROME.
11
Chapter 73
The most commonly described mutation in HPS3 is

a 3904-bp deletion mutation that includes the entire
first exon, found in a Puerto Rican population, which
is distinct from the HPS1 Puerto Rican mutation.72 In
addition, a splice site mutation has been described in
Ashkenazi Jews with HPS3 who are either homozygous for this mutation or compound heterozygous for
this mutation and other, nonconserved mutations.73
The HPS3 protein associates with the HPS5 and HPS6
proteins in the 340-kDa BLOC-2 complex.91,92 Melanocytes from HPS3 patients exhibit defective localization
of tyrosinase and TYRP1 in later stage melanosomes,
whereas proteins normally incorporated into earlystage melanosomes, such as silver/Pmel17/gp100 and
melan-a/MART1, are unaffected.85,93 These melanocytes exhibited lower levels of melanin than control
melanocytes, suggesting that the trafficking defect in
tyrosinase, and perhaps also TYRP1, is responsible for
the pigmentary dilution that can be observed in these
patients.
787
11
Section 11
::
alleles that likely encode LYST polypeptides with partial function. Furthermore, some patients with the CHS
phenotype do not have LYST mutations detectable
with established techniques.98
The hypopigmentation phenotype of CHS is variable and can be quite mild. Hair color is light brown to
blond, and commonly has a silvery or metallic sheen.96
Iris pigment is present, and nystagmus and photophobia may be present or absent. Histologic studies
of the eye in CHS have shown reduced iris pigment,
a marked reduction in retinal pigment granules, and
infiltration of the choroid with reticuloendothelial
cells.99 Cutaneous hypopigmentation is probably a
consequence of both the giant, hypopigmented melanosomes clustered around the nucleus within CHS
melanocytes, and their inefficient transfer to keratinocytes.100 Pigment granules in the hair shaft are large
and have an irregular shape.101
The giant, peroxidase-positive lysosomal granules
in neutrophils are a hallmark of the disease. These
granules appear to inhibit neutrophil function, which
along with neutropenia commonly observed is a
likely determinant of the recurrent bacterial infections.96 CHS natural killer (NK) cells have defective
lytic granule secretion,102 and defective cytotoxic
T lymphocyte-associated antigen 4 function has been
proposed as a potential mechanism for the accelerated,
lymphoproliferative stage of the disease.103 A reduced
number of irregular platelet dense granules in CHS is
responsible for the bleeding diathesis component.69,96

CLINICAL FEATURES OF CONGENITAL
WAARDENBURG SYNDROME. WS, described
by the Dutch physician Petrus Waardenburg in 1951,104
is the prototypic congenital disorder of pigmentation.
Although it was originally described as a syndrome
combining pigmentary defects of the hair (poliosis
or white forelock) and iris, congenital deafness, and
developmental craniofacial abnormalities, it was
subsequently realized that additional phenotypic

of Congenital Disorders of
Pigmentation
Waardenburg syndromes types 14
Tietz syndrome
Piebaldism
Woolfs syndrome
Generalized vitiligo
Segmental vitiligo
VogtKoyanagiHarada syndrome
Chemical leukoderma
Tuberous sclerosis (hypopigmented macules and
patches)
ZiprkowskiMargolis syndrome (X-linked albinism
deafness syndrome)
manifestations could be part of the same syndrome.

Four types of WS, WS1 through WS4, have been
described.105110 The discovery of molecular mutations
accounting for the different types of WS has helped to
explain its wide variety of manifestations as well as
to illuminate the importance of specific genes for the
development of different tissues and organs (Table
73-2). While practically all cases of WS1 and WS3
show mutated PAX3,105,105,109,110 WS4 individuals either
have homozygous mutations in EDN3 (the endothelin-3 gene)111113 or EDNRB (the endothelin-B receptor
gene)114 or heterozygous mutations in SOX10.115 On
the other hand, WS2 appears to arise more heterogeneously, as a mutation in MITF has been shown in only
a small fraction of WS2 patients.107,108
Waardenburg Syndrome Type 1. Individuals with WS1 (OMIM #193500) are usually heterozygous for mutations in PAX3; hence, WS1 is autosomal
dominant in inheritance. Although many different
mutations in PAX3 have been associated with WS1,
these mutations are thought either to be functionally
TABLE 73-2
Waardenburg and Tietz Syndrome Characteristics
788
Disorder
Clinical Signs
Mutated Gene(s)
Waardenburg syndrome (WS) type I
Hypopigmented patches, heterochromia irides, dystopia

canthorum, sensorineural deafness (75%)
PAX3
WS type II
Same as type I, but no dystopia canthorum
MITF
SNAI2/SLUG (homozygous)
WS type III
Same as type I with limb abnormalities
PAX3
WS type IV
Same as type I with Hirschsprungs disease (congenital

aganglionosis of the colon)
EDN3
EDNRB
SOX10
Tietz syndrome
Generalized hypopigmentation and sensorineural deafness
MITF
Linkage
analysis of families with WS2 (OMIM #193510, 608890,
Waardenburg Syndrome Type 2.
::
null alleles or to abrogate the interactions of PAX3 with

DNA.116
Individuals with WS1 have pigmentation abnormalities associated with craniofacial abnormalities
(see Fig. 73-6). Dystopia canthorum, which is lateral
displacement of the medial canthi of the eyes, is the
hallmark craniofacial defect found in virtually all cases
of WS1. A broadening of the nasal root, the presence
of hypoplastic alae nasi, and synophrys are other craniofacial abnormalities associated with WS1. Poliosis,
such as the presence of a white forelock, is the most
common pigmentation abnormality associated with
WS1. Depigmented white spots on the skin occur less
commonly, but are often located at the ventral midline
reflecting the compromised migration of dysfunctional
melanocyte precursors from their origin in the dorsal neural crest. Pigmentary abnormalities of the iris,
including complete heterochromia irides (differently
colored irises), partial heterochromia irides (variations
of color within an iris), or hypoplastic blue irides, can
also be associated with WS1. Premature graying may
also be observed in WS1. Congenital deafness is present in 57% of cases.117
The importance of PAX3 for the expression of
MITF,118,119 with consequent effects upon melanocyte
survival during development, is likely to account for
the pigmentary defects of WS1. A role for PAX3 in governing the development of neural crest derivatives that
contribute to bony and cartilaginous structures of the
face,120 particularly those contributing to the formation
of the frontal bone, explain the craniofacial anomalies
observed in WS1. Sensorineural deafness, observed with
incomplete penetrance in WS1, results from the variable
failure of melanoblasts to migrate to or to survive in the
stria vascularis in the lateral wall of the cochlea.121,122
11
Chapter 73
Figure 73-6 Waardenburg syndrome type 1. Note poliosis (white forelock) and dystopia canthorum (lateral displacement of the medial canthi of the eyes).
600193, 606662) identifed the MITF locus as a candidate locus for the disease gene. At least nine different
of mutations have been found in the coding region of
the MITF gene in WS2 families.107,123 However, MITF
mutations account for only a minor portion (15%) of
WS2 cases. A mutation in the transcription factor gene
SLUG/SNAI2 has also been associated with WS2,124 as
have heterozygous deletion mutations in SOX10,125 but
mutations in other, as yet undefined genes are likely
to be implicated in the future. WS2 is inherited in an
autosomal dominant pattern. Since most of the known
MITF mutations in WS2 compromise the HLHZip
region, thereby interfering with dimerization of
mutant MITF with wild-type MITF,126 the pigmentary
developmental pathology in most cases of WS2 probably occurs through haploinsufficiency (reduced gene
dosage, expression, or protein activity) rather than
through dominant-negative effects.123 Tietz syndrome,
described later, is likely to result from dominant-
negative effects of mutant MITF.
That mutations in MITF cause a subtype of WS is
mechanistically attractive because of the crucial importance of MITF in melanocyte survival during development. An epistatic relationship exists between PAX3
and SOX10 and MITF in melanocyte development
during embryogenesis. PAX3 and SOX10, as transcription factors, synergically transactivate MITF.33,34
Since mutations of PAX3 and SOX10 also cause auditory-pigmentary symptoms in other types of WS, it is
likely that failure of MITF transactivation is the main
determinant of pigment cell developmental dysfunction in these other subtypes as well. SLUG/SNAI2, as
a transcriptional target of MITF,35 may act in the same
pathway as an important downstream MITF effector
in melanocytes whose activity is inhibited in SLUGassociated WS2.
Although all types of WS have skin, hair, and iris
pigmentation anomalies and the possibility of hearing
loss, WS2 is notable for featuring only these auditorypigmentary symptoms. Diagnostic criteria for WS2
have previously been defined.116 Individuals fulfilling
two of the following four criteria, in the absence of
dystopia canthorum, limb deformity, or Hirschsprung
disease, should be counted as affected:
1. Congenital sensorineural hearing loss
2. Pigmentary disturbance of iris
a. Complete heterochromia irides (two eyes of
different color)
b. Partial or segmental heterochromia (segments of
blue or brown pigmentation in one or both eyes)
c. Hypoplastic blue irides (characteristic brilliant
blue, with thin iris stroma, in both eyes)
3. Pigmentary disturbance of the hair

a. White forelock from birth or in teens
b. Premature graying before age 30 years
4. A first- or second-degree relative with two or
more of criteria 13
A survey of 124 cases of WS2 and 270 cases of WS1

revealed differences of phenotypic penetrance between
WS2 and WS1: congenital sensorineural hearing loss
occurred in 77% and 57%, respectively; heterochromia
irides in 48% and 27%, respectively; hypoplastic blue
789
11
eye in 9% and 17%, respectively; white forelock in 9%

and 17%, respectively; early graying in 23% and 26%,
respectively; and white skin patches in 6% and 31%,
respectively. The higher incidence of hearing loss in
WS2 may be due to the difficulty of diagnosing WS2
in individuals without hearing loss. The hearing loss is
congenital, sensorineural, and nonprogressive, showing marked variation between and within families.
Among 81 WS2 cases in one series, 84% of patients
reported bilateral hearing loss; 40% of patients noted
profound loss, whether unilateral or bilateral.117
Section 11
::
Waardenburg Syndrome Type 3. WS3 (OMIM

#148820), also known as KleinWaardenburg syndrome,
is regarded as a variant of WS1. Most affected persons
are heterozygous for a mutation in PAX3, although
a few severely affected homozygotes have been
described.109 No specific mutations in PAX3, with the
possible exception of a missense mutation at Asp47,
have been correlated with the WS3 phenotype rather
than the WS1 phenotype, although individuals with
either homozygous or compound heterozygous mutations in PAX3 may tend to exhibit a severe WS3 phenotype instead of WS1.127 In addition to the features of
WS1, WS3 patients have musculoskeletal abnormalities, manifested as limb contractures and hypoplasia
of the limb musculature. The WS3 phenotype is consistent with the previously described role of PAX3 in the
activation of transcription factors that govern muscle
and limb development,128 distinct from its role regulating development of neural crest derivatives.
Waardenburg Syndrome Type 4. WS4
(OMIM #277580), also known as ShahWaardenburg
syndrome, is caused by heterozygous mutations in the
transcription factor gene SOX10, or by homozygous
mutations in the gene encoding the peptide ligand
endothelin-3, EDN3, or its receptor, EDNRB.129 In addition to governing aspects of melanocyte development,
these genes are important determinants of the development of the distal aspect of enteric nervous system
cells, also neural crest derived, that innervate the distal
part of the colon, which explains the association with
Hirschsprungs disease or congenital aganglionosis of
the colon. WS4 is the combination of the WS1 phenotype with Hirschsprungs disease.
TIETZ SYNDROME. Tietz syndrome130 (OMIM
#103500) is a hypopigmentationdeafness syndrome
resulting, like WS2, from mutations in MITF. Tietz syndrome has been described in three families to date. In
each case, the mutation is found in the region of the
MITF gene encoding the DNA-binding domain. In two
cases,131,132 an in-frame deletion mutation (DelR217) has
been described, which affects the DNA-binding basic
domain of MITF, leaving the dimerization HLHZip
domain intact and functional. In these heterozygous
Tietz syndrome individuals, it is likely that DelR217MITF binds with wild-type MITF and interferes with
the ability of the dimer to bind to DNA, a dominantnegative effect. Indeed, the identical mutation in
790
mice133 causing a semidominant phenotype, a phenotype that is incomplete in the heterozygous state, in
vivo with a mild heterozygous spotting phenotype,
but a prominent homozygous phenotype with early
embryonic loss of all melanocyte precursors,134 was
shown to have a dominant-negative effect in vitro.126
In addition, another mutation described in the family
originally reported with the syndrome is predicted to
exhibit an Asn210Lys substitution in the basic region.135
The localization of this mutation to the DNA-binding
region also suggests that it has dominant-negative
effects.
Although sometimes regarded as a variant of
WS2A (MITF-associated WS2),136 Tietz syndrome
individuals exhibit generalized cutaneous hypopigmentation similar to that found in OCA2, rather
than distinct depigmented patches. Reduced melanosomes in keratinocytes found in one affected
individual132 may account for the generalized
hypopigmentation that is observed. Affected individuals invariably exhibit profound hearing loss.
Interestingly, a child with a deletion on chromosome
arm 3p encompassing the entire MITF locus not only
exhibits generalized hypopigmentation reminiscent
of Tietz syndrome but also mild craniofacial anomalies and retention of some hearing function, as can
be seen in types of WS.137
PIEBALDISM. Piebaldism (OMIM #17280) is caused

by mutations in the KIT proto-oncogene.138 Stimulation of the KIT receptor tyrosine kinase by its ligand,
stem cell factor (SCF)/KIT ligand, results in the
phosphorylation of MITF and potentiation of MITF
activity.139 This relationship between the KIT receptor
and MITF, as a final common effector of melanocyte
survival during development, is likely to explain the
developmental patchy loss of melanocytes occurring
in human piebaldism when KIT receptor function is
compromised.
Patients with piebaldism generally have depigmented patches on the ventral or lateral trunk and/
or the mid-extremities, sparing the hands and feet.
Poliosis is a common feature. The depigmented
patches tend to be larger than those observed in WS.
Typically, piebaldism is not associated with deafness, although piebaldism with deafness, otherwise
referred to as Woolf syndrome, has been molecularly
confirmed.140
DYSCHROMATOSIS SYMMETRICA HEREDI
TARIA. Dyschromatosis symmetrica hereditaria
(DSH; OMIM #127400), an autosomal dominant

condition, was recently shown to be caused by
mutations in ADAR1, formerly known as DSRAD,
encoding adenosine deaminase acting on RNA 1,
an RNA-editing enzyme.141,142 It is not known how
reduced activity of this enzyme results in pigmentary loss at acral sites. Patients exhibit speckled
hypopigmentation, which is limited to the dorsa of
the hands and feet.
COMPLICATIONS OF ALBINISM
AND CONGENITAL DISORDERS
OF PIGMENTATION
MANAGEMENT OF ALBINISM
AND CONGENITAL DISORDERS
OF PIGMENTATION
All individuals with albinism should be under the care
of an ophthalmologist and should have annual examinations until adult life. Most are hyperopic or myopic,
and many have significant astigmatism; refractive correction aids in their visual attentiveness and performance.
Proper dermatologic care and protection from UV
radiation of the sun and care by a dermatologist are
strongly advised for individuals with OCA. Precautions
KEY REFERENCES
9. Wei ML: Hermansky-Pudlak syndrome: A disease of
protein trafficking and organelle function. Pigment Cell
Res 19:19-42, 2006. doi:10.1111/j.1600-0749.2005.00289.x
18. Spritz RA et al: Detection of mutations in the tyrosinase
gene in a patient with type IA oculocutaneous albinism.
N Engl J Med 322:1724-1728, 1990
27. King RA et al: Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous
albinism. J Clin Invest 87:1046-1053, 1991
47. Brilliant MH: The mouse p (pink-eyed dilution) and
human P genes, oculocutaneous albinism type 2 (OCA2),
and melanosomal pH. Pigment Cell Res 14:86-93, 2001
96. Introne W, Boissy RE, Gahl WA: Clinical, molecular, and
cell biological aspects of Chediak-Higashi syndrome.
Mol Genet Metab 68:283-303, 1999
117. Liu XZ, Newton VE, Read AP: Waardenburg syndrome
type II: Phenotypic findings and diagnostic criteria. Am J
Med Genet 55:95-100, 1995
123. Tassabehji M et al: The mutational spectrum in Waardenburg syndrome. Hum Mol Genet 4:2131-2137, 1995
136. Steingrimsson E, Copeland NG, Jenkins NA: Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet 38:365-411, 2004
141. Miyamura Y et al: Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet
73:693-699, 2003
With the exception of individuals with OCA1A,

patients with OCA can realize gradual pigmentation
of the skin and hair over the course of their lives, and
develop melanocytic nevi.
As long as the life-threatening aganglionic megacolon of WS4 is recognized at birth and corrected
surgically, the prognosis of congenital disorders of pigmentation is favorable, with minor long-term health
consequences. Spontaneous repigmentation of both
the white forelock and white spots has been reported,
as has contraction of the white spots.
::
OF ALBINISM AND CONGENITAL
11
Chapter 73
The complications of albinism revolve around the

impact of the reduced visual acuity and hypopigmentation upon the affected individual. The primary
medical complications are the early appearance of
skin tumors in individuals with inadequate sun protection in equatorial climates. Delayed recognition
and management of squamous cell carcinoma and
melanoma in this setting can lead to metastasis and
early death.
The complications of congenital disorders of pigmentation are more likely to relate to their associated
manifestations, such as deafness or aganglionic megacolon, than the pigmentary loss.
include the use of sunscreens, hats, and long sleeves, as

well as sun avoidance.
For HPS patients, topical control of bleeding can
be achieved with thrombin and Gelfoam. In advance
of dental procedures or biopsies, intravenous infusion of 1-desamino-8-d-arginine vasopressin can be
used prophylactically.69 The accelerated phase of
CHS is managed initially with multimodal immunomodulatory therapy and maintenance cyclosporine
followed by allogeneic hematopoietic cell transplantation.143
No treatment has been reported for the pigmentary
loss associated with congenital disorders of pigmentation. However, melanocyte grafting, either with epidermal grafts or epidermal cell suspensions as used for
the treatment of stable vitiligo,144146 might be an option
to consider. Cochlear implants in the pediatric population with WS have led to positive outcomes.147 It is
important to recognize the hearing defect early so that
proper management, including proper social and mental development and schooling, can be implemented.
Genetic counseling can help affected individuals
assess their chances of transmitting the disorder to
their progeny.
791
11
Chapter 74 :: Vitiligo

:: Stanca A. Birlea, Richard A. Spritz, &
David A. Norris
VITILIGO AT A GLANCE
The most frequent depigmenting disorder,
affecting 0.3%0.5% of the population
worldwide
Section 11
An acquired disease involving multiple

genes and nongenetic environmental factors
::
Characterized by progressive autoimmunemediated destruction of epidermal

melanocytes
Typical presentation: patches of white skin

and hair
Cause of physiological and social stigma
among affected individuals
Increased risk for other autoimmune
diseases, unpredictable evolution and
unsatisfactory therapeutic outcomes
EPIDEMIOLOGY
The prevalence of vitiligo is reasonably consistent
among different populations: 0.38% in Caucasians,1
0.34% in Afro-Caribbeans,2 0.46% in Indians,3 though
perhaps somewhat less frequent in Han Chinese,
0.093%.4 Vitiligo appears to affect both genders equally,
though women are overrepresented among patients
seeking clinical care. Vitiligo can develop at any age,5
with a mean age-of-onset in Caucasian patients of
about 24 years.6 The most common subtype, generalized vitiligo (GV), is an autoimmune disease that is
associated with other autoimmune diseases in about
20%30% of patients, most frequently autoimmune
thyroid disease (Hashimotos thyroiditis or Graves
disease), rheumatoid arthritis, psoriasis, type 1 diabetes (usually adult-onset), pernicious anemia, systemic
lupus erythematosus, and Addisons disease.7
792
Vitiligo is a multifactorial, polygenic disorder, with a

complex pathogenesis that is not yet well understood.8
Of various theories of disease pathogenesis, the most
accepted is that genetic and nongenetic factors interact
to influence melanocyte function and survival, eventually leading to autoimmune destruction of melano-
cytes.7 Other suggested explanations have included

defects of melanocyte adhesion,9 neurogenic damage,10
biochemical damage,11 autocytotoxicity,12 and others.
GENETICS OF VITILIGO
Large-scale epidemiological surveys have shown that
most cases of vitiligo occur sporadically, although
about 15%20% of patients have one or more affected
first-degree relatives. Typically, familial aggregation
of cases exhibits a non-Mendelian pattern suggestive
of polygenic, multifactorial inheritance.8 Concordance
in monozygotic twins is 23%,6 indicating that both
genetic and nongenetic (presumably environmental)
factors play major roles in disease pathogenesis.
Almost all studies of vitiligo genetics have focused
on GV. Several genes involved in immune function,
including loci in the MHC, CTLA4, PTPN22, IL10,
MBL2, and NALP1 (NLRP1), have been implicated in
susceptibility to GV on the basis of genetic linkage
or association studies.7 A recent, very large genomewide association (GWA) study of European Caucasian
GV patients and families identified at least ten different loci that contribute to GV risk.13 Seven of these
GV susceptibility loci have also been associated with
other autoimmune diseases [(1) HLA class I, (2) HLA
class II, (3) PTPN22, (4) LPP, (5) IL2RA, (6) UBASH3A,
and (7) C1QTNF6], two loci encode proteins involved
in immune function [(1) RERE and (2) GZMB], and
another locus, TYR, encodes tyrosinase, a key enzyme
of melanin biosynthesis and the major GV autoantigen.
Segmental vitiligo (SV) appears to be genetically
distinct from GV. Its generally sporadic occurrence
and unilateral distribution have led to the suggestion
that it might result from somatic mosaicism for de
novo mutations,14,15 perhaps in genes that are critical
for melanoblast/melanocyte development or survival,
although this hypothesis remains to be confirmed.
AUTOIMMUNE HYPOTHESIS
There is compelling biological evidence supporting
an autoimmune basis for GV.16 GV is epidemiologically associated with a number of other autoimmune
diseases,6,17 both in patients and in their close relatives, indicative of a heritable autoimmune diathesis.
Humoral immunity was first implicated by the finding in some cases of circulating antimelanocyte autoantibodies18 that target various melanocyte antigens,
including tyrosinase, tyrosinase-related protein-1,
dopachrome tautomerase, and others, and that have
the capability to kill melanocytes in vitro19 and in
vivo.20 Currently, these autoantibodies are thought to
reflect secondary humoral responses to melanocyte
Vitiligo
There is some evidence that vitiligo is a disease of

the entire epidermis, possibly involving biochemical
abnormalities of both melanocytes and keratinocytes.11
The specific morphological and functional abnormalities observed in vitiligo melanocytes and keratinocytes
are thought to have a genetic background.11 Ultrastructural abnormalities of keratinocytes from perilesional
vitiligo skin have been related to impaired mitochondrial activity,26 and are thought to affect the production
of specific melanocyte growth factors and cytokines
that regulate melanocyte survival.11 An essential biochemical finding is elevated levels of H2O2 in affected
regions of epidermis,27 that may be caused in part by
reduced enzymatic antioxidant capacity of keratinocytes and melanocytes.11,19 A defective antioxidant
defense may confer melanocytes an increased susceptibility both to immunologic cytotoxicity and to cytotoxicity induced by reactive oxygen species.19
::
BIOCHEMICAL HYPOTHESIS
11
Chapter 74
destruction rather than a primary cause of GV.18 A

greater role is attributed to the inflammatory infiltrate
sometimes seen at the margins of active GV lesions,
composed mainly of cytotoxic T lymphocytes. As these
T cells express a type-1 cytokine profile and colocalize
with epidermal melanocytes, it has been hypothesized
that these cells are actively cytolytic toward remaining
melanocytes, via the granzyme/perforin pathway.21
An immune mechanism has also been suggested
to underlie chemical leukoderma.22 The so-called
occupational vitiligo may occur in individuals who
encounter large doses of phenolic compounds, usually 4-tertiary butyl phenol (4-TBP) and other phenolic
compounds that may be contained in cleaning solutions. Occupational vitiligo usually initially involves
the hands and forearms (the site of contact with the
inciting agent). At present, it is unclear whether these
agents are directly toxic to melanocytes, or whether
some individuals might be genetically susceptible to
melanocyte injury from aliphatic phenolic derivatives,
ultimately resulting in melanocyte death, release of
antigenic intracellular proteins, loss of tolerance, and
autoimmunity.
An immune mechanism has also been proposed for
the vitiligo-like depigmentation, which can appear in
the course of IL-2 immunotherapy-based treatments
for cutaneous melanoma, possibly via the stimulatory effect of IL-2 on T cell growth and activation.2325
Some melanoma-associated antigens (e.g., MART-1,
gp100, and tyrosinase) are expressed on normal melanocytes, suggesting that the occurrence of treatmentrelated vitiligo-like depigmentation in melanoma may
involve cross-reaction of some antimelanoma immune
responses with normal melanocytes.
Figure 74-1 Vitiligo vulgaris in an adult.

orders. On the basis of the polymorphic distribution,
b
extension, and number of white patches, vitiligo is classified into generalized (vulgaris, acrofacial, mixed),
universalis, and localized (focal, segmental, and mucosal) types.28 Vitiligo is also classified as segmental and
nonsegmental types, on the basis of distinctive clinical
features and natural histories.29 According to this classification, non-SV includes all cases not classified as segmental, including localized, generalized, and acrofacial.

Vitiligo vulgarismultiple scattered lesions distributed in a more or less symmetrical pattern; the most
common presentation of GV (Fig. 74-1).
Acrofacial vitiligoaffects the distal end of fingers
and facial orifices in a circumferential pattern; a
subtype of GV (Fig. 74-2).
CLINICAL FEATURES
The principal clinical manifestation of vitiligo is the
appearance of acquired milk-white macules with
fairly homogeneous depigmentation and well-defined
Figure 74-2 Acrofacial vitiligo.
793
11
Section 11
::
Figure 74-3 Vitiligo universalis.

794
Mixed vitiligocombination of acrofacial and vulgaris, or segmental and acrofacial types.

Vitiligo universaliscomplete or nearly complete
depigmentation of the whole body (Fig. 74-3); the
most severe form of GV.
Focal vitiligocharacterized by the presence of
one/few macule(s) in one area but not distributed
in a segmental pattern (Fig. 74-4); considered a
precursor form of GV.
Mucosal vitiligoa term reserved for depigmentation of mucous membrane alone.
SVcharacterized by macules having unilateral
dermatomal distribution that do not cross the mid-
Figure 74-4 Focal vitiligounique macule of focal vitiligo.
Figure 74-5 Segmental vitiligo of the face and neck.

line (Fig. 74-5). It generally affects young children
and typically remains localized, the depigmented
lesions persisting unchanged for many years.30
The occurrence of concomitant other autoimmune
diseases is uncommon, compared with GV.29,31,32
Vitiligo often demonstrates a predilection for sunexposed regions, body folds, and periorificial areas,
although any part of the body can be affected. Various
precipitating factors have been suggested, including
physical trauma to the skin, sunburn, psychological
stress, inflammation, pregnancy, contraceptives, vitamin deficiency, and many others. However, at this time
no specific environmental triggers have been proven.
Vitiligo may appear at sites of skin trauma (Koebners phenomenon) (Fig. 74-6).
Figure 74-6 Koebnerization under brassiere.
Trichrome vitiligo is characterized by the presence

of patches of intermediate hue (hypopigmentation)
between the normal skin and the completely depigmented skin.
Quadrichrome vitiligo is characterized by the presence of a fourth color (dark brown) at sites of perifollicular repigmentation. It is more often encountered in patients with darker skin phototypes.
Pentachrome vitiligothe occurrence of five shades
of color: (1) white, (2) tan, (3) medium brown, (4)
dark brown, and (5) black.
Confetti vitiligo or vitiligo ponctu tiny punctatelike depigmented macules on a hyperpigmented
macule or on normal skin.
Red vitiligothe depigmented lesions have a raised
erythematous border.
Blue vitiligoa bluegray appearance of the skin,
which corresponds histologically with the absence
of epidermal melanocytes and presence of numerous dermal melanophages.

COMORBID ASSOCIATIONS
GV has been often associated with a variety of other
conditions, principally autoimmune diseases.33 The
Vitiligo
SPECIFIC RARE CLINICAL

PHENOTYPES
::
Leukotrichia (depigmentation of hair within vitiligo

macules (Fig. 74-7), can be quite variable (10%60%), and
is considered to indicate destruction of the melanocyte
reservoir within the hair follicle, therefore, predicting a
poor therapeutic response.28 Premature graying of the hair
has been described in up to 37% of patients with vitiligo,28
although poor definition and quantitation of this feature
makes this supposed clinical association uncertain.
11
Chapter 74
Figure 74-7 Leukotrichia. (Reprinted with permission

from Falabella R: Vitiligo and the malanocyte reservoir.
Indian J Dermatol 54(4):313-318, 2009.)
most prevalent associated autoimmune disease is

autoimmune thyroid dysfunction, either hypothyroidism (Hashimotos thyroiditis) or hyperthyroidism (Graves disease). Other autoimmune diseases
such as rheumatoid arthritis, psoriasis, type 1 diabetes mellitus (usually adult-onset), pernicious
anemia, systemic lupus erythematosus, and Addisons disease also occur with increased frequency
in patients with GV.6,17 Most of these disorders,
including GV, can occur in various combinations
and constitute components of the APECED (APS1)
and Schmidt (APS2) multiple autoimmune disease
syndromes.
Vitiligo can also be part of the VogtKoyanagi
Harada (VKH) syndrome, a multiorgan disorder that
affects pigmented structures, such as the eye, inner
ear, meninges, and skin.34 Several clinical and experimental studies have pointed to a role of cell-mediated
immunity in VKH, particularly involving CD4+ T cells
and Th1 cytokines.35,36
Another very rare multiorgan disorder, Alezzandrini syndrome, associates facial skin depigmentation,
poliosis, deafness, and unilateral tapetoretinal degeneration of the eye.37 However, many investigators now
believe that VKH and Alezzandrinis syndrome are
merely different clinical expressions of the same fundamental disease.38
DEPIGMENTATION OTHER
THAN VITILIGO
Skin depigmentation may occur in melanoma patients
in three different clinical contexts39: partial depigmentation (regression) of the tumor, leukoderma acquisitum centrifugum around the tumor, and vitiligo-like
depigmentation, occurring at distant sites. Vitiligolike depigmentation is thought to be a marker of the
patient developing immunity against melanoma cells
and to be an indicator of favorable prognosis, especially in advanced stages.25
The most common form of leukoderma acquisitum
centrifugum appears around pigmented nevi (called
halo nevi), and often progress to spontaneous disappearance of the nevus,39 presumably via lymphocytemediated destruction of nevus cells.
DIAGNOSIS
The diagnosis of vitiligo is established principally on
clinical grounds, which may include distribution and
extent of lesions, and natural history of disease.40
LABORATORY. Given the association between vitiligo and other autoimmune diseases, several screening laboratory tests are helpful, including T4 and
thyroid-stimulating hormone levels, antinuclear antibodies, and complete blood count. Clinicians should
also consider testing for serum antithyroglobulin and
antithyroid peroxidase antibodies, particularly when
patients have signs and symptoms suggestive of
thyroid disease.
795
11
HISTOLOGY. A skin biopsy is rarely necessary to

confirm the diagnosis of vitiligo. Generally, histology
shows an epidermis devoid of melanocytes in lesional
areas,41 and sometimes sparse dermal, perivascular,
and perifollicular lymphocytic infiltrates at the margins of early vitiligo lesions and active lesions, consistent with cell-mediated immune processes destroying
melanocytes in situ.42 Some reports42 have suggested
that melanocytes may never be completely absent

from the depigmented epidermis and that residual
melanocytes maintain the capability of recovering
functionality. Further studies are needed to clarify this
highly debated issue with obvious therapeutic implications.
Differential diagnosis for vitiligo is presented in
Box 74-1 and Box 74-2.43,44
Box 74-1 Differential Diagnoses for GENERALIZED VITILIGO

Section 11
::
Condition
Distinguishing Features
Inherited hypomelanoses
Piebaldism
Waardenburgs syndrome
Tuberous sclerosis
Itos hypomelanosis
Stable and circumscribed white patches (with absence of melanocytes)

affecting anterior body and limbs; white forelock; autosomal dominant.
White forelock, white skin macules, hypertelorism, deafness,
Hirschsprung disease; multiple genes-autosomal dominant or recessive.
Ash leaf hypopigmented macules, facial/periungual angiofibromas,
shagreen patches; autosomal dominant.
Linear distribution, unilateral or bilateral pattern of hypopigmented
macules; sporadic; chromosomal or genetic mosaicism.
Infectious disorders
Tinea versicolor
Secondary syphilis
Leprosy (tuberculoid/borderline forms)
Hypopigmented lesions, beginning as reddish macules with fine scales

upon scraping and seborrheic distribution. At mycologic examination:
hyphae and spores.
Depigmented round/oval patches (postinflammatory depigmentation)
around the neck (necklace of Venus), trunk, limbs, or depigmented
patches with peripheral reticular hyperpigmentation (primary lesion).
Serological tests for treponemal infection are positive.
Depigmented patches with polymorphic presentation, usually
accompanied by localized anesthesia; histology: compact skin
granulomas.
Postinflammatory hypopigmentation
Discoid lupus erythematosus, scleroderma, lichen sclerosis et atrophicus,
psoriasis
Patients have history of preexisting dermatosis.
Paramalignant hypomelanoses
Mycosis fungoides
Cutaneous melanoma
Autoimmune reactions to advanced
melanoma
Hypomelanotic macules or diffuse depigmentation especially in

darker skin phototypes. Flat skin patch, plaque, and tumors. Histology:
epidermal infiltrates with mononuclear cells.
Halo depigmentation around or within the tumor.
Depigmentation at a distance from the tumor; the presence of tumor
excludes typical vitiligo.
Idiopathic disorders
Postinflammatory pigment loss
Hypopigmented well circumscribed macules, sharply defined and small

in size. They are slow progressive and nonconfluent. Histology indicates
epidermal atrophy and reduction in melanin content.
Postburn hypopigmentary lesions, shaped in the form of the burn.
Hypopigmenting inflammatory reactions leave ill-defined, poorly
circumscribed lesions. The history of preceding eruption/injury excludes
vitiligo.
Toxin-induced depigmentation
Drug-induced depigmentation
Vitiligo-like depigmentation generally caused by topical occupational

exposure to phenoliccatecholic derivatives, often affecting the hands
and forearms.
Caused by use of systemic drugs (chloroquine, fluphenazine,
physostigmine, imatinib, or topical imiquimod).
From Taeb A, Picardo M: Clinical practice. Vitiligo. N Engl J Med 360:160, 2009.
796
11
Box 74-2 Differential Diagnoses

for Localized Vitiligo
NEVUS
DEPIGMENTOSUS
NEVUS ANEMICUS
TREATMENT
FUNDAMENTS OF VITILIGO THERAPY:
MELANOCYTE REPOPULATION
The key principle of vitiligo therapy is facilitating
repopulation of depigmented patches of the interfollicular epidermis with active melanocytes that are able to
migrate, survive to repopulate the depigmented skin,
and carry out melanin biosynthesis.45 Repigmentation
may occur spontaneously and may also be therapyinduced. Spontaneous repigmentation is unpredictable, often clinically insignificant, and tends to be
cosmetically unacceptable.46,47 It occurs in fewer than
50% of patients, most commonly in younger patients
and in sun-exposed areas, where natural sunlight may
act as an inducing agent.48 In clinical practice, the most
frequently encountered pattern of repigmentation is
perifollicular (Fig. 74-8), though other patterns, such
as marginal, diffuse, or combined also may occur.
The principal source of melanocytes involved in
repopulation of vitiligo skin is most likely melanocyte
precursors derived from the outer root sheath (ORS) or
bulge area of the hair follicle.4951 A secondary potential reservoir may be located near lesional borders.
Vitiligo
The clinical course of any given case of GV is unpredictable, but is typically gradually progressive and
difficult to control with therapy. Sometimes lesions
spread over time, whereas in other cases disease activity stops, persisting in stable status for a long period.
Some clinical parameters such as a long duration of the
disease, occurrence of Koebners phenomenon, leukotrichia, and mucosal involvement have been suggested
as indicators of relatively poor prognosis.28
The middle and lower parts of the ORS are populated

by l-3,4-dihydroxyphenylalanine (DOPA)-negative,
amelanotic melanocytes,49,50 which may be recruited
from the ORS of the hair follicle in response to ultraviolet (UV), corticosteroids, or other stimuli. As a result,
the number of melanocytes in the ORS of hair follicles
increases significantly and some become active, suggesting that melanocyte precursors proliferate and at
least some undergo maturation.50 Activated ORS melanocytes acquire all of the structural and enzymatic
proteins required for melanogenesis, proliferation and
maturation as they migrate up the hair follicle into the
nearby epidermis, where they spread centrifugally and
form perifollicular pigment islands. They then become
larger cells, with intense DOPA oxidase activity.
Vitiligo repigmentation is assessed in terms of the
proportion of treated subjects in whom a specified
degree of repigmentation is achieved; depending on
the study, more than 50% or more than 75% repigmentation may be considered a good response.52 Woods
lamp (UVA) examination is useful to monitor response
to therapy. In the absence of epidermal melanin that
otherwise absorbs most of the UVA light, more photons reach the dermis, where they are absorbed by
collagen that then fluoresces and emits bright visible
light. In contrast, visible wavelengths of ambient room
light are less well absorbed by melanin in the normally
pigmented epidermis than UVA wavelengths and do
not produce fluorescence in the dermis. Hence, under
Woods light the vitiligo area appears brighter and the
normal skin appears darker than when illuminated
with ambient room light (Fig. 74-9).
::
CLINICAL COURSE AND

PROGNOSIS
Figure 74-8 Follicular repigmentation in vitiligo after

psoralen and ultraviolet A light therapy.
Chapter 74
Solitary hypopigmented macule well circumscribed with

irregular borders, stable in
size, solitary, most often present at birth.
Hypochromic pale lesion
with well-defined borders
and irregular margins; often
solitary, located on the trunk.
Histology and electron microscopic examination reveal no
abnormality in melanocytes
or melanization.
THERAPEUTIC APPROACHES
Different treatment strategies (Box 74-3) have been
designed to inhibit the immune response in vitiligo,
thereby reducing melanocyte destruction, and also
enhancing epidermal repopulation by melanocytes,
both by stimulating recovery of damaged melanocytes
in situ and by reactivating residual melanocytes or
stimulating melanocyte in-migration from neighboring skin or hair follicles. However, at present it is not
clearly understood to what extent treatments must
suppress the autoimmune process versus stimulate
797
11
Section 11
::
Figure 74-9 Woods lamp examination. Woods lamp provides bright reflection of white patches and enhanced details
on intermediate pigment tones (A), as compared with white light (B). (Reprinted with permission from Taieb A, Picardo M:
Vitiligo. NEJM 260:160-169, 2009.)
melanocyte repopulation of the epidermis to provide

maximum efficacy.
UV radiation therapy includes phototherapy with
narrowband UVB (NB-UVB311 nm) or broadband
UVB (BB-UVB290320 nm), and photochemotherapy. UV therapy is thought to act as a skin immunomodulator, regulating the activity of inflammatory
cytokines, depleting of Langerhans cells, modulating
the activity of regulatory T cells, and polarizing the
immune response toward the Th2 profile, thereby
reducing or stabilizing the depigmentation process
in vitiligo.45 In addition, UV radiation coordinates
several of the pathways via which melanogenic cytokines stimulate melanogenesis.45 Furthermore, UV
may also induce the release of epidermal factors that
stimulate melanocyte proliferation and migration,
although this speculation has not been substantiated

in repigmenting vitiligo lesions. The release of several
paracrine factors produced by UV-exposed keratinocytes53 that regulate melanocyte functions is thought
to be under p53 regulation,54 although further studies
are needed.
ULTRAVIOLET B NARROWBAND
Narrowband UV (NB-UVB) light, with peak emission
at 311 nm, is considered the most effective and safest current therapy for vitiligo, and thus is currently
the treatment of choice for patients with moderateto-severe GV. Recent studies evaluating psoralen and
UVA (PUVA) versus NB-UVB indicate that NB-UVB
Box 74-3 Treatments for Vitiligo

Topical
Physical
First line
Corticosteroids
Calcineurin inhibitors
Ultraviolet B (narrowband)
Systemic psoralen and ultraviolet A light (PUVA)
Second line
Calcipotriol
Topical PUVA
Excimer laser
798
Systemic
Surgical
Corticosteroids
(pulse therapy)
Grafting
Melanocyte transplant
CORTICOSTEROIDS
TOPICAL CORTICOSTEROIDS
Topical corticosteroids represent the first-line therapy
for localized vitiligo, and are highly recommended
for facial or small lesions and for use in children.
Advantages include ease of application, high compliance rate, and low cost. Compared with PUVA, which
promotes a predominantly perifollicular pattern of
repigmentation, topical corticosteroids result in more
diffuse repigmentation, which occurs more quickly
Vitiligo
Until recently, PUVA was considered the mainstay of

therapy for patients with widespread vitiligo. PUVA
consists of a combination of topical or oral 8-methoxypsoralen with UVA (320400 nm) irradiation. The
psoralen of choice, methoxsalen, is given in an oral
dose of 0.4-mg/kg body weight, 12 hours prior to
UVA exposure. For topical PUVA therapy, methoxsalen 0.1% is applied to areas of vitiligo 3060 minutes before exposure to UV radiation. Topical PUVA
is indicated in patients whose vitiligo involves less
than 20% of the body surface area, and painful burns
(phototoxicity reactions) are unfortunately difficult to
avoid. Oral psoralens can be used for patients with
more extensive involvement or in patients who do not
respond to topical PUVA (see Chapter 237). After oral
treatment, patients must wear UVA-blocking glasses,
and it is also recommended they use broad-spectrum
sunscreens and wear protective clothing. Patients with
darker complexions tend to respond best to PUVA,
possibly because they tolerate higher PUVA exposures.61 Potential side effects of PUVA therapy are discussed in Chapter 237. PUVA is not recommended for
use in children under the age of 12 years owing to the
long-term delayed risks of cataract formation and skin
cancer.
11
::
PHOTOCHEMOTHERAPY (PUVA)
but is less stable.62 Light and electron microscopy of

skin biopsies from control and steroid-treated areas
showed marked repopulation by functional melanocytes in the repigmented vitiliginous skin. In steroid
repigmented areas melanocytes appeared dendritic
and DOPA-positive, and unlike melanocytes in the
pigment margins of untreated areas of vitiligo, contain many melanosomes of normal size and shape.63
The current trend, based on the results of a large
meta-analysis that included randomized controlled
trials of 29 patient series, is that class 3 and 4 corticosteroids are the most effective for treatment for
localized vitiligo.52 Thus, localized lesions can be
treated with a high-potency fluorinated corticosteroid (e.g., clobetasol propionate ointment, 0.05%) for
12 months. Treatment can be gradually tapered to
a lower potency corticosteroid (e.g., hydrocortisone
butyrate cream, 0.1%). Caution is necessary when
using topical steroids on and around the eyelids, as
their use can increase intraocular pressure and exacerbate glaucoma. Vitiligo recurrence after cessation
of treatment and corticosteroid-induced side effects
(i.e., skin atrophy, telangiectases, striae, and, rarely,
contact dermatitis) are the limiting factors. Combination therapy (corticosteroids + UVB, corticosteroids
+ calcineurin inhibitors, corticosteroids + vitamin
D analogs) may be beneficial in some cases, as two
agents together may act synergistically on pigment
restoration and on immune suppression, at lower
individual doses, thus, potentially minimizing overall side effects.
Chapter 74
produces higher repigmentation rates and better color

matching).55 NB-UVB has fewer short-term adverse
reactions such as painful erythema and appears to
have fewer long-term side effects such as epidermal
thickening, atrophy, and photocarcinogenesis than
PUVA.56 Several clinical studies have reported high
rates (75%) of repigmentation in at least 40% of
patients treated with NB-UVB.5760
The most commonly used NB-UVB protocol43
involves twice-weekly administration of a fixed starting dose of 0.21 J/cm2, increasing the dose by 20% at
each session until the minimal erythema dose (the
lowest dose that results in visible erythema on depigmented skin at 24 hours) has been reached. Approximately 9 months of therapy are required to achieve
maximal repigmentation; at least 3 months of treatment are warranted before the condition can be classified as nonresponsive.
The most responsive sites are face, trunk, and limbs,
and the least responsive sites are the hands and feet.
SYSTEMIC CORTICOSTEROIDS
Systemic corticosteroids have been used in pulse therapy and for short periods to halt rapid spread of depigmentation in some cases of GV.61
CALCINEURIN INHIBITORS
Calcineurin inhibitors can be effective in vitiligo
therapy because of their capacity to restore the
altered cytokine network. Tacrolimus has been
shown to inhibit T cell activation by downregulating
transcription of genes encoding proinflammatory
cytokines IL-2, IL-3, IL-4, IL-5, interferon- (IFN-),
tumor necrosis factor- (TNF-), and granulocytemacrophage colony-stimulating factor (GM-CSF)
in T cells.64 In addition, a direct effect of tacrolimus
on melanocyte growth and migration during repigmentation has been reported.65 Topical calcineurin
inhibitors (e.g., tacrolimus ointment 0.03%0.1%,
pimecrolimus ointment 1%) are generally preferred
for treating localized vitiligo lesions of the face and
neck,43 and seem to be more effective in combination with UV radiation delivered by high-fluency
UVB devices.43 Although several reports have
emphasized the advantages of calcineurin inhibitors (selective mode of action, absence of skin atrophy, and systemic absorption), additional studies
of their effectiveness are needed, as well as more
799
11
i nformation about possible risks of cutaneous and

extracutaneous cancers.
TOPICAL VITAMIN D DERIVATIVES
Section 11
::
Vitamin D analogscalcipotriol ointment (0.005%)

and tacalcitol ointment (20 g/g)restore pigmentation in vitiligo by inducing skin immunosuppression, which halts the local autoimmune process, and
via direct activation of melanocytic precursors and
melanogenic pathways.66 Some studies report more
efficient repigmentation when vitamin D analogs are
used in combination therapy, probably because of
more complex stimulation of the repopulation process, targeting both melanocyte growth (with corticotherapy or UV) and differentiation (with a vitamin D
analog). Vitamin D derivatives are indicated for use
in localized disease; benefits include lack of skin atrophy and their easy application. However, their role
in vitiligo treatment remains controversial; whereas
some studies have reported substantial benefit, others
found vitamin D analogs ineffective.45
PSEUDOCATALASE
Pseudocatalase has been used to reconstitute deficient activity of catalase in vitiligo epidermis,
degrading excessive H2O2 and allowing recovery
of enzyme activities in vitiligo skin.67 Pseudocatalase monotherapy or combination with NB-UVB
has shown apparent efficacy in repigmentation and
prevention of disease progression in uncontrolled
trials,68,69 while in other studies showed no substantial benefit.7072 Therefore, its effect in vitiligo needs
further validation.
LASER THERAPY
UV B narrowband excimer laser (XeCl) and monochromatic excimer light (MEL) are currently used
for treatment of localized vitiligo. These are similar
to classical NB-UVB treatments, with the advantage of fewer side effects because only one lesion is
treated at a time. These treatments produce optimal
aesthetic results, with minor contrast between normal and affected skin.56 The XeCl has laser-coherent
emission of monochromatic rays, whereas the MEL
device can generate and selectively deliver 308-nm
UVB light. No data for cancer risk and other longterm side effects are available; therefore, caution is
currently advised.73
SURGICAL TREATMENT
800
Autologous skin grafts are an option for repigmentation only in patients with stable vitiligo that is refractory or only partially responsive to medical treatment,
and in general limited in extent (less than 3% of
body-surface area).43 The most frequent side effects
are infection, postinflammatory hyperpigmentation, unaesthetic repigmentation, cobblestoning, and

scarring.55 UV-light therapy generally hastens and
improves repigmentation when combined with surgical methods.
Autologous skin graft approaches can be categorized into five principal groups.55 Of note, in the United
States any procedure in which cells are manipulated
(e.g., cultured) must be performed in a good manufacturing practices (GMP) facility.
NONCULTURED EPIDERMAL
SUSPENSIONS
This technique is performed by grafting noncultured
suspensions containing both keratinocytes and melanocytes74,75 (eFigs. 74-9.1A and 74-9.1B in online edition);
suspensions are obtained by 0.25% trypsin digestion of
a thin piece of donor skin and are injected into blisters
raised by liquid nitrogen freezing or seeded on recipient sites denuded by superficial dermabrasion. An
advantage of this method is lack of scarring if recipient
and donor sites are carefully manipulated.
THIN DERMALEPIDERMAL GRAFTS

Grafts are harvested at a depth of 0.10.3 mm, placed
directly on recipient abraded areas next to each other,
and are secured with surgical dressings under mild
pressure for 1 week. Repigmentation occurs during the
following weeks. Good results have been reported on
dorsal hands and fingers.76,77
MINIGRAFTING
Minigrafting represents the most commonly used
current surgical method for vitiligo repigmentation
(eFigs. 74-9.2A and 74-9.2B in online edition). Multiple perforations are made on recipient sites using
1.01.2-mm punches 34 mm apart from each other.
Next, minigrafts are harvested from the donor site
using a similar punch and are transferred to recipient sites with fine forceps or a hypodermic needle.78
Repigmentation occurs around each minigraft up
to 25 mm by coalescence of spreading pigment.
Good results are achieved in patients with refractory lip leukoderma, although the risk of cobblestoning seems to be high.76,79 An advantage of this
method is its simplicity.
EPIDERMAL GRAFTING
Grafts are harvested at negative pressure using
different custom-made suction devices, 55 the preferred donor sites being the inner aspect of the
thigh and the flexor aspect of the forearm. 80 Recipient sites are prepared by removing the epidermis
using liquid nitrogen freezing or superficial dermabrasion 81 or laser ablation. 55 Epidermal grafts
have been successfully used for lip vitiligo. 82 The
11
Chapter 74
::
Vitiligo
Figure 74-10 Treatment with MBEH. Response of disfiguring facial vitiligo to treatment with MBEH (A) before, (B) after
4 months, (C) after 6 months and (D) after 8 months.
801
11
main advantage is the absence of scarring in donor

and recipient sites.
IN VITRO-CULTURED EPIDERMIS WITH

MELANOCYTES AND MELANOCYTE
SUSPENSIONS55
Section 11
EPIDERMIS WITH MELANOCYTES. An epidermal suspension collected from a small donor

skin sample is prepared by 0.25% trypsin digestion
and seeded in culture flasks. After 3 weeks, epidermal sheets are harvested from the culture vessel
and transplanted onto depigmented recipient sites
previously denuded by liquid nitrogen freezing,
superficial dermabrasion, lasers, or diatermo surgery. A hyaluronic artificial matrix for growing keratinocytes and melanocytes has also been used with
success.83
::
MELANOCYTE
SUSPENSIONS.
In vitrocultured melanocyte suspensions are obtained in a

similar manner using specific and defined cultured
media such as Hams F12. During subculturing,
pigment cells increase in number and may be transplanted onto denuded areas at a density of up to
100,000 melanocytes/cm2. The suspension spreads
onto recipient areas and is covered for a week, providing a good cellular take.74,84 The large population
of cells obtained from a small donor site represents a
great advantage for treating extensive vitiligo areas
in a single session.
MICROPIGMENTATION
Micropigmentation is useful for vitiligo lesions on
mucous and mucocutaneous areas. It is accomplished
by tattooing inert pigment granules into the dermis
within collagen bundles and extracellularly at a depth
of 12 mm, delivered by multiple electrically driven
needles. Combinations of white, yellow, black, red,
and brown pigments are used.55
DEPIGMENTATION
802
Some adult patients with extensive vitiligo may elect

to undergo depigmentation of residual pigmented
patches on facial and exposed areas. Depigmentation
is achieved using 20% monobenzyl ether of hydroquinone (MBEH; monobenzone), which induces melanocyte loss via necrotic death without activating the
caspase cascade or DNA fragmentation.85 MBEH is first
applied as a patch test for 48 hours to detect hypersensitivity. Subsequently, twice-daily applications for at
least a year are followed by irreversible depigmentation86 (Figs. 74-10AD). Sunlight protection of depigmented skin is essential to prevent nonmelanoma skin
cancers.55
We propose a treatment algorithm for vitiligo, considering the therapeutic approaches presented above
(Fig. 74-11).
Determine extent of
involvement of vitiligo
If <20% of
skin surface
If 20% of
skin surface
Topical corticosteroids,
immunomodulators, or calcipotriol
or a combination of these agents
Phototherapy:
NB-UVB or PUVA
or PUVASOL
If no response
Topical PUVA therapy or
targeted phototherapy
If no response and
skin involvement is >50%
If no response
Skin grafting or
melanocyte transplantation
Depigmentation
Figure 74-11 Treatment algorithm for vitiligo.
CAMOUFLAGE, SUN PROTECTION,

AND PSYCHOLOGICAL SUPPORT
Use of cosmetic camouflage, on the face and other
exposed areas, and clothing to conceal affected areas
can improve the quality of life for patients with
vitiligo. Modern camouflage dyes and creams are
waterproof, and the wide range of color and shades
available can enable patients to choose the most suitable ones for their own skin color (Figs. 74-12A and
74-12B).
Tanning should be avoided since it enhances the
contrast of vitiligo lesions with normally pigmented
skin. Moreover, sunscreens are needed to prevent sunburn of depigmented unprotected skin. However, this
is somewhat problematic, as moderate sun exposure
(heliotherapy) in many cases can induce epidermal
repopulation with melanocytes. As well, it has been
suggested that skin friction due to repeated application
of sunscreen might exacerbate the disease,43 although
there is no evidence to support this hypothesis. Depigmented skin in vitiligo tends to show increased tolerance to UVB light over time (photoadaptation), with
the extent of tolerance based in part on skin phototype,
supposedly due to both pigmentary and nonpigmentary influences,87 although the specific mechanism
remains unknown.
Psychological support may be beneficial to some
patients. Listening to patients complaints and concerns and providing reassurance with advice about
possible treatments and capacity for improvement is
usually helpful for patients. Consider psychiatric evaluation for patients with marked low self-esteem and
depression.
11
Chapter 74
::
NONTRADITIONAL TREATMENTS
A wide range of nontraditional treatments have been
suggested for vitiligo, and some may be considered
as alternative approaches for patients who either
failed or are unsuitable for the above therapies. The
most commonly used include vitamin and nutritional
supplements, immunomodulators, human placental
extracts, khellin, and topical and systemic phenylalanine, among many others. There is no convincing
evidence that any of these nontraditional treatments
is effective.
PREVENTION
Patients, patient support groups, and purveyors of
alternative medicines have developed extensive and
diverse hypotheses regarding vitiligo causation and
approaches to its prevention. At present, there is no
compelling evidence that any approach to vitiligo prevention is effective. Moreover, there is currently no
useful approach to identify individuals at high risk for
developing vitiligo.
Vitiligo
Figure 74-12 Cosmetic camouflage. Focal vitiligo of chin before (A) and after (B) application of cosmetic camouflage.
KEY REFERENCES
7. Spritz RA: The genetics of generalized vitiligo. Curr Dir
Autoimmun 10:244, 2008
13. Jin Y et al: Variant of TYR and autoimmunity susceptibility
loci in generalized vitiligo. New Engl J Med 362(18):16861697, 2010
16. Ongenae K, Van Geel N, Naeyaert JM: Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res 16:90,
2003
21. Oyarbide-Valencia K et al: Therapeutic implications of autoimmune vitiligo T cells. Autoimmune Rev 5:486, 2006
28. Hann S-K, Nordlund JJ: Clinical features of generalized
vitiligo. In: Vitiligo, edited by S-K Hann, JJ Nordlund. London, Blackwell Science, 2000, p. 35
43. Taeb A, Picardo M: Clinical practice. Vitiligo. N Engl J
Med 360:160, 2009
45. Birlea SA, Costin GE, Norris DA: New insights on therapy
with vitamin D analogs targeting the intracellular pathways that control repigmentation in human vitiligo. Med
Res Rev 29:514, 2009
55. Falabella R, Barona MI: Update on skin repigmentation
therapies in vitiligo. Pigment Cell Melanoma Res 22:42,
2009
803
11
Chapter 75 :: Hypomelanoses and Hypermelanoses

:: Hilde Lapeere, Barbara Boone,
Sofie De Schepper, Evelien Verhaeghe,
Mireille Van Gele, Katia Ongenae,
Nanja Van Geel, Jo Lambert, &
Lieve Brochez
Section 11
HYPOMELANOSES AND
HYPERMELANOSES AT A GLANCE
::
Pigmentation disorders confront the clinician

with a sometimes complex differential
diagnosis, but can be approached logically as
follows:
Congenital or acquired
Isolated or part of a syndrome
Diffuse or circumscribed
Epidermal or dermal
With or without inflammation
Altered skin pigmentation may be caused by
the following factors:
Increased or decreased melanin
Abnormal melanin distribution
Decreased hemoglobin
Deposition of exogenous pigments
AN ALGORITHMIC APPROACH TO
PIGMENTATION DISORDERS
Pigmentation disorders of the skin can either be
hypomelanotic, hypermelanotic, or may present with
a pattern of mixed hypo- and hypermelanosis. The
diagnosis of these disorders can be quite challenging.
An algorithmic approach based on clinical features and
history of pigmentary disorders is used throughout this
chapter and serves as a guide for the clinician diagnosis and treatment (eFigs. 75-0.1 and 75-0.2 in online edition) (Table 75-1, eTable 75-1.1 in online edition).
804
HYPOMELANOSIS
Generalized hypopigmentation, including the various
defects, classified as albinism has been discussed in
Chapters 73 and 74. Localized forms of hypomelanosis can be related to defects in melanocyte precursor
migration and disordered pigment transfer between
melanocytes and keratinocytes, and as a result of
postinflammatory changes.
CONGENITAL HYPOMELANOSIS
Some genetic disorders with reduced skin and hair pigmentation are caused by impaired melanocyte migration/differentiation or melanosome abnormalities.1
Piebaldism, Waardenburg syndrome, and Tietze syndrome, characterized by a localized absence of melanocytes resulting in white-patch patterns, belong
to the first group whereas oculocutaneous albinism
(OCA), Griscelli syndrome (GS), Elejalde syndrome
(ES), ChdiakHigashi syndrome (CHS), and HermanskyPudlak syndrome (HPS) belong to the second
group. OCA, CHS, and HPS are discussed in Chapter
73; GS and ES are discussed here. They are rare autosomal recessive disorders with abnormal biogenesis or
transport of lysosome-related organelles (a group
of specialized cytoplasmic organelles including melanosomes, platelet dense bodies, and lymphocyte lytic
granules).2 GS, ES, and CHS are termed silvery hair
syndromes because hair of these patients has a particular silvergray hue.3
GRISCELLI SYNDROME. Three types of GS [GS

types IIII (GS13)] are known. The phenotype of the
patients is characterized by various degrees of skin
hypopigmentation and hair with a silvery shine (Fig.
75-1), usually lighter than in unaffected family members. Furthermore, neurological signs and symptoms
and/or immunologic impairment with accelerated
phases of uncontrolled lymphocyte and macrophage activation with lymphohistiocytic infiltration
of the central nervous system (CNS) are associated.4
This lymphoproliferative syndrome is similar to that
observed in, for example, virus-associated hemophagocytic syndrome.5
Briefly, patients with GS type I (GS1) are characterized by primary and severe neurological symptoms
11
TABLE 75-1
Differential Diagnosis and Management of Dermal Melanocytosis
Nevus of Ota
Nevus of Ito
Mongolian Spot
Nevus of Hori
Dermal
Melanocyte
Hamartoma
Congenital
Often familial
Asian, African,
and Hispanic
population
with slight male
predominance
Acquired
Familial or sporadic
Asian and female
predominance
Congenital
Clinical
presentation
B
lue to slate-gray
mottled macular
hyperpigmentation
B
lue to slate-gray
mottled macular
hyperpigmentation
U
niform blue to
slate-gray macular
hyperpigmentation
B
rownblue
progressing
to slate-gray
mottled macular
hyperpigmentation
M
ottled
hyperpigmentation
with small bluegray
macules in a diffuse
pigmented patch
Distribution
Trigeminal nerve
A
cromioclavicular
nerve
L ower back and

sacrum
E specially malar
region of the cheek
(also forehead,
upper eyelids,
temple)
D
ermatomal
distribution
Histology
S pindle-shaped
melanocytes
diffusely throughout
the dermal layers.
Sometimes
more band-like
melanocytic
proliferation and
stromal fibrotic
reaction.
S pindle-shaped
melanocytes
diffusely throughout
the dermal layers.
Sometimes
more band-like
melanocytic
proliferation and
stromal fibrotic
reaction
S pindle-shaped
melanocytes
diffusely
throughout the
dermal layers
D
ermal
melanocytes in
the upper and
middermis
D
ermal melanocytes
in the upper
two-thirds of the
dermis (including
subpapillary layer)
Therapy
Q-switched laser
Cryotherapy
Surgery
Q-switched laser
Cryotherapy
Surgery
U
sually
spontaneous
regression during
childhood
Q
-switched laser in
combination with
bleaching cream
and chemical peels
None
Associated
features
R
are malignant
transformation
N
o associated
features of medical
concern
P
ossible association
with inborn errors
of metabolism
N
o associated
features of medical
concern
None
occurring early in life or even at birth without signs of

an accelerated phase. These symptoms can include seizures, spasticity, psychomotor retardation, peripheral
facial palsy, hemiparesis, encephalopathy, and hypotonia. CNS disorder is pertinent and never regresses
with time.
Immunological and hematological manifestations
are only observed in GS type II (GS2) and include:
anemia, neutropenia, and lack of natural killer cell
function, with development of an accelerated phase of
the disease with fever, jaundice, hepatosplenomegaly,
lymphadenopathy, pancytopenia, and generalized
lymphohistiocytic infiltrates of various organs, including the CNS. Onset of the accelerated phase seems to
be associated with viral or bacterial infections. When
a remission occurs, recurrent accelerated phases with
increasing severity will be observed.
Neurological problems may also occur in GS2
patients and are related to lymphocyte infiltration
of the CNS. Associated symptoms are, for example,
hyperreflexia, seizures, signs of intracranial hypertension (e.g., vomiting), hypertonia, nystagmus, and
ataxia. Psychomotor development is normal at onset,
and regression of CNS signs, at least in part, can be
observed during remission, although some sequelae
may be irreversible. Skin hypopigmentation and
silvery-grey hair in Griscelli patients are not caused
by deficient melanosome biogenesis but by impaired
intramelanocytic melanosome transport. Murine models with autosomal recessive mutations on the dilute
(d), ashen (ash), and leaden (ln) locus present a phenotype close to that of their human GS counterparts.6
These loci respectively encode three molecules, myosin
Va, Rab27a, and melanophilin (Mlph) that act as a tripartite complex linking the melanosome to subcortical
actin. When MYO5A (GS1), RAB27A (GS2), or MLPH
(GS3) is mutated in human melanocytes, the tripartite
complex fails to form and melanosomes can no longer
be tethered near the plasma membrane for transfer to
keratinocytes, leading to a pigmentary defect.7
Hypomelanoses and Hypermelanoses
Mostly congenital
Sporadic (rare
familial cases)
Asian and female
predominance
::
Mostly congenital
Sporadic (rare
familial cases)
Asian and female
predominance
Chapter 75
Epidemiology
805
11
drome or immunological impairment associated with

GS2.23,24
Certain patients with ES have clinical and histologic
features suggestive of GS1, indicating that these are
other cases of MYO5A mutations.25,26 Further work will
be required to define the molecular basis of ES and to
group all patients with these rare disorders correctly.
ACQUIRED LOCALIZED
HYPOMELANOSIS
Section 11
Figure 75-1 A Griscelli patient with silvery gray eyebrows/

eyelashes.
::
The prognosis for patients with GS is generally bad.

They usually die in the first or second decade of their
life if accelerated phases are not treated adequately. As
for GS2 therapy, allogeneic bone marrow transplantation has appeared to be successful in some cases, especially when carried out at an early age.811 Palliative
therapy consists of suppressing the accelerated phases
with immunosuppressive therapy (high-dose corticosteroids, cyclosporine) and chemotherapeutic agents
(methotrexate, etoposide, cytosine arabinoside). For
GS1 there is no therapy. Palliation consists of treating
infections with antibiotics.12
The hematologic, immunologic, and neurologic findings in GS13 presumably relate to organelle transport
difficulties in the respective organ systems.
ELEJALDE SYNDROME (OMIM #256710).
ES, also referred to as neuroectodermal melanolysosomal

disease, is another autosomal recessive pigment mutation with silvery hair, pigment abnormalities, and
severe CNS dysfunction21,22 similar to those of GS1.
ES patients do not manifest the hemophagocytic syn-
806
PITYRIASIS VERSICOLOR. (See Chapter 189).

Pityriasis versicolor is characterized by slightly scaling macules that can either be hypopigmented, pink
or salmon-colored, or hyperpigmented (Fig. 75-2);
variants with red and black macules have also been
described. The prevalence of pityriasis versicolor is
very high in hot and humid climates.
This superficial mycosis is caused by Malassezia species of which M. globosa, M. sympodialis, and M. Furfur
are most frequently identified in lesional scales. M.
Furfur cultures produce a wide range of fluorochromes
and pigments that appear to lead to depigmentation,
high resistance to ultraviolet (UV)-induced tanning,
and lack of inflammation observed in pityriasis versicolor.27 In approximately one out of three patients,
a yellowgreen fluorescence is visible using Woods
light. It should be differentiated from the nonscaling
depigmented lesions of vitiligo that frequently affect
hands and feet, whereas pityriasis versicolor is mainly
located on the trunk. The slightly scaling patches of
pityriasis alba (PA) usually occur on the face and limbs
and are nonfluorescent. Many local and systemic antifungal preparations are effective but relapses often
occur.28,29
PIGMENTARY DEMARCATION LINES. Originally described in Japanese patients as a line present on upper and lower extremities corresponding
to a border of transition between the more deeply
pigmented skin of the outer (dorsal) surfaces and
the lighter inner (ventral) surfaces, the concept of
Figure 75-2 Pityriasis versicolor. A. Typical macules are round, very well circumscribed, have fine scale, and are off-white
to tan colored. Typical distribution involves the upper back and upper chest. Involvement of the lower arms and legs and
of the face is unusual. B. Confluent macules create scalloped borders. This is a characteristic pattern of macules of pityriasis
versicolor.
11
territorial control by different homeobox genes during

development.32
igmentary demarcation lines was expanded to

p
include five specific patterns, labeled AE, with A:
upper anterolateral arms, across pectoral area (Fig.
75-3), B: posteromedial portion of lower limb, C: vertical hypopigmented line in pre- and parasternal area,
D: posteromedial area of spine, and E: bilateral aspect
of chest, marking from midthird of clavicle to periareolar skin. In a population survey of black and white
patients it was determined that these lines appeared
in early childhood. They are present in the majority
of female black adults, with types A and B being most
prevalent. Seventy-five percent of black adult males
had at least one type of pigmentary demarcation
line, with type C the most prevalent. Fifteen percent
of white female adults had at least one line, and 14%
of black women saw type B lines appearing during
pregnancy.30 The lines of pigmentation are often called
Futchers lines in the United States.
The pathogenesis of pigmentary demarcation lines
is uncertain. Some authors believe that these lines coincide with lines of Blaschko and are secondary to a form
of pigmentary mosaicism. Others suggest that there is
no true genetic difference but hypothesize that the difference between cells on the dark, posterior side versus
the light, anterior side are due to the normal function
of genes, such as the agouti locus.31
According to some reports, pigmentary demarcation
lines do not follow lines of Blaschko but have a pattern
similar to lines of Voigt, which separate dermatomes
arising from nonconsecutive dorsal roots. The difference in melanogenesis would be explained by a strict
::
Figure 75-3 Pigmentary demarcation line (Futcher line).

These lines are often barely perceptible but common in
darker skinned phototypes.
PITYRIASIS ALBA. PA is a common benign condition mainly affecting the head and neck region of
preadolescent children. Although the disease is more
noticed in darker skin types, there is no predilection for
either sex or skin type. The etiology and pathogenesis
remain poorly understood. PA is widely understood
to represent mild atopic dermatitis. Unprotected sun
exposure, frequent bathing, and hot baths are strongly
related to the development of PA. Lower serum levels
of copper, a cofactor for tyrosinase, could also play a
role in the pathogenesis of this condition.
PA may present as a pink patch with an elevated
border, fading after several weeks into a paler spot
covered with powdery white scale (Fig. 75-4). The
lesions progress to nonscaly hypopigmented macules
persisting for months or years. The three stages may
occur simultaneously.
Histologically, there is markedly reduced pigment
in the epidermis of lesional skin, but no significant
difference in melanocyte count was found between
lesional and normal skin. Ultrastructurally, degenerative changes in melanocytes and a reduced number of
melanosmes within keratinocytes were seen.33 Extensive PA often also involves the inferior torso in a symmetric pattern. The lack of a preceding inflammatory
phase and spongiosis differentiate extensive PA from
the classic form. This particular form of PA may overlap with progressive macular hypomelanosis (PMH),
a condition mainly described in young female adults,
characterized by relapsing hypopigmented, nonscaling patches involving the back, particularly after
summer.34
Pigmenting PA is a variant associating classic PA with
a superficial dermatophyte infection, almost always
affecting the face. It is clinically characterized by a bluish hyperpigmentation, attributed to melanin deposits
in the dermis surrounded by a hypopigmented scaly
area. One-third of patients have concurrent classic PA.
Differential diagnosis includes any localized form of
hypopigmentation, especially inflammatory skin conditions associated with postinflammatory hypopigmentation, such as psoriasis, but also with fungal
infection, nevus depigmentosus, nevus anemicus,
tuberous sclerosis, mycosis fungoides (MF), or vitiligo.
Chapter 75
Figure 75-4 Pityriasis alba.
807
11
The disease is self-limited and treatment is often not

completely successful. Topical steroids and emollients
are helpful. Topical tretinoin has also been used with
success, but may be irritating. Extensive PA and pigmenting PA have also responded to UV therapy and
oral antifungals, respectively. Supportive measures
such as decreasing sun exposure, use of sunscreens,
and reducing frequency and temperature of baths
should be recommended.
The pathogenesis of pigment loss is unclear.3438
Section 11
::
SARCOIDOSIS. (See Chapter 152). Hypopigmentation is a rare manifestation of sarcoidosis. Hypopigmented macular lesions scattered over the trunk and
extremities but also papular or nodular lesions may be
present. The presence of noncaseating dermal granulomas, usually most evident in biopsies of indurated
lesions, reinforce the diagnosis. A reduction in melanin
content of the epidermis with preservation of melanocytes has been demonstrated.
The pathogenesis of pigment loss is unclear.3941
SCLERODERMA. (See Chapter 157). Hypopigmentation has been described as a pigmentary change
in morphea (localized scleroderma) (Fig. 75-5) and
scleroderma (progressive systemic sclerosis). Localized hypopigmentation and/or hyperpigmentation are
seen in areas of localized sclerosis. Focal depigmentation with perifollicular hyperpigmentation (salt and
pepper pigmentation) especially on upper trunk and
extremities, mimicking vitiligo, is reported in up to 30%
of patients with scleroderma. The coexistence of scleroderma/morphea and vitiligo has also been reported.4244
LUPUS ERYTHEMATOSUS. (See Chapter 155).
Pigment alterations are frequently seen in discoid
lupus erythematosus. Hypopigmented patches
result from interface dermatitis with destruction of
808
Figure 75-5 Morphea. Note the discrete hyperpigmentation in the area of localized sclerosis.
the epidermal basal layer containing melanocytes.

Burned out lesions are atrophic and depigmented
and may be surrounded by hyperpigmentation. Cutaneous depigmentation is also reported in systemic
lupus erythematosus, usually localized to inflammatory skin lesions. Biopsy specimens in depigmented
skin feature degeneration of the basal layer with epidermal atrophy, a variable number of melanocytes,
and pigmentary incontinence in the superficial dermis.
The mechanism of hypopigmentation in lupus is not
known but could be postinflammatory or cicatricial.
Vitiligo has also been reported in association with
lupus erythematosus.45 A shared genetic predisposition may explain the association of these two autoimmune disorders.46
MYCOSIS FUNGOIDES. (See Chapter 146). MF,

the most common type of cutaneous T-cell lymphoma,
is clinically characterized by three cutaneous phases:
(1) the patch phase, (2) the plaque phase, and (3) the
tumor phase. Several pigmentary changes have been
described in MF.
In poikiloderma vasculare atrophicans, a variant of
the patch stage, mottled pigmentation, atrophy and
telangiectasia of the involved skin are observed. A mix
of hyper- and hypopigmentation may remain after
regression of the skin lesions following treatment.
Hypopigmented MF is an uncommon variant of
this lymphoma. It mainly develops before the fourth
decade, predominantly in juvenile-onset cases and in
dark-skinned individuals, without sex predilection.
Irregular hypopigmented patches with variably distinct borders are preferentially located on trunk and
extremities. Erythema, scaling, and infiltration may be
present. A central area of normal pigmentation may be
observed. These lesions may also be associated with
the more typical lesions of the three cutaneous phases.
The hypopigmentation develops without preceding
skin changes and occasionally complete depigmentation is observed.
Histopathologically, hypopigmented MF is characterized by minimal dermal involvement, lack of epidermal atrophy, and moderate to marked exocytosis.
Pigment incontinence and decrease or absence of melanin may be observed. Infiltrating lymphocytes often
have a T-suppressor cell CD8+ phenotype, but a CD4+
phenotype has also been reported.
Electron microscopy may disclose degenerative
changes in melanocytes. Melanocytes may be incompletely melanized or occasionally reduced in number.
The number of melanosomes within keratinocytes is
normal or decreased and melanin-containing macrophages can be observed in the papillary dermis. T-cell
receptor gene rearrangement analysis may help to
confirm the diagnosis but is often negative, as in early
stage MF.
The pathogenesis of hypopigmented MF is not clear.
At least in cases showing a CD8+ phenotype, hypopigmentation could be due to the melanocytotoxic effect
of nonneoplastic CD8+ lymphocytes, as hypothesized
in vitiligo.
Hypopigmented MF responds well to treatment,
particularly psoralen and UVA light (PUVA) or
11
arrowband UVB therapy. It has a relatively benign

n
course, although recurrences are common. Hypopigmented MF should be distinguished from other causes
of diffuse hypopigmentation, especially vitiligo, tinea
versicolor, PA, or postinflammatory hypopigmentation.4751
INFECTIONS
Treponematoses.
::
Figure 75-6 Pinta. The hypomelanosis in pinta is a vitiligolike hypomelanosis that occurs later in the disease and is
associated with deep blue to slate-gray areas of hyperpigmentation.
depressed, hairless lesions occur that appear hypopigmented in black patients and erythematous in white
patients.56
Onchocerciasis. (See Chapter 207). Several different skin manifestations can become apparent during
the course of onchocerciasis. Onchocercal depigmentation or leopard skin is rarely associated with itch
and is one of the most common skin manifestations
of onchocerciasis. Hypopigmented patches with perifollicular spots of normally pigmented skin, typically
occur symmetrically on the pretibial area of older people in endemic areas.53 (Fig. 75-7).
Chapter 75
(See Chapters 200 and 201).

Nonvenereal treponematoses are currently endemic
in parts of Central and South America, Africa, Asia,
and the Pacific Islands and can be severely disfiguring. Depigmentation is seen in several stages of yaws,
bejel, and pinta. When the primary lesion of yaws
disappears, a typical depigmented and pitted scar
remains. In the tertiary stage of bejel, gummatous
nodules develop in the skin and in other organs. Most
skin lesions regress, leaving depigmented, noncontracted scars. Pinta is the only treponematosis that only
affects the skin and causes pigmentary abnormalities
in the first, second, and third stages of the disease.
The sentinel lesion of pinta may heal at the end of the
primary stage, leaving a macular dyschromia. The
secondary stage is characterized by the appearance of
the so-called pintids, which are initially red but often
turn brown, slate-blue, gray, or black. This stage can
last several years, leading to a mix of depigmentation
and hyperpigmented lesions. Generalized pigmentary
abnormalities develop during the tertiary stage. A
symmetrical pattern of vitiligo-like lesions and brown,
gray or blue and black lesions is seen over bony prominences (Fig. 75-6).52
CHEMICAL AND PHARMACOLOGIC AGENTS.
The potential for chemicals to induce hypopigmentation

was discovered in the first half of the twentieth century.
Leukoderma was noticed in rubber workers exposed to
Post-kala-Azar Dermal Leishmaniasis

(PKDL). (See Chapter 206). Post-kala-azar dermal
leishmaniasis develops in insufficiently treated kalaazar or visceral leishmaniasis, which is caused by

Leishmani. donovani. Skin manifestations of PKDL are
nodules and plaques, facial erythema, and hypopigmented macules. Nodules and plaques typically
develop around the mouth and spread to the face,
arms and chest, but the macules may occur more generalized over the whole body. Mild disease can resolve
spontaneously, but severe forms require systemic treatment.54,55
Leprosy. (See Chapter 186). The presence of a

hypopigmented lesion with reduced sensation is the
hallmark of leprosy and is one of the diagnostic criteria (Fig. 75-8). Indeterminate leprosy, frequently the
first manifestation of leprosy, is characterized by the
presence of a few such lesions. Tuberculoid leprosy
usually manifests as a limited number of well-defined,
Figure 75-7 Onchocerciasis.
809
11
Section 11
scavengers. Finally, some agents act after melanin

synthesis because they are responsible for tyrosinase degradation, inhibition of melanosome transfer, or acceleration of skin turnover, leading to
depigmentation.59
MBEH was used as a lightening agent until its
ability to cause total permanent and often confettilike depigmentation became apparent. It should
be used only to produce total depigmentation in
patients with diffuse vitiligo. A formulation with
20% MBEH is usually prescribed for that purpose.
Hydroquinone is one of the most popular depigmenting substances and is frequently used for the
treatment of melasma in concentrations between
2% and 5%. Concentrations higher than 5% incur a
risk of permanent depigmentation. Adverse effects
are irritation, postinflammatory pigmentation, and
exogenous ochronosis.57,5961
::
PHYSICAL AGENTS. Heat, freezing, X-ray, ionizing radiation, UV irradiation, and laser light can cause
hypopigmentation or permanent depigmentation
by damaging melanocytes, leading to destruction or
impaired function.62
810
Figure 75-8 Leprosy. A characteristic off-white hypomelanotic and anesthetic macule.
the monobenzylether of hydroquinone (MBEH), a frequently used antioxidant in the rubber industry. Since
then, depigmenting properties have been attributed to
many chemicals and new therapeutic depigmenting
agents have been developed.57
Occupational exposure to chemicals that have
a destructive effect on melanocytes can result in
chemical leukoderma. Agents such as para-tertiary
butylphenol, para-tertiary butyl catechol, MBEH,
and hydroquinone can cause permanent depigmentation. The depigmentation caused by chemicals is
difficult to distinguish from idiopathic vitiligo. The
former usually starts at the hands and forearms,
presumptive sites of contact, but depigmentation
at a distance is also possible (Fig. 75-9). Chemical leukoderma spreads by coalescence of small
macules, whereas the sudden appearance of large
patches with perifollicular sparing is more suggestive of vitiligo. Chemical leukoderma is very likely
if several exposed workers develop depigmentation.
However, not all exposed individuals develop leukoderma and it is hypothesized that the individual
susceptibility is variable.57,58
Chemicals are also employed therapeutically or
cosmetically to lighten skin color. There are three
main mechanisms of action for bleaching agents.
Some act before melanin is synthesized by inhibiting tyrosinase transcription and glycosylation.
Other agents act during melanin synthesis by inhibiting enzymes such as tyrosinase or peroxidase or
act as reducing agents or radical oxygen species
LICHEN SCLEROSUS. (See Chapter 65). Lichen

sclerosus typically presents as a pruritic erythematous
patch in the early stage, evolving to a depigmented
atrophic plaque with porcelain white appearance.
Mechanisms believed to play a role in this idiopathic
leukoderma include decreased melanin production,
blocked transfer of melanosomes to keratinocytes, and
loss of melanocytes.
MELANOMA-ASSOCIATED LEUKODERMA.
(See Chapter 124). Regression in a primary melanoma

lesion typically causes a depigmented scar-like area
within the lesion.
Melanoma-associated hypo- or depigmentation,
also known as leukoderma acquisitum centrifugum,
can occur around the primary melanoma or metastases or at distant sites. The latter is often called vitiligo, although the resemblance is limited. Whereas
vitiligo depigmentation is usually symmetric and
spreads centripetally to the trunk, melanoma-associated hypo- or depigmentation tends to be extensive, patchy, and asymmetric. The lesions may be
mottled (hypomelanotic) or milk white (amelanotic).
In most cases, leukoderma appears simultaneously
with the finding of metastases. Histologic examination of lesions shows a decrease or complete absence
of melanocytes. Macromelanocytes with stubby dendrites can also be observed. Melanoma with associated leukoderma may be associated with a better
survival rate than comparably advanced lesions without epidermal pigment loss. Strong evidence suggests
that melanoma-associated leukoderma results from
host immune reaction against the malignancy, involving humoral and cellular mechanisms. Both passive
and active immunotherapeutic strategies used in the
treatment of melanoma have been associated with
leukoderma (Fig. 75-10).63,64
11
Chapter 75
::
Figure 75-9 Chemical leukoderma. A. O-Syl (a phenolic

disinfectant)-induced chemical leukoderma that mimics
vitiligo clinically. Repeated exposure is required to depigment, but antecedent clinical inflammation is not observed. B. Reversible hypomelanosis of the face in a South
African woman after several weeks application of topical
hydroquinone. Note color contrast of face to that of (untreated) hand. C. African-American factory worker depigmented from repeated exposure to monobenzyl ether of
hydroquinone.
Figure 75-10 Melanoma-associated leukoderma. A. This hypomelanosis may resemble vitiligo clinically and be characterized by an absence of melanocytes. It may be associated with a favorable prognosis. B. These macules in a different
patient developed after the patient developed metastases to the skin. They surround the individual metastases.
811
11
ACQUIRED DIFFUSE
HYPOPIGMENTATION
Nutritional disorders and endocrinopathies mainly
cause hyperpigmentation. Diseases such as copper
deficiency, vitamin B12 deficiency, kwashiorkor, Addison disease, hyperthyroidism, and diabetes can also be
associated with hypopigmentation, but are discussed
under Section Hypermelanosis because hyperpigmentation is their main feature.
Section 11
::
HYPOTHYROIDISM. (See Chapter 151). Hypothyroidism is frequently associated with cutaneous

alterations. The skin is pale due to anemia and vasoconstriction. Yellowish discoloration of the palms, soles,
and nasolabial folds is caused by an accumulation of
carotene in the stratum corneum. The associated hypercarotinemia results from reduced capacity of the liver
to convert -carotene to vitamin A. Vitiligo has been
associated with autoimmune hypothyroidism.6567
HYPOPITUITARISM. Panhypopituitarism results

from a variety of conditions that compromise the
anterior pituitary. As a consequence, release of pituitary-derived factors including melanocyte-stimulating hormone (MSH), thyroid-stimulation hormone,
adrenocorticotrophic hormone, luteinizing hormone,
follicle-stimulating hormone, growth hormone, and
vasopressin is decreased. Due to the reduction of circulatory pituitary hormones, production of cortisol,
thyroxine, estrogens, and testosterone in target organs
is lowered.
Patients suffering from panhypopituitarism look
pale due to anemia and decreased cutaneous blood
flow. As well, generalized hypopigmentation results
from decreased adrenocorticotrophic and MSH that
stimulate epidermal melanogenesis.66
HYPOGONADISM. Castrated human males are
characteristically pale and their genital skin is not
hyperpigmented as in normal men. An impaired tanning response to UV radiation has been described.
Administration of testosterone makes the skin turn
darker and restores the tanning response.68
SELENIUM DEFICIENCY. Loss of hair and skin
pigmentation due to selenium deficiency has been
described in children receiving long-term total parenteral nutrition. After selenium supplementation, skin
and hair darken.69
COPPER DEFICIENCY. Acquired copper deficiency
occurs in severely malnourished infants. Hypopigmentation of the hair is attributed to copper deficiency,
presumably because tyrosinase is a copper-dependent
enzyme, but as multiple nutritional deficiencies tend
to coexist pathogenesis is difficult to confirm.70
IDIOPATHIC GUTTATE HYPOMELANOSIS.
812
Idiopathic guttate hypomelanosis (IGH) is an acquired

leukoderma, characterized by discrete, round,
or oval porcelain-white macules of approximately
25-mm diameter, which increase in number with aging
Figure 75-11 Idiopathic guttate hypomelanosis. Lesions

on the leg of an African-American individual.
(Fig. 75-11). Any associated hairs often remain pigmented. Lesions are found in a photodistribution
and tend to occur in chronically sun-damaged skin.
They are often seen pretibially and on the forearms,
although they may also arise on other sun-exposed
areas, including the face, neck, and shoulders. IGH has
been hypothesized to be UV-induced, although controversy exists. Some suggest that IGH may reflect the
normal aging process.71
Histologically, IGH lesions are characterized by
slight basket-weave hyperkeratosis with epidermal
atrophy and flattening of the rete pegs. Lesions show
a decrease in melanocytes and melanin content of the
affected epidermis and pigment granules are irregularly distributed.
A variety of therapies with variable success are
described, including cryotherapy, superficial dermabrasion, topical steroids, and topical retinoids.72,73
LEUKODERMA PUNCTATA. Leukoderma punctata was first described by the development of multiple punctiform hypopigmented and achromic spots
after several months of PUVA treatment.74 Later, similar cases were described after UVB therapy for psoriasis and after topical PUVA in one case of segmental
vitiligo.75
Lesions are predominantly present on the extremities, upper back and chest. They are round or oval,
sharply demarcated, and small (0.51.5 mm), without
follicular distribution. Spontaneous reduction of the
leukodermic lesions has been observed.74
It has been suggested that phototoxicity damage to

keratinocytes and melanocytes is the etiologic factor.
Leukoderma punctatum is suggested to be distinct
from IGH on the basis of the clinical and histologic
features. In IGH, lesions are larger and spontaneous
resolution is not reported. Ultrastructurally, leukoderma punctata demonstrates slight-to-severe damage of keratinocytes and melanocytes not reported
in IGH.
CANITIES.
PROGRESSIVE MACULAR HYPOMELANOSIS. PMH is an entity that affects the trunk with num-
mular, hypopigmented nonscaly macules. It affects

young adults, mainly women. Although described in
people of mixed racial ancestry (known as Creole dyschromia),80 it is seen in all races. It can be mistaken for
PA and pityriasis versicolor. Topical and systemic antifungal treatment and topical steroids are ineffective,
but the disorder may resolve, sometimes temporarily,
after sun exposure or phototherapy.
ACQUIRED DIFFUSE
HYPOPIGMENTATION WITH
VASCULAR CAUSES
ANEMIA. The color of the skin is determined by
several chromophores, usually predominantly melanin pigment, but the hemoglobin content of the skin
also contributes to the skin color. The pale skin color
observed in anemia is due to decreased levels of circulating oxyhemoglobin and is proportional to the severity of the anemia.
WORONOFFS RING. (See Chapter 18). Woronoffs

ring represents a blanched halo surrounding a psoriatic lesion. It is observed after UV treatment or topical
steroid treatment, but may also occur in untreated psoriasis. The pathogenesis is not clear. A decreased melanin content has been found in both psoriatic and halo
epidermis suggesting a true hypomelanosis. A local
decreased prostaglandin synthesis with decreased vasodilatation or a diffusion of anti-inflammatory mediators
from the psoriatic lesion to the halo is also postulated.
CUTANEOUS EDEMA. Cutaneous edema produces an appearance of leukoderma that is not true
hypomelanosis. Decreased absorption of light, reduced
capillary blood flow, and increased dermal thickness
may contribute to the pale appearance of the skin.
HYPERMELANOSIS
CONGENITAL DIFFUSE
HYPERMELANOSIS
CONGENITAL DIFFUSE LINEAR
HYPERMELANOSIS
Linear and Whorled Nevoid Hypermelanosis. Linear and whorled nevoid hypermelano-
sis (LWNH) is characterized by hyperpigmented

macules in streaky configuration along the lines of
Blaschko without preceding inflammation or atrophy.89 Similar cases have been described under
different descriptive names (zosteriform hyperpigmentation, zosteriform lentiginous nevus, zebra-like hyperpigmentation). Lesions are typically located on the trunk
and limbs and do not cross the midline. Face, palms,
soles, eyes, and mucous membranes are spared.
Kalter et al described LWNH as having onset within
a few weeks of age and progression during the initial years of life.89 The pigmentation can fade gradually with increasing age. Several cases have been
reported with both hyper- and hypopigmentations.
Pigmentary mosaicism is a useful term to encompass
all these different phenotypes.90
The presence of mosaicism has been confirmed in a
few cases (mosaic trisomy 7, 14, 18, 20, and X-chromosomal mosaicism) by chromosomal analysis on lymphatic cultures or dermal fibroblasts.91
LWNH may be differentiated from incontinentia
pigmenti (IP) and epidermal nevus.89
Extracutaneous abnormalities have been observed
in a number of LWNH cases, including developmental and growth retardation, facial and body asymmetry,
ventricular septal defect, and pseudohermaphroditism.
Chronic hemodialysis patients

frequently show disorders of skin pigmentation, primarily involving hyperpigmentation of sun-exposed
body areas. Hypopigmentation of skin and hair is
rather exceptional but occurs, possibly due to a disturbance of phenylalanine metabolism.
ently hypopigmented areas, usually on arms and legs

in young adults, resulting in a reticulated appearance.
The surrounding skin is erythematous and blanches
with pressure causing the hypopigmented macules
to disappear. The condition is a vascular anomaly with
vasoconstriction in the pale areas and venodilatation
in erythematous skin.81,82
::
HEMODIALYSIS.
11
Chapter 75
Hair graying or canities is a process of

chronological aging and occurs regardless of gender or
race.76 The age of onset, which appears to be hereditary, is usually in the fourth decade. The average age
for whites is mid-30s, for Asians late 30s, and for Africans mid-40s. Premature canities (before 20s or 30s) can
be associated with pernicious anemia, hyper/hypothyroidism, osteopenia, and several rare syndromes
like progeria and pangeria (Werner syndrome). Graying usually appears at the temples first, then the vertex, and, finally, the occiput. Beard and body hair are
affected later. Gray hairs seem to be thicker and longer than normally pigmented hairs. The perception of
gray hair derives in large part from the admixture of
pigmented and white hair, but individual hair follicles
can indeed exhibit pigment dilution or suboptimal
melanocytecortical keratinocyte interactions during the graying process.7779 An acute episode of alopecia areata may result in a very sudden overnight
graying (so-called canities subita) that is caused by the
preferential loss of pigmented hair in this immunemediated disorder.
BIER SPOTS. Bier spots are small, irregular appar-
813
11
Histologic examination reveals increased pigmentation of the basal layer and prominence or vacuolization of melanocytes. Pigment incontinence is usually
but not always absent.92
Incontinentia Pigmenti.
Section 11
::
IP, also known as

BlochSulzberger syndrome, was first described by Garrod et al in 1906. It is an X-linked, dominantly inherited
disorder, reported primarily in females, and believed
to be embryonic lethal in the majority of males. In
most cases, IP is due to a mutation in the gene NEMO
[nuclear factor B (NF-B) essential modulator] on
the X chromosome at Xq28.9396 In IP females, inactivation of one of the two X chromosomes through a
process termed lyonization occurs during embryogenesis. Epidermal cells expressing the defective NEMO
gene give rise to typical skin lesions along the lines
of Blaschko, reflecting the embryonic migration path
of the affected keratinocytes. Lesions usually proceed
through four cutaneous stages, sometimes with some
overlap: (1) vesicular stage (from birth or shortly thereafter), (2)verrucous stage (between 2 and 8 weeks of
age), (3) hyperpigmented stage (several months of age
into adulthood), followed by (4) hypopigmentation
stage (from infancy through adulthood) (Fig. 75-12). A
significant percentage of IP patients have ocular, dental, skeletal, and CNS anomalies.97
The cutaneous lesions in the first stage represent the
population of NEMO-deficient cells that fail to activate
NF-B, leading to apoptosis, as NF-B normally protects against tumor necrosis factor-induced apoptosis.
814
The number of NEMO-deficient cells decreases secondary to apoptosis and is replaced by cells expressing the normal allele. Subsequently, the inflammatory
and vesicular stage ends. The hyperproliferation in
the second stage is likely due to compensatory proliferation of normal NEMO keratinocytes. Hyperpigmentation in the third stage results from incontinence
of melanin pigment from the destroyed epidermis into
the dermis.
The hyperpigmentation appears in streaks and
whorls along the lines of Blaschko and is usually most
pronounced on the trunk, but can also appear on the
extremities. The degree of hyperpigmentation varies
among individuals. Histologically, the areas of pigmentation show many melanin-laden melanophages,
extensive deposits of melanin in the basal cell layer
and dermis. There is vacuolization and degeneration
in the epidermal basal cell layer. Usually, the hyperpigmentation fades gradually after several years and
the skin can become hypopigmented (stage 4), which
represents postinflammatory dermal scarring. The
hypopigmentation stage is characterized by linear,
atrophic, hairless scars following the Blaschkos lines.
Histologically, the number of melanocytes seems to
be normal, although a reduced number of melanocytes
also has been reported. The epidermis is thinner and
there is an absence or reduction of skin appendages
in the dermis that may contribute to the impression of
hypopigmentation.98
A beneficial effect of topical steroids and topical tacrolimus in the vesicular stage has been described.99,100
Figure 75-12 Incontinentia pigmenti in a mother and her baby. A. Verrucous lesions in a 2-week-old baby. B. Hypopigmented atrophic lesions following the Blaschkos lines.
CONGENITAL DIFFUSE RETICULAR

HYPERMELANOSIS
Dyskeratosis Congenita. Dyskeratosis
melanocytic proliferations are characterized by the
ophthalmomaxillaris) was first described by Ota in

1939.112 It is characterized by blueblack or graybrown
dermal melanocytic pigmentation and typically occurs
in areas innervated by the first and second branches
of the trigeminal nerve. Mucosal pigmentation may
occur involving conjunctiva, sclera, and tympanic
membrane (oculodermal melanocytosis), (Fig. 75-13)
or other sites. It is most frequently seen in the Asian
population, has a female predominance, and is usually congenital, although appearance in early childhood or at puberty has been described. Nevus of Ota
is now subclassified as mild (type 1), moderate (type
2), intensive (type 3), and bilateral (type 4). Bilateral
cases should be differentiated from Hori nevus, which
is acquired, does not manifest mucosal involvement
and is less pigmented (see Table 75-1).113
Malignant melanoma may rarely develop in a nevus
of Ota. This necessitates careful follow-up of the lesion,
especially if it occurs in Caucasian patients, in whom
malignant degeneration seems to be more frequent.
Malignant melanocytic tumors in association with
nevus of Ota have been shown to arise in the chorioidea, brain, orbit, iris, ciliary body, and optic nerve.114,115
In addition, association with ipsilateral glaucoma and
intracranial melanocytosis has been described.116
Nevus of Ito. Nevus of Ito is a congenital dermal

melanocytosis first described by Ito in 1954 as nevus
fuscocaeruleus acromiodeltoideus.117 It can be considered as a variant of nevus of Ota but with involvement
of the acromioclavicular and deltoideal region. Clinical, demographical, and histological characteristics
are similar to nevus of Ota and both lesions can occur
simultaneously (see Table 75-1).
CONGENITAL CIRCUMSCRIBED HYPERMELANOSIS WITH DERMAL MELANOCYTOSIS. Dermal melanocytoses or dermal dendritic
Nevus of Ota. Otas nevus (nevus fuscocaeruleus
::
CONGENITAL CIRCUMSCRIBED
HYPERMELANOSIS
11
Chapter 75
congenital (DKC) or ZinnserEngmannCole syndrome is characterized by reticulate skin pigmentation, nail atrophy,
leukoplakia, and bone marrow failure. Bone marrow
failure and malignancy develop in the second and third
decades. In all characterized cases of DKC, the causative
mutations are present in components of the telomerase
complex. Rapidly dividing somatic cells express low but
detectable levels of telomerase activity that slows the
otherwise progressive telomere shortening that occurs
with each cycle of DNA replication and eventually leads
to cellular senescence (permanent loss of proliferative
capacity). It is now thought that DKC is due to defective telomere maintenance, limiting the proliferative
capacity of hematopoietic and epithelial cells. Increased
melanin synthesis is now recognized to occur in senescent melanocytes, likely accounting for the pigmentary
phenotype of DKC; and critically short telomeres may
force cells into replicative crisis, at which time activation of an alternative ALT mechanism for lengthening telomeres in the absence of telomerase may lead to
development of malignancies. The finding of shortened
telomeres in DKC was indeed the first evidence of the
role of telomeres in cell biology (cellular aging).101
X-linked DKC is caused by mutations in the DKC1
gene located at Xq28, encoding for dyskerin. Females
carrying one mutated allele are protected by expression
of normal telomerase on the unaffected allele. In autosomal dominant DKC the majority of cases are due to
mutations in TERC, the RNA component of the telomerase complex. TERT (telomerase reverse transcriptase)
is affected much less often in autosomal dominant DKC.
The autosomal dominant form has the better prognosis,
presumably because some telomerase activity is preserved, due to the presence of an unaffected allele.
In the autosomal recessive form of DKC, mutations in
telomerase-associated proteins such as NOP10, NHP2, and
TINF2 are involved.102104 Skin biopsy of hyperpigmented
skin shows nonspecific changes, including epidermal
atrophy, a chronic inflammatory infiltrate with numerous
melanophages in the upper dermis. DKC may be confused
with Fanconis syndrome, characterized by short stature,
hypoplastic or aplastic thumbs, and a reduced number of
carpal bones. Here, there is a patchy hyperpigmentation of
the trunk, neck, groin, and axillary region that manifests
itself earlier than in DKC, i.e., in the first few years of life.
For a discussion of NaegeliFranceschettiJadassohn syndrome, dermatopathia pigmentosa reticularis,
DowlingDegos disease, GalliGalli disease, Kitamura
reticular acropigmentation, Habers syndrome, and
Partington syndrome, see online edition.
presence of melanin-producing dendritic melanocytes

in the dermis. They include the nevus of Ito, nevus
of Ota, and Mongolian spot and dermal melanocyte
hamartoma (Table 75-1). Associated vascular malformation has been described in phakomatosis pigmentovascularis (Port-wine stain type, KlippelTrenaunay or
SturgeWeber syndrome).111
Mongolian Spots. Mongolian spots are congenital,
benign hyperpigmentations preferentially occurring in

the African, Asian, and Hispanic population and only
rarely seen in Caucasians.118 They occur in both sexes
but with a slight male predominance,119 usually in the
sacral area. (Fig. 75-14) They can also be found in the
gluteal and lumbar region and on the thorax, abdomen, arms, legs, and shoulders. In most cases Mongolian spots spontaneously regress during childhood,
but persistence into adulthood has been described.120
Histologically, these macules consist of spindle-shaped
melanocytes in the lower dermis that have failed to
migrate to the dermalepidermal junction during fetal
life. Several cases are described with extensive Mongolian spots involving large areas of the trunk and extremities, associated with inborn errors of metabolism such
as GM1 gangliosidosis and mucopolysaccharidosis.121,122 Laser treatment in childhood or adolescence
can give favorable results with sacral Mongolians spots
being more laser-resistant than extrasacral ones.
815
11
Section 11
::
Figure 75-13 Nevus of Ota in a 20-year-old woman. A. Hyperpigmentation around the orbita. B. The hyperpigmentation
extends into the sclera.
Dermal Melanocyte Hamartoma.
Dermal
melanocyte hamartoma is a distinctive form of congenital dermal melanocytosis first described by Burkhart
et al in 1981.123 Grayblue pigmentation, caused by
melanocytes residing in the dermis, occurs in a dermatomal pattern.
CONGENITAL CIRCUMSCRIBED
HYPERMELANOSIS WITH LENTIGINOSIS
Familial Lentiginosis Syndromes. Familial
lentiginosis syndromes are characterized by the presence of lentigine-circumscribed brown macules (usually <5 mm in diameter), which display an increased
number of melanocytes in the epidermis (epidermal
melanocytic hypermelanosis) and an increased incidence of cardiovascular, endocrine, or gastrointestinal
neoplasias. They include Carney complex, Peutz
Jeghers syndrome (PJS), LEOPARD syndrome (LS)
(lentigines, electrocardiogram conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities
of genitalia, retardation of growth, and sensorineural
deafness), arterial dissection and lentiginosis, LaugierHunziker disease, familial benign lentiginosis,
BannayanRuvalcabaRiley syndrome (BRSS), centrofacial lentiginosis, and segmental and agminated
lentiginosis.124 (See Fig. 75-16.) Genetic loci and gene
mutations have been identified for Carney complex,
PJS, and BRRS.
PeutzJeghers Syndrome.
816
Figure 75-14 Classic Mongolian spot in the lumbosacral

region and aberrant or extrasacral Mongolian spots on the
back.
PJS is an autosomal dominant cancer predisposition syndrome first

described by Peutz (1921) and Jeghers (1949).125 Mucocutaneous pigmentation and intestinal hamartomatous
polyposis are hallmarks of the disease. (See Fig. 75-15.)
The pigmentary lesions resemble those of Carney complex, with small hyperpigmented macules typically
appearing in childhood (not present at birth) on the
lips and buccal mucosa, but they may also involve the
eyelids, hands, and feet.124
The most common malignancies associated with PJS
are gastrointestinal (small intestine, colorectal, stomach, pancreas). In addition, nongastrointestinal neoplasms such as breast, cervix, and endocrine tumors
(thyroid, testicular, ovarian) have been described.
More than half of all cases of PJS can be attributed to
a mutation in the serine/threonine kinase 11 (STK 11
11
Chapter 75
::
Figure 75-15 PeutzJeghers syndrome. A. Lentigines, which are dark-brown to grayblue, appear on the lips,
around the mouth, and on the fingers. Lip macules may, overtime, disappear. B. Macules of the buccal mucosa
are blue to blueblack and are pathognomonic; unlike lip lesions, these do not tend to disappear with time.
Figure 75-16 A and B. A 27-year-old woman with LEOPARD (lentigines, electrocardiogram conduction defects, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness) syndrome.
Note the characteristic widespread lentigines and several caf-au-lait macules.
817
11
or LKB 1) gene,126 which is therefore thought to act as

a tumor-suppressor gene. Close surveillance of PJS
patients from a young age is warranted.
LEOPARD Syndrome. LS is an autosomal domi-
Section 11
::
818
nant genodermatosis124 The characteristic lentigines

usually develop during childhood and in the first
months of life. Clinical diagnosis is primarily based
on the typical facial features and the presence of
hypertrophic cardiomyopathy and/or caf-au-lait
macules (CALMs). The disorder is caused by mutations in the PTPN11 gene, coding for the protein
tyrosine phosphatase SHP-2 and situated on chromosome 12. LS is allelic to Noonan syndrome and shares
several clinical features (Fig. 75-16).127 Recently missense mutations in the RAF1 gene were found in two
LS patients in whom no PTPN11 mutations could be
discovered.128
For Carney complex, BRSS, and centrofacial lentiginosis, see online edition.
CONGENITAL CIRCUMSCRIBED HYPERMELANOSIS WITH CAF-AU-LAIT MACULES. CALMs consist of sharply bordered
hyperpigmented patches of skin, varying in size from

0.5 cm to more than 20.0 cm. They are often present
at birth or appear in the early months of life. Between
0.3% and 18% of all newborns display isolated
CALMs.137 Histologically, isolated CALMs show a
normal number of melanocytes but increased epidermal melanin (epidermal melanotic hypermelanosis).
Multiple CALMs are well-known markers for several
multisystem disorders.
Neurofibromatosis Type 1. Neurofibromatosis type 1 (NF1) was first recognized by Friedrich von
Recklinghausen in 1882 and is therefore also called von
Recklinghausens disease (see Chapter 141 for detailed
discussions).
NF1 is an autosomal dominant disease caused by
a mutation in the NF1 gene, situated on chromosome
17q11.2 and encoding the neurofibromin protein. Neurofibromin takes part in several signaling pathways
and exhibits multiple isoforms through alternative
splicing mechanisms. The most important neurofibromin function involves downregulation of the Ras
signal transduction pathway and it is, therefore, considered a tumor-suppressor gene.124,138
NF1 has been considered as a neurocristopathy and
is characterized by a number of cutaneous and noncutaneous pigment cell-related manifestations such as
CALMs, intertriginous freckling, and iris Lisch nodules.138,139 In 1987, the US National Institutes of Health
Consensus Development Conference established clinical diagnostic criteria for NF1 (see Chapter 141). The
presence of six or more CALMs greater than 5 mm in
greatest diameter in prepubertal individuals or greater
than 15 mm after puberty is one of the hallmarks of
the disease. NF1-associated CALMs, contrary to isolated CALMs, contain a significantly increased number of melanocytes in the epidermis.140 Intertriginous
freckles, pathognomic for NF1, also display increased
numbers of epidermal melanocytes, which differenti-
ates them from ordinary freckles (ephelides). (See eFig.

75-16.1 in online edition.)
MccuneAlbright
Syndrome. McCune
Albright syndrome (MAS) was first described by
McCune (1936) and Albright (1937) as a triad of poly/
monostotic fibrous dysplasia, CALMs, and hyperfunctioning endocrinopathies, including precocious
puberty, hyperthyroidism, hypercortisolism, hypersomatotropism, and hypophosphatemic rickets.141,142 The
CALMs are fewer in number and have more irregular borders than those seen in NF1. They are classically demarcated at the midline. MAS is caused by a
postzygotic activating mutation of the subunit of the
cAMP-regulating Gs protein. Consequently, a mosaic
distribution of MAS cells bears the constitutively
active adenylate cyclase.143
For Bloom, Watson, and SilverRussel syndromes,
see online edition.
ACQUIRED DIFFUSE NONFIGURED
HYPERMELANOSIS
ENDOCRINOPATHIES
Addisons Disease. (See
Chapter 151). Addisons disease is a clinical syndrome characterized by

salt-wasting and skin hyperpigmentation, associated
with adrenal deficiency with inadequate secretion
of corticosteroid and androgenic hormones, leading
to compensatory overproduction of adrenocorticotropic hormone (ACTH) secretion by the pituitary
gland.157
In the developed world, Addisons disease is usually autoimmune in etiology.
Hyperpigmentation is the most striking cutaneous
sign of patients with chronic Addisons disease and is
the consequence of ACTH binding to the melanocortin-1 receptor (see Chapter 72). The hyperpigmentation
is diffuse and occurs preferentially on sun-exposed
areas (face, neck, hands), on sites of trauma, scars,
or chronic pressure (knees, spine, knuckles, elbows,
shoulders), in the palmar creases, and on nipples, areolae, axillae, perineum, and genitalia.157
Cushings Syndrome. (See Chapter 151). Cushing

syndrome is characterized by clinical signs and symptoms due to chronic glucocorticoid excess.
Various degrees of hyperpigmentation can be seen,
usually most severe in patients with the ectopic ACTH
syndrome. As in Addison disease, hyperpigmentation
is generalized, but most prominent in sun-exposed
areas such as face, neck, and dorsal hands, as well as
in areas subject to chronic mild trauma or pressure
(shoulders, midriff, waist, elbows, knuckles, spine,
knees) and on mucosal surfaces.158,159
Nelsons Syndrome. Nelsons syndrome comprises an enlarging pituitary tumor associated with
elevated fasting plasma ACTH levels, hyperpigmentation, and neuro-ophthalmological symptoms in
patients with Cushings disease after bilateral adrenalectomy and inadequate hormonal replacement.160
11
Pheochromocytoma.
Pheochromocytoma is a
tumor derived from chromaffin cells of the adrenal
medulla with associated excessive production of catecholamines. Pallor of the face due to vasoconstriction may be observed. In contrast, addisonian-like
hyperpigmentation has been reported and is probably due to ectopic ACTH and MSH production by
the tumor. Pigmentation rapidly fades after surgical
treatment.161
Carcinoid Syndrome.
Melasma. Melasma is a common hypermelanosis

that typically occurs on sun-exposed areas in the face.
The pathogenesis is poorly understood, but genetic
and hormonal influences in combination with UV
radiation are important. Specific precipitants include
birth-control pills, estrogen replacement therapy,
mild ovarian or thyroid dysfunction, ovarian tumors,
cosmetics, nutrition, phototoxic and photoallergic
medications, phototoxic drugs, and medication for
epilepsy.
Melasma is rarely reported before puberty and
is far more common in women, especially those of
reproductive age and often begins or is exacerbated
during pregnancy, explaining the common appellation mask of pregnancy. People with darker skin
types are more frequently affected. The lesions are
brownish macules with irregular borders and symmetric, photodistribution usually on the face (Fig.
75-17), often coalescing in a reticular pattern. Sun
Figure 75-17 Melasma. Typical yellowish to brownish

macules with irregular borders on the forehead of a young
woman.
exposure intensifies the lesions. There are three major

patterns of distribution of the lesions: (1) centrofacial
(63%: forehead, nose, chin, and upper lip), (2) malar
(21%: nose and cheeks), and (3) mandibular (16%:
ramus mandibulae). The anterior chest and dorsal
forearms may also be affected.
From its appearance under Woods lamp, melasma
is classically classified into epidermal, dermal, and
mixed. (Epidermal pigmentation is accentuated under
Woods lamp, whereas dermal pigmentation is less
apparent.)
Sun protection is central to management. Epidermal pigmentation is known to be more responsive to
topical treatment than dermal pigmentation. Hypopigmenting agents such as hydroquinone, tretinoin, azelaic acid, rucinol, and kojic acid are helpful when used
for prolonged periods. The so-called Kligman formula
is a popular combination of hydroquinone, tretinoin,
and a mild topical corticoid. Chemical peels and laser
therapy may be helpful in the treatment of melasma,
but can also result in further unwanted hyperpigmentation. Sometimes, melasma slowly disappears after
discontinuation of the hormonal stimulus and/or careful sun avoidance.165167
Pregnancy. During pregnancy increased pigmentation occurs in 90% of women and is most prominent
in darker skin types. Preexisting pigmented lesions
such as nevi and ephelides become darker. Also, recent
scars often darken. In normally pigmented areas, such
as nipples, areolae, and genitalia, the pigmentation
becomes more intense. The linea alba, the median
line on the anterior abdominal wall, often becomes
hyperpigmented during pregnancy and is then called
linea nigra. In a small proportion of pregnant women,
hyperpigmentation occurs in the axillae or the inner
upper thighs. Melasma or mask of pregnancy (see
Section Melasma) occurs in more than 50% of pregnant women (see Chapter 108).168,169
(See Chapter 151). Thyrotoxicosis has multiple causes. The most common cause is
Graves disease, characterized by circulating antibodies against thyroid-stimulating hormone receptors.
The occurrence of hyperpigmentation in thyrotoxic patients has been estimated from 2% to as
high as 40% in large series. The increased cutaneous pigmentation can be localized or generalized
and is more common in dark-skinned people. The
distribution of hyperpigmentation is often similar
to that in Addisons disease with pigment deposition in the creases of the palms and soles. However,
several features distinct from that of Addisons disease have been noted. Involvement of the mucous
membranes is uncommon and pigmentation of the
nipples and genital skin is less striking. Hyperpigmentation associated with thyrotoxicosis is thought
to be due to an increased release of pituitary ACTH,
compensating for accelerated cortisol degradation.
The response of hyperpigmentation to therapy for
the hyperthyroidism is reported to be poor.162164
Autoimmune Graves disease has been reported in
association with vitiligo.
::
Hyperthyroidism.
Chapter 75
Diffuse hyperpigmentation due to MSH-producing tumors, such

as gastric or thymic carcinoid tumors, have been
described in carcinoid syndrome. Carcinoid syndrome can also be accompanied by a pellagra-like
rash occurring on light-exposed skin. The rash is
secondary to a tryptophan deficiency, as a large
amount of dietary tryptophan is diverted to serotonin by the tumor.
819
11
Acanthosis Nigricans.
Acanthosis nigricans is
discussed in Chapters 151 and 153.
Diabetes. (See Chapter 151.) A higher vitiligo preva-
lence has been reported in patients with diabetes type

I and II compared to the general population. Diabetic
dermopathy is characterized by asymptomatic, irregular, light brown, depressed patches on the anterior
lower legs,65 but the pathogenesis is not known.
Section 11
NUTRITIONAL CONDITIONS. (See Chapter 130

and online text). Pigmentary changes can be secondary
to nutritional conditions such as kwashiorkor, vitamin
B12 deficiency, folic acid deficiency, or pellagra. The
skin changes are reversible on correction of the nutritional deficiency.
::
METABOLIC CONDITIONS
Porphyria Cutanea Tarda.
(See Chapter 132.)

Porphyria cutanea tarda is a metabolic disorder that
has been associated with diffuse brown hypermelanosis accentuated in sun-exposed areas. In females,
a melasma-like hyperpigmentation of the face can be
observed.
Hemochromatosis. Hereditary hemochromatosis is an autosomal recessive disorder associated with

increased intestinal absorption of iron and deposition
of excessive amounts of iron in the liver, pancreas, and
other organs, including the skin. In the past, hemochromatosis was usually diagnosed at an advanced
stage by the classic triad of hyperpigmentation, diabetes mellitus (bronze diabetes), and hepatic cirrhosis. Darkening of the skin was present in 70% of the
patients due to two different mechanisms: (1) hemosiderin deposition causing a diffuse, slate-gray coloring and (2) increased epidermal melanin production.
Because hemochromatosis is now usually diagnosed
early, hyperpigmentation is less frequently observed.
The pigmentation is usually generalized, but may be
more pronounced in sun-exposed areas, genitalia, and
scars. Skin bronzing is reversible by phlebitic therapy.178180
TUMORAL CONDITIONS
Mast Cell Disorders and Melanoma.
820
Mast
cell disorders and melanoma can lead to hyperpigmentation and are discussed in Chapters 149 and 124,
respectively. Diffuse, generalized melanosis associated with advanced metastatic melanoma is a rare,
although well-documented, event. It is characterized
by a slate bluish-gray to brown discoloration of the
skin (Fig. 75-18). Histology reveals melanin particles
and melanin-containing histiocytes and dendritic cells
in the dermis and subcutaneous fat. No melanoma cells
can be detected in the skin, and there is no increase
in epidermal melanin pigment or number of melanocytes. Melanosomes circulating in the blood have
been detected, supporting the hypothesis that diffuse
melanosis may result from tumor lysis183 with release
of their organelles into the circulation and subsequent
deposition in the skin.
Figure 75-18 Metastatic melanoma-associated, slategray, dermal pigmentation involving the entire body.
There was melanogenuria and at autopsy all internal
organs were found to be black.
PHYSICAL AGENTS
Ultraviolet Radiation. (See Chapter 90.) A major
acute effect of UV radiation on normal human skin is

tanning.
Ionizing Radiation. (See Chapter 240.) Exposure
of skin to ionizing radiation during accidents, such as

in Chernobyl, or after local fractionated radiotherapy
can give rise to a cutaneous radiation syndrome characterized by fibrosis, keratosis, telangiectasias, and
sharply demarcated lentiginous hyperpigmentation,
resembling UV-induced lentigines (radiation dermatitis). Small hypopigmented spots can be intermingled
with zones of hyperpigmentation. Skin biopsy shows
altered melanin content in melanocytes and basal keratinocytes, corresponding to the clinical appearance.
Electron beam therapy has been reported to induce
tan-like transient hyperpigmentation and transverse
melanonychia.184189
Thermal Radiation. In superficial thermal burn

injuries, when the melanocyte-bearing basal epidermis has not been destroyed, various degrees of hyperpigmentation result, depending on the skin color and
time after the injury. Thermal injury resulting from
laser therapy with intense, high-dose visible light
also can give rise to hyperpigmentation, especially in
dark-skinned patients. Cryotherapy, tissue destruction
by application of cold, commonly causes (sometimes
permanent) hypopigmentation in combination with
11
peripheral hyperpigmentation in treated skin due to

melanocyte injury.190193
Trauma. Friction melanosis in an acquired pigmentary disorder due to repeated rubbing of the skin 194
TOXIN- AND MEDICATION-INDUCED
HYPERPIGMENTATION
Chapter 75
::
Figure 75-19 Amiodarone hyperpigmentation. This

patient exhibits a striking amiodarone-induced, slate-gray
pigmentation of the face. The blue color (ceruloderma) is
due to the deposition of a brown pigment in the dermis,
contained in macrophages and endothelial cells (Lindall
effect).
sition of a drugmelanin complex in the dermis (eFig.

75-19.1 in online edition). The nail unit and hard palate
may also be involved. Exogenous ochronosis has been
reported after chronic hydroquinone use (see Section
Ochronosis ).
Chlorpromazine and related phenothiazines can
produce a bluish-gray pigmentation, especially in sunexposed areas, and pigmentation of the conjunctivae.
Minocycline can induce skin hyperpigmentation, as
well as pigmentation of the nails, sclerae, oral mucosa,
thyroid, bones, and teeth. Skin hyperpigmentation
may present as a blueblack discoloration, especially
at sites of inflammation, but also in noninflamed sites,
especially the anterior legs. In some patients, there is
a dull brown discoloration, especially in sun-exposed
areas. Argyria patients present with a generalized
grayish-blue pigmentation; the nails and the sclerae
may also be involved.
Treatment of toxin- and medication-induced hyperpigmentation involves discontinuation of the responsible agent, if possible. In a small subset of patients,
the hyperpigmentation persists even after discontinuation, particularly the bluish or gray pigmentation characteristic of dermal deposition. Sun protection should
be advised, especially in forms entailing melanin accumulation. Laser treatment has been reported to be successful in some cases (e.g., amiodarone).195
Hyperpigmentation caused by toxic agents or

medication accounts for 10%20% of all cases of
acquired hyperpigmentations. CNS drugs, antineoplastic agents, anti-infectious drugs, antihypertensive medications, and hormones are most commonly
responsible (eTable 75-1.1 in online edition).
In the majority of cases of medication-induced
hyperpigmentation, the underlying pathogenetic
mechanism involves one of the following.
Hyperpigmentation can be due to deposition of
melanin in the dermis, usually in macrophages.
Sometimes this melanin is complexed to the drug
[drug-pigment complex (e.g., hydroxychloroquine)].
Accumulation of melanin can occur after cutaneous
inflammation (postinflammatory) and/or DNA damage (e.g., carmustine). This type of hyperpigmentation
is often increased by UV exposure and is usually more
pronounced in sun-exposed areas.
Some substances (e.g., carotene, heavy metals) are
directly deposited in the skin. Sometimes this type of
pigmentation is also accentuated in sun-exposed areas
as UV can induce a transformation in the deposited
drugs, which may then become more visible.
In other cases, the dyschromia is caused by nonmelanin pigments synthesized or produced under the
direct or indirect influence of the drug.
Clinical features vary with characteristic sites, patterns, and shades of discoloration. The forms associated with melanin accumulation are often worsened
by sun exposure. Sometimes, the manifestation is more
or less specific for the responsible drug, although the
mechanism is often poorly understood. For example,
a linear, sometimes flagellate hyperpigmentation can
be observed in patients taking bleomycin or zidovudine. A diffuse hyperpigmentation on the palms and
soles may be present in patients taking cyclophosphamide or doxorubicin. Bleomycin and doxorubicin may
produce localized hyperpigmentation around small
joints. Estrogen-related hormonal substances and
phenytoin-like medication may cause melasma-like
pigmentation. Nail unit involvement can be observed
with some medications, most frequently chemotherapeutic agents, zidovudine, psoralens, minocycline,
antimalarials, and gold. Mucosal hyperpigmentation
has been reported with cyclophosphamide, doxorubicin, zidovudine, minocycline, and some heavy metals.
Amiodarone can produce bluegray pigmentation
in sun-exposed areas due to accumulation of a lipidlike substance in macrophages. Some of these patients
display photosensitivity (Fig. 75-19). (Hydroxy) chloroquine may give rise to a yellowbrown to bluishgray pigmentation on the face, neck, lower extremities,
and forearms after several years of intake, due to depo-
821
11
Focal depigmentation with perifollicular hyperpigmentation may occur, especially on friction sites (e.g.,
shins, elbows, and dorsum of the hands). There can be
localized hyper- and hypopigmentation.
A streaky hyperpigmentation over blood vessels on
a background of depigmentation has been reported.
Diffuse reticulated hyperpigmentation accentuated on
the trunk has been reported in one case.43
Section 11
INFECTIONS. (See Chapter 201.) Erythematous,

scaling papules termed pintids develop during the
secondary stage of pinta. These initially red lesions can
turn brown, slate-blue, black, or grayish.52
Chronic papular onchodermatitis is one of the skin
manifestations of onchocerciasis. It is characterized by
a severely pruritic maculopapular rash with hyperpigmented macules, most often occurring on shoulders,
buttocks, and extremities (see Chapter 207).53
::
Figure 75-20 Exogenous ochronosis. Hyperpigmentation

on the nose and cheeks after the use of a hydroquinone
cream.
OCHRONOSIS
Endogenous Ochronosis/Alkaptonuria.
Endogenous ochronosis/alkaptonuria is discussed in
Chapter 131.
Exogenous Ochronosis. Exogenous ochronosis

results from the use of certain medications, which form
a homogentistic acid polymer-like substance during
their metabolism. It presents as asymptomatic hyperpigmentation of the face, sides and back of the neck,
back, and extensor sites of the extremities (Fig. 75-20).
Histopathologically, there is a collection of yellowishbrown (ochronotic) globules in the papillary dermis.
There is no articular, renal, or cardiovascular involvement. It has been most frequently reported in association with hydroquinone (bleaching creams), usually
in skin phototype VI patients, although it has been
described in other skin types. Exogenous ochronosis
has also been noticed after the use of antimalarials and
products containing resorcinol, phenol, mercury, and
picric acid. Treatment is rarely helpful, but the offending drug should be stopped to prevent progression.196
For POEMS syndrome and CronkhiteCanada syndrome, and zidovudine-induced hyperpigmentation
see online edition. The hyperpigmentation associated
with the following disorders is discussed briefly online
and/or the other indicated chapters: systemic sclerosis (Chapter 157), pinta (Chapter 201), onchocerciasis
(Chapter 207), phytophotodermatitis (Chapter 90), flagellate pigmentation due to bleomycin (Chapter 227).
822
SYSTEMIC SCLEROSIS. (See Chapter 157.) Different types of abnormal pigmentation have been
described in systemic sclerosis. A diffuse, generalized
hyperpigmentation similar to Addisons disease but
with normal levels of MSH can be observed in severe
systemic sclerosis.
ACQUIRED CIRCUMSCRIBED
HYPERMELANOSIS
PHYTOPHOTODERMATITIS. Contact with
plants containing phototoxic agents such as psoralens,
with subsequent UV exposure, may lead to phytophotodermatitis, which is followed by patterned hyperpigmentation.
FLAGELLATE PIGMENTATION
BLEOMYCIN. (See Chapter 227.)
DUE TO
FLAGELLATE MUSHROOM DERMATITIS.
Flagellate mushroom dermatitis is characterized by

linear grouped, erythematous, and intensely pruritic
papules, a clinical pattern very similar to bleomycininduced flagellate dermatitis. It is caused by eating
raw or insufficiently boiled shiitake mushrooms (Lentinus edodes) and is not elicited by topical contact or
ingestion of well-boiled shiitake. The pathogenesis is
not yet known, but it is hypothesized that a thermolabile polysaccharide is responsible.199201
HYPERMELANOSISACQUIRED
DIFFUSE PATTERNED OR RETICULAR
ERYTHEMA AB IGNE. Erythema ab igne is caused
by a chronic exposure to moderate heat. The reticular
erythema can be accompanied by epidermal atrophy,
scaling, and hyperpigmentation. It was seen in the past
in people who frequently sat in front of open fires or
stoves for warmth, but it occurs less often since the
introduction of central heating. Nevertheless, it is still
seen after local application of heating pads, hot water
bottles, or heating blankets. Modern appliances that
have been reported to elicit erythema ab igne are furniture with built-in heaters, car heaters, and laptop computers (Fig. 75-21).204206
PRURIGO PIGMENTOSA. Approximately 200
cases of prurigo pigmentosa have been published in
the international literature since it was first described
simultaneously with other pigmentary abnormalities

such as melasma, freckles, solar lentigines, and nevus
of Ota.113,209
Combination treatments of pigment-specific laser
(Q-switched lasers) with chemical peels and topical bleaching agents have been used with variable
results.210
11
BECKERS NEVUS (BECKER HAMARTOMA,

BECKER MELANOSIS). This acquired hyperpig-
::
in 1971 by Nagashima. Prurigo pigmentosa presents

itself as intensely pruritic erythematous papules,
papulovesicles, and vesicles that involute in several
days. The lesions develop symmetrically on the back,
chest, neck, and lumbosacral region. The papulovesicular lesions heal spontaneously, leaving a nonpruritic reticular hyperpigmentation (see eFig. 75-21.1 in
online edition). The disease has a fluctuating course
with exacerbations and recurrences. It is twice as frequent in females as in males. The eruption and pruritus respond well to minocycline and dapsone but the
pigmentation does not and must resolve spontaneously. Environmental and metabolic factors have been
suggested as causative agents but the pathogenesis
remains unknown.207
Chapter 75
Figure 75-21 Reticular hyperpigmentation (erythema ab

igne) resulting from repeated applications of a heating
pad over several years.
mented epidermal nevus was first described in 1949

(Fig. 75-22). It preferentially occurs in the scapular
region, although it has been described in any area of
the body, and classically after an intense sun exposure.
The lesion is androgen-dependent and becomes more
prominent in adolescence, especially in the male population. Hypertrichosis in the lesion is often associated.
Associated anomalies, such as ipsilateral breast hypoplasia, musculoskeletal abnormalities (scoliosis, ipsilateral limb hypoplasia, etc.), maxillofacial abnormalities,
and additional cutaneous hypoplasias, occur in the
rare Beckers nevus syndrome. Microscopic examination demonstrates normal numbers of melanocytes,
but increased levels of melanin in the basal epidermal
layer (epidermal melanotic hypermelanosis). The epidermis is acanthotic with variable hyperkeratosis and
elongation of the rete ridges. In the dermis, the number
of arrector pili muscles is increased, making it difficult
to differentiate from the related smooth muscle hamartoma. Good therapeutic results have been reported
using a long-pulsed alexandrite laser.215
ACQUIRED CIRCUMSCRIBED
HYPERMELANOSIS
NEVUS OF HORI. Nevus of Hori was first described
in 1984 as acquired, bilateral nevus of Ota-like macules termed ABNOM.208 It consists of bluebrown to
slate-gray mottled hyperpigmentation on the face
with predilection for the malar regions. Similar to
nevus of Ota, it typically affects the Asian population
and has a female predominance. However, the lack
of ocular and mucosal membrane involvement and
the acquired bilateral character distinguish the entities. Histologically, melanocytes with stage III or IV
melanosomes reside in the upper and middle layers
of the dermis. Sun exposure and hormonal changes
during pregnancy have been described as triggering
factors.209 Hori described three possible mechanisms
for the pathogenesis of ABNOM: (1) dropping of
epidermal melanocytes into the dermis, (2) migration
of melanocytes from hair bulbs, and (3) reactivation of
preexisting latent or immature dermal melanocytes.208
The latter has been suggested as being the most probable mechanism with UV-radiation and sex hormones
as activating factors. In some cases, ABNOM can occur
Figure 75-22 Beckers nevus on the upper arm and

shoulder of a young man. Note the typical localization and
marked hypertrichosis.
823
11
Beckers nevus is suggested to follow a paradominant inheritance pattern, which means it (almost)
always occurs sporadically. The rare familial cases that
have been described (especially in Beckers nevus syndrome) can be explained by a somatic mutation during
embryogenesis, resulting in loss of heterozygosity and
formation of a mutant cell population. This hypothesis is supported by the identification of chromosomal
mosaicism in fibroblasts derived from a Beckers
nevus.216218
Section 11
::
EPHELIDES. Ephelides or freckles are small light

brown macules appearing in sun-exposed skin of fairskinned individuals, often those with red or blond hair
and Celtic ancestry. They are more pronounced during
spring and summer and fade during the winter period.
They appear in early childhood and often regress later
in life. Histopathologic examination shows a normal
to reduced number of sometimes hypertrophic melanocytes but increased melanin in the basal epidermal
layer.
POSTINFLAMMATORY HYPERPIGMENTATION. Postinflammatory hyperpigmentation (PIH) is
a common condition caused by numerous preceding

cutaneous insults such as drug and phototoxic reactions, infections, physical injury or trauma, allergic
reactions, and inflammatory diseases. Clinically, PIH
consists of a macular hyperpigmentation at the site
of inflammation (Fig. 75-23).179 It is far more common
and persistent in darker skin types (Fitzpatrick types
IIIVI) and can be characterized by epidermal as well
as dermal melanotic hypermelanosis. A Woods lamp
examination can determine depth of the hyperpig-
mentation (see Section Melasma). Histologic features include pigment incontinence with accumulation
of melanophages and increased melanin in dermal or
epidermal layers.219 Management of PIH remains difficult,220222 although epidermal PIH often shows slow
spontaneous fading.
FAMILIAL PERIORBITAL HYPERPIGMENTATION. Increased pigmentation of the upper and lower
eyelids has been described in a number of families.

Histologically, increased basal pigmentation and dermal melanophages are seen. However, inflammation
does not appear to precede the hyperpigmentation.223
PARTIAL UNILATERAL LENTIGINOSIS. Partial

unilateral lentiginosis (PUL) is also known as unilateral lentigines, lentiginous mosaicism, zosteriform lentiginous nevus, segmental lentiginosis, and agminated
lentiginosis.
RIEHL MELANOSIS. Riehl melanosis, also known
as female facial melanosis, is mostly seen in middleaged women, especially in darker skin types, such
as Mexicans and Asians (see eFig. 75-23.1 in online
edition).
It is characterized by a rapid onset of a reticular
graybrown to almost black hyperpigmentation.
The face (especially the forehead, zygomatic area,
and temples) and the neck are principally involved,
but the hands, forearms, and trunk can also be affected.
Inflammatory findings such as erythema and pruritus
are usually absent.
The main histopathologic feature is liquefactive
degeneration of the basal layer of the epidermis, resulting in pigment incontinence in the dermis. The pathogenesis is not understood.226,227
The hyperpigmentation has been postulated to be
induced by repeated contact with threshold doses of a
contact sensitizer such as fragrances, some pigments,
and bactericides used in cosmetics and optical whiteners, but is poorly documented in most cases.
CUTANEOUS AMYLOIDOSIS. Macular amyloidosis presents as brown to graybrown macules,
mainly on the back (see Chapter 133).
ATROPHODERMA OF PASINIPIERINI. (See
Chapter 67). The cutaneous lesions of atrophoderma
of PasiniPierini can be described as single or multiple
gray to violaceous-brown atrophic patches from 1 cm
to more than 10 cm in diameter with slight depression
with a characteristic cliff drop border.
FIXED DRUG ERUPTION. Fixed drug eruption
can cause hyperpigmentation (see Chapter 41).
824
Figure 75-23 Postinflammatory hyperpigmentation.

May follow a drug eruption, psoriasis, or lichen planus,
especially in skin phototypes V and VI as was the case in
this middle-aged East Indian woman. Postinflammatory
hyperpigmentation is a major problem in young women
with skin phototypes V and VI.
ERYTHEMA DYSCHROMICUM PERSTANS.
Erythema dyschromicum perstans, also known as

ashy dermatosis, dermatosis cenicienta, and erythema
chronicum figuratum melanodermicum, was first
described by Ramirez in 1957. Patients with this eruption were labeled as los cenicientos, the ashy ones.229
MIXED HYPO- AND

HYPERMELANOSIS
DYSCHROMATOSIS HEREDITARIA
UNIVERSALIS
Dyschromatosis hereditaria universalis is an autosomal dominant disorder that usually presents in infancy
or early childhood in Asian families and is characterized by pinpoint to pea-sized hypo- and hyperpigmented macules, distributed in a reticulated pattern
RETICULATE ACROPIGMENTATION
OF DOHI
Reticulate acropigmentation of Dohi is a localized form
of dyschromatosis universalis hereditaria, also called
dyschromatosis symmetrica hereditaria. It is characterized by small, symmetric hyper-, and hypopigmented
macules on the dorsal hands and feet, and is mainly seen
in young children in South American and Asian families.
WESTERHOF SYNDROME
Westerhof syndrome, described in three generations of
one family, displays congenital hypo- and hypermelanotic macules. There is also small stature and mental
retardation.234
VAGABOND LEUKODERMA
Vagabond leukoderma is a condition found in persons
living in poor hygienic conditions. Many abuse alcohol, live on an inadequate diet, and are infested with
lice and/or scabies. Diffuse light-brown hyperpigmentation is present at the shoulder and waist girdle,
and the neck and back are dotted with depigmented
macules. The condition improves on institutions of a
healthier lifestyle and likely represents a coexistence of
many of the disorders.235
KEY REFERENCES
Idiopathic eruptive macular hyperpigmentation is an

uncommon disorder of pigmentation characterized,
as the name suggests, by an eruption of asymptomatic, brown macules (5 mm to several cm in diameter)
involving the trunk, neck, and proximal extremities in
children and adolescents. No previous drug exposure
has been implicated, and the lesions disappear gradually over several months to years.
Histopathologically, there is hyperpigmentation of
the basal layer of the epidermis and prominent dermal
melanophages. The number of mast cells is normal.232
11
::
IDIOPATHIC ERUPTIVE MACULAR

HYPERPIGMENTATION
over the trunk, abdomen, and limbs, usually sparing

the face and palmoplantar surfaces.233
Chapter 75
The disease is characterized by hyperpigmented

macules and patches of variable shape and size with an
ashen-gray to brownblue color. They may have a thin,
raised erythematous border in the early stage that later
can be absent or, mainly in darker skin types, evolve into
a hypopigmented border that accentuates the hyperpigmentation. The eruption can also be polymorphic,
presenting simultaneously hypo- and hyperpigmented
macules. Lesions occur primarily on the face, the neck,
the trunk, and the proximal part of the arms. The lesions
are usually asymptomatic, although slight pruritus can
be present. There is a slow progression of the lesion over
several years, usually without spontaneous regression.
Erythema dyschromicum perstans is mainly
observed in intermediate skin types. It is a disease of
young adults, although there are small series reporting
the disease in prepubertal children. There is no clear
sexual predilection.230
Histologic examination of the inflammatory border
may demonstrate lichenoid dermatitis with vacuolization of the basal cell layer, occasional colloid bodies,
and increased epidermal melanin. The dermal changes
are edema of the papillary dermis, a moderate or
mild lymphohistiocytic infiltrate, and dermal melanophages. The pathogenesis of erythema dyschromicum
perstans is unclear and likely influenced by many factors. An HLA-DR-associated susceptibility to develop
erythema dyschromicum perstans has been described
in a Mexican population.231
In inactive lesions, there is no vacuolization of the
basal cell layer, a diminished dermal infiltrate, and an
increased number of dermal melanophages. There is
no effective treatment.229,230

1. Dessinioti C et al: A review of genetic disorders of
hypopigmentation: Lessons learned from the biology of
melanocytes. Exp Dermatol 18:741-749, 2009
3. Van Den Bossche K, Naeyaert JM, Lambert J: The quest
for the mechanism of melanin transfer. Traffic 7:769-778,
2006
26. Bahadoran P et al: Comment on Elejalde syndrome and
relationship with Griscelli syndrome. Am J Med Genet A
116A:408-409, 2003
48. El-Shabrawi-Caelen L et al: Hypopigmented mycosis
fungoides: Frequent expression of a CD8+ T-cell phenotype. Am J Surg Pathol 26:450-457, 2002
55. Zijlstra EE et al: Post-kala-azar dermal leishmaniasis.
Lancet Infect Dis 3:87-98, 2003
56. Ramos-e-Silva M, Rebello PF: Leprosy. Recognition and
treatment. Am J Clin Dermatol 2:203-211, 2001
61. Engasser PG, Maibach HI: Cosmetic and dermatology:
Bleaching creams. J Am Acad Dermatol 5:143-147, 1981
72. Kumarasinghe SPW: 35 second cryotherapy is effective
in idiopathic guttate hypomelanosis. J Dermatol 31:437439, 2004
83. Braun RP et al: Dermoscopy of pigmented skin lesions. J
88. Zanardo L et al: Progressive hyperpigmentation and
generalized lentiginosis without associated systemic
symptoms: A rare hereditary pigmentation disorder in
south-east Germany. Acta Derm Venereol 84:57-60, 2004
825
11
Section 11
::
826
103. Vulliamy TJ et al: Very short telomeres in the peripheral

blood of patients with X-linked and autosomal dyskeratosis congenita. Blood Cells Mol Dis 27:353-357, 2001
116. Sinha S, Cohen PJ, Schwartz RA: Nevus of Ota in children. Cutis 82:25-29, 2008
126. Jenne DE et al: Peutz-Jeghers syndrome is caused by
mutations in a novel serine threonine kinase. Nat Genet
18:38-43, 1998
133. Gorlin RJ et al: Bannayan-Riley-Ruvalcaba syndrome.
Am J Med Genet 44:307-314, 1992
158. Slominski A et al: Melanin pigmentation in mammalian skin
and its hormonal regulation. Physiol Rev 84:1155-1228, 2004
172. Lechner K et al: [Vitamin B12 deficiency. New data on an

old theme]. Wien Klin Wochenschr 117:579-591, 2005
188. Steinert M et al: Delayed effects of accidental cutaneous
radiation exposure: Fifteen years of follow-up after the
Chernobyl accident. J Am Acad Dermatol 49:417-423, 2003
203. Greenberg RG, Berger TG: Nail and mucocutaneous
hyperpigmentation with azidothymidine therapy. J Am
Acad Dermatol 22:327-330, 1990
212. Hidano A, Kaneko K: Acquired dermal melanocytosis of
the face and extremities. Br J Dermatol 124:96-99, 1991
215. Choi JE et al: Treatment of Beckers nevi with a longpulse alexandrite laser. Dermatol Surg 35:1105-1108, 2009
Disorders of the Oral and Genital

Integument
Chapter 76 :: Biology and Pathology of the Oral Cavity

:: Sook-Bin Woo
ORAL MUCOSAL DISEASE
At A GLANCE
Idiopathic recurrent aphthous ulcers affect
15%20% of the population; severe cases can
be debilitating.
Oral ulcers may also be associated with
Crohn disease and other gastrointestinal
disorders or due to herpes simplex,
other viral infections, vasculitis, or other
autoimmune disorders.
Candidiasis of the oral cavity is common
and painful. Predisposing factors include
immunosuppression, hyposalivation, and
use of steroids or antibiotics.
Hair leukoplakia is due to EpsteinBarr viral
infection and may be the presenting sign of
HIV/AIDS.
Oral lichen planus (LP) and lichenoid
reactions affect 1%2% of the population
and are the most common cause of
desquamative gingivitis; LP probably reflects
a hypersensitivity response to endogenous
or exogenous antigens.
Leukoplakia is a premalignant condition
associated with smoking and/or alcohol
ingestion that must be distinguished from LP
and benign frictional keratoses.
Bullous diseases that affect the mouth
include pemphigus, pemphigoid, and lupus
erythematous.
Intraoral pigmented lesions include nevi,
postinflammatory hyperpigmentation,
drug reactions, tattoos, and rarely
melanoma.
INTRODUCTION
The mouth is the beginning of the aerodigestive tract
and an extension of the skin barrier. It plays an important role in mastication, deglutition and digestion,
speech, and immunologic defense. The oral mucosa,
salivary glands (both major and minor), jawbones,
and teeth are frequently the site of primary inflammatory or neoplastic disease. However, the oral cavity
may present with manifestations of systemic disease
and in some cases, oral findings may precede systemic
signs and symptoms by months or years. Lesions in
the maxillary sinus and nasal cavity may lead to pain
in the upper teeth or may extend inferiorly and present in the maxilla or palate. Metastatic lesions may
present as nodules on the gingiva or masses in the
jawbones.
This chapter focuses only on the more common
mucosal and salivary gland diseases encountered in
dermatology practice.
EVALUATION OF THE PATIENT

As with evaluation of the skin, obtaining a comprehensive medical and medication history and careful
inquiry into current symptoms are essential. The extraoral examination should begin with an examination
of the skin of the face and in particular the perioral
region, palpation of the submandibular and submental
lymph nodes, and palpation of the temporomandibular joints for clicking or pain on opening. Clicking with
no pain occurs in 20%30% of the population and is of
no clinical significance but should be noted. Clicking
with pain and/or limitation of opening may indicate
temporomandibular joint myofascial pain syndrome
and requires referral to a dental specialist for management.
The intraoral examination should be directed to the
following areas:
1. The mucosal surfaces as outlined above, taking
note of where the lesions are located, and in

particular, whether they are on the keratinized or
nonkeratinized sites.
12
3. Palatal and mandibular tori: These are benign,
usually symmetric exostoses that are present in

the midline of the hard palate or bilaterally on
the lingual aspect of the mandible (Fig. 76-2).
They may be large and multilobated, but patients
are usually unaware of their presence.
PRESCRIBING TOPICAL
MEDICATIONS
TOPICAL STEROIDS
Section 12
Figure 76-1 Fordyce granules.

2. The presence or absence of saliva in the floor
::
Disorders of the Oral and Genital Integument
of mouth and whether the saliva is of the usual

watery consistency or whether it is ropey.
3. The dentition and whether there are grossly
carious teeth.
4. The use of a removable prosthesis (upper and/
or lower denturescomplete or partial); this is
particularly important for some mucosal diseases
caused by denture trauma and for the diagnosis
and treatment of candidiasis since the denture acts
as a fomite.
NORMAL ANATOMIC STRUCTURES

There are several structures in the oral mucosa that are
considered variations of normal. These include:
1. Fordyce granules: These are sebaceous glands that
present as painless yellow papules, 12 mm in

diameter located in a bilateral symmetric fashion
on the posterior buccal mucosa, and lips (usually
vermilion) (Fig. 76-1). Sebaceous hyperplasia of
these glands may form discrete larger yellow
papules several millimeters in size.
2. Linea alba: This is a linear keratosis located on the
buccal mucosa bilaterally where the upper and lower
teeth meet. It is a form of frictional keratosis and
exaggeration of this is seen in patients who habitually
chew the buccal mucosa, a condition known as
morsicatio mucosae oris (MMO) (see below).
828
Figure 76-2 A. Palatal torus. B. Mandibular tori.
Topical steroids are the mainstay of treatment for many

inflammatory and autoimmune mucosal diseases.1 The
only topical steroid that is FDA-approved for intraoral
use is Kenalog-in-Orabase dental paste (0.1% triamcinolone; Apethecon, Princeton, NJ). This is a Class IV steroid and is weakly efficacious as an anti-inflammatory
agent in the oral cavity, although the Orabase (methylcellulose) is useful and soothing as a covering agent in
some conditions. In general, most oral medicine specialists use fluocinolone, fluocinonide, clobetasol, and
topical tacrolimus for the management of mucosal disease. Principles applying to use of these medications
in the oral cavity regardless of specific diagnosis are
found in Table 76-1 and eBox 76-0.1 in online edition.
TOPICAL ANALGESICS
Viscous lidocaine (2%) may be used alone or combined
with diphenhydramine, Kaopectate (Pfizer, NY), or
Maalox (Novartis, NJ) in equal volumes as a swish and
spit out preparation for pain control. This is particularly useful for diffuse painful lesions, acute or chronic.
Localized ulcers may be treated with over-the-counter
benzocaine preparations, or covering agents such as
methylcellulose (Orabase; Colgate-Palmolive, NY).
As with any disease condition, provision of upto-date information on the disease allays many fears
and misconceptions, empowers patients, and helps
patients to better understand their condition. Information on the nature, management, and prognosis of
common mucosal conditions are available on the Web
12
TABLE 76-1
Commonly-Used Medications for Oral Lesions

How to Prescribe
Topical immunosuppressive agents

Triamcinolone 0.1% dental paste
Fluocinolone 0.05% gel
Clobetasol 0.05% gel
Betamethasone 0.05% gel
Dexamethasone elixir 0.5 mg/5 mL
Prednisolone syrup (15 mg/5 mL)
Tacrolimus solution (5 mg/mL)
Cyclosporine (100 mg/mL)
Nasal sprays used orally (such as fluticasone and budesonide)
Intralesional steroid injection with triamcinolone
5-mg tube; apply to affected site tid or qid (this forms a barrier)
15-60 g tube dry area, apply to affected site tid or qid; no food or
drink for 30 minutes after OR
Place gel in stent and wear for 30 minutes, bid or tid
Dispense 300500 mL; swish 5 mL. (dexamethasone, tacrolimus,
or cyclosporine) or 510 mL. (prednisolone) for 3 minutes
(timed) and spit out tid or qid; no food or drink for 30 minutes
after
12 puffs 23 times a day
15 mg triamcinolone per cm2 of ulceration
Antifungal therapy
Nystatin 1:100,000 units/mLa
Denture treatment in patients with candidiasis

Denture soaks such as:
Nystatin 1:100,000 units/mL
Chlorhexidine digluconate 0.12%
3% sodium hypochlorite diluted in water (1:10)
2% sodium benzoate
Topical pain medications
Viscous lidocaine 2%
Benzydamine hydrochloride 0.15%
Dyclonine hydrochloride 1%
Systemic immunosuppressive therapy
Prednisone
Pentoxifylline
Hydroxychloroquine
Dapsone
Colchicine
Azathioprine
Thalidomide
Swish and spit out tid or qid for pain
Topical therapy should be started concomitant with systemic

therapy.
0.51.0 mg/kg to begin for 710 days with a rapid taper over
23 weeks
400 mg three times a day or 800 mg twice a day
200400 mg daily
25 mg to begin, increasing to 75100 mg/day
10003000 mg daily
0.6 mg once or twice a day
50100 mg daily
50100 mg tid to begin; begin taper to maintenance dose
(which may be weekly) or discontinue completely
Biology and Pathology of the Oral Cavity
Mycostatin/triamcinolone cream
::
Clotrimazole 10 mg trochesa
Fluconazole 100 mg
Dispense 300500 mL; swish and spit out (or swallow) 5 mL tid
or qid
Suck on one troche tid or qid
Take one tablet in the morning qd 310 days (depending on
the severity of the infection)
Apply to corners of mouth tid or qid for angular cheilitis
Paint onto denture base tid and wear denture
Soak denture in solution overnight.
Chapter 76
Medication
Formulations contain cariogenic sugars that may lead to caries if used for months.
sites of the American Academy of Oral and Maxillofacial Pathology (www.aaomp.org) and the American
Academy of Oral Medicine (www.aaom.com). These
can be modified to suit your practice needs.
ORAL MANIFESTATIONS OF
SYSTEMIC DISEASE AND
SYNDROMES
Systemic diseases often have distinctive presentations
in the oral cavity and many skin conditions also have
concomitant oral findings. eTable 76-1.1 in online edi-
tion provides a list of some of the more common systemic diseases and syndromes that present with oral
findings. Some are discussed in greater detail below.
DISEASE CLASSIFICATION
The disease entities to be described are those normally
treated by the dermatologist and are divided primarily into how the lesions present clinically (e.g., ulcers,
nodules, or red and white lesions). However, there is
also a section based on lesions that are site-specific.
Pathogenetic mechanisms for diseases such as the
autoimmune bullous disorders will not be discussed
829
12
in any detail since they are presented elsewhere in this

book.
ULCERATIVE CONDITIONS
The oral ulcer appears as a yellowwhite papule or plaque
of fibrin (often referred to as a pseudomembrane), usually with a surrounding red rim. It does not appear crusty
because of the wet environment. Such lesions are always
painful unless the ulcer represents a squamous cell carcinoma (SCC), which is often painless. Several conditions
fall into this category and only the most common will be
discussed here (eTable 76-1.2 in online edition).
Section 12
RECURRENT APHTHOUS ULCERS/STOMATITIS (CANKER SORES). Recurrent aphthous
::
ulcer (RAU) is a T-cell-mediated disorder and tumor

necrosis factor (TNF)- plays an important role in its
occurrence.2 There is usually a family history of aphthous ulcers and there is a significant association with
a number of HLA-haplotypes.3 Stress, systemic illness,
and local trauma predisposes to their occurrence in
susceptible individuals.
Aphtheiform ulcers are aphthous-like in their
appearance and history but they may occur sometimes
on the dorsum of the tongue if they are a result of hematinic deficiency or inflammatory bowel disease. RAU
are seen in all patients with Behet disease and may
precede other findings by years. Behet disease, a vasculitic disorder, has a predilection for Turkish and Japanese populations and is associated with an increase in
830
HLA-B51.4 In periodic fever-adenopathy, pharyngitis,

aphthae (PFAPA) syndrome, ulcers are often so severe
that children miss days at school.5,6 Patients with other
systemic or skin conditions and aphthous ulcers form
part of the complex aphthosis syndrome and include
those with MAGIC (mouth and genital ulcers with
inflamed cartilage) syndrome (eTable 76-1.2 in online
edition). Approximately 3% of patients with RAU have
gluten-sensitive enteropathy7 and some show sensitivity to foods and sodium lauryl sulfate.
Clinical Findings. Idiopathic RAU occurs in 15%

20% of the population beginning in the second decade
of life and the disease generally becomes less severe
over the age of 50. Patients often report the sensation
of a small nodule beneath the epithelium before the
ulcer appears. The painful yellowwhite ulcers are surrounded by an erythematous halo.
There are four clinical forms of RAU and these are
always painful:
a. Minor ulcers (<1 cm, 110 at each episode lasting
12 weeks) (Fig. 76-3A); this is by far the most

common form.
b. Major ulcers (>1 cm lasting several weeks and
healing with scarring) (Fig. 76-3B).
c. Herpetiform ulcers (<1 cm, usually 0.10.5 cm
each, >10 clustered ulcers at each episode, lasting
12 weeks (Fig. 76-3C).
d. Severe aphthous ulcers where patients have minor
ulcers but with continuous ulcerations with
minimum or no ulcer-free days for months.
Figure 76-3 A. Recurrent aphthous minor. B. Recurrent aphthous major. C. Recurrent herpetiform aphthous
ulcers.
Idiopathic RAU are almost always confined to the

nonkeratinized mucosa. They may occur on the nonattached gingiva, but generally do not cross the mucogingival junction onto the attached gingiva, except in
some cases of RAU major.
Differential Diagnosis and Laboratory

Studies. Traumatic lesions must be considered
Box 76-1 Obtaining a Biopsy

A biopsy of any mucosal condition is readily performed with a skin punch (35 mm in diameter). Here
are a few helpful suggestions:
1. Use a local anesthetic such as 2% lidocaine with
1:50,000 epinephrine instead of 1:100,000 epinephrine if possible. Since only a small volume is
used, this should not cause problems even with
hypertensive patients, but will reduce the amount
of bleeding encountered during the biopsy.
2. Punch biopsies of the attached gingiva and hard
palate are not readily closed with sutures and the
use of silver nitrate or aluminum chloride is preferable.
3. Labial, buccal mucosa, and tongue biopsies should
be closed in an anteroposterior direction.
4. Excision using an elliptical incision is preferable to
a shave biopsy in most cases, unless the lesion is
small, exophytic, and obviously benign (e.g., small
fibroma or papilloma).
Any positive
findings should be followed up. For example, it may
be useful to keep a food diary and to change tooth-
eases associated with oral ulcers are Crohn disease,

ulcerative colitis, malabsorption syndromes leading to
hematinic deficiency, and celiac disease.8
Oral lesions are seen in up to 20% of patients
with Crohn disease if nonspecific mucogingivitis is
excluded.9 Ulcers of Crohn disease typically present as
linear lesions along the maxillary and mandibular vestibule/sulcus (Fig. 76-4A). In addition, patients often
also present with papulous folds of tissues, swelling
of the lips (indistinguishable from cheilitis granulomatosa), and cobblestoning of the mucosa.10 Other manifestations of Crohn disease include severe and diffuse
erythema and inflammation of the mucosa, sometimes
associated with Staphylococcus aureus infection (Fig.
76-4B).11 A reliable finding is a dusky-red firm area of
the perivermilion skin that has a slight pitted, orange
peel appearance.
Pyostomatitis vegetans (oral analog of pyoderma
gangrenosum) associated with inflammatory bowel
disease presents as snail-track ulcers of the oral
mucosa.12 Dental enamel defects (enamel hypoplasia)
are associated with celiac disease in children.13
::
Management and Prognosis.
ORAL ULCERATIVE LESIONS ASSOCIATED

WITH GASTROINTESTINAL DISEASE
Clinical Findings. The most common bowel dis-
12
Chapter 76
because the oral cavity is subject daily to mechanical

trauma (such as mastication) (eTable 76-1.2 in online
edition). However, traumatic ulcers are not the same
as RAU, although patients with RAU readily develop
ulcers at sites of trauma. A history of trauma and the
nonepisodic nature of the condition help to differentiate between traumatic ulcers and those of RAU.
Chemotherapy-associated ulcers are not generally considered aphthous ulcers but rather chemotherapy- and
neutropenia-associated (similar to cyclic neutropenia);
they also tend to occur on the nonkeratinized mucosa.
Herpetic ulcers in healthy patients occur intraorally on
the keratinized mucosa of the gingival margin and the
palate. However, in immunocompromised patients,
they may resemble RAU, especially RAU major in
patients with HIV disease. Culture and biopsy (Box
76-1) are indicated in such patients. Lesions of chronic
recurrent oral erythema multiforme must also be
considered in the differential diagnosis. Oral manifestations of Crohn disease and other gastrointestinal
conditions are discussed below.
The biopsy is nonspecific and shows only a fibrin membrane with acute and chronic inflammation and granulation tissue, but may exclude an infectious etiology.
paste to one that does not contain sodium lauryl sulfate. In most cases, the work-up is negative.
The treatment for minor RAU is topical steroids
(Table 76-1) or intralesional steroid injection if the ulcers
are large and persistent, especially those of aphthous
major or in patients with HIV disease. Topical agents
that may be useful include cyanoacrylate (Soothe-NSeal; Colgate Palmolive, NY) and anti-inflammatory
agents such as amlexanox 5% paste (Aphthasol, Uluru,
Texas), 2 mg amlexanox mucoadhesive disc (Oradisc,
Uluru, Texas), or tetracycline oral rinse. Lesions may
also be cauterized with 28%50% sulfuric acid and
sulfonated phenolics (Debacterol, Epien Medical Inc.)
or with silver nitrate (shaving sticks). Topical anesthetics in paste form are available over-the-counter, in
particular benzocaine of varying strengths. Systemic
therapy with prednisone for a few weeks and maintenance with pentoxifylline may reduce the number,
duration and size of ulcers, and reduce the number of
episodes. In appropriate patients, thalidomide therapy
is extremely effective, although patients often develop
irreversible neuropathy with long-term use. Other
agents that are variably efficacious include colchicine
and azathioprine.

Studies. Oral ulcers ultimately associated with
inflammatory bowel disease may predate gastrointestinal lesions by years in up to 60% of patients,10 so that
absence of gastrointestinal symptoms does not exclude
this etiology. Elevated tissue transglutaminase and the
presence of endomysial antibodies support the diagnosis of celiac disease.
A biopsy of oral lesions of Crohn disease shows
granulomatous inflammation or while pyostomatitis
vegetans shows acantholysis.
831
12
Section 12
Figure 76-4 A. Aphtheiform ulcer in Crohn disease. B. Mucosal erythema in Crohn disease.
::
In the absence
of gastrointestinal findings, treatment is with topical
steroid therapy and in severe cases, prednisone for
rapid control of lesions with maintenance on topical
steroids or other anti-inflammatory agents similar to
the protocol for management of idiopathic aphthous
ulcers.14 If gastrointestinal disease is active, this should
be brought under control first and oral ulcers may then
resolve.
Oral manifestations generally wax and wane with
the severity of systemic disease.
CHEMOTHERAPY-ASSOCIATED
ULCERATIVE MUCOSITIS. Damage from chemotherapy
agents is mediated via production of cytokines, cytokine modulators, and stress responders, leading to
apoptosis of dividing epithelial cells.15 Ulcers are
potential portals for bacteremia and septicemia, particularly because patients are also often neutropenic. Depending on the regimen, 25%30% of patients
develop this complication. Agents often associated
with such lesions include cytarabine and cisplatin,
especially when combined with radiation.
Clinical Findings.
These ulcers are generally

located on the nonkeratinized sites and in particular
the buccal mucosa and ventral tongue. They begin
within 35 days of the start of chemotherapy and generally resolve when absolute neutrophil counts recover,
usually a course of 710 days. Lesions are extremely
painful and may measure several centimeters in size.16

Studies. Recrudescent herpes simplex virus (HSV)
832
infection is common in immunocompromised patients

such as patients with cancer and, unlike in healthy
hosts, often occurs on nonkeratinized sites. Hence,
patients who undergo hematopoietic stem cell transplantation, if seropositive for HSV antibodies, are prophylactically placed on antiviral agents during their
hospital course. However, a positive culture may represent shedding of HSV in the oral fluids and saliva
rather than true recrudescence within the ulcers.
Deep fungal infections and cytomegalovirus infection may all present with large ulcers on the mucosa,
but these generally do not heal with recovery of neutrophil counts.
Radiation to the head and neck leads to severe erythema, inflammation, and ulceration (radiation mucositis).17,18
In patients who have received allogenic hematopoietic transplants, persistence of oral ulcers after
engraftment may herald the development of acute
graft-versus-host disease. In such situations, involvement of the keratinized tissues of the tongue dorsum
and hard palate is not uncommon.
Management and Prognosis. Ulcers are selflimiting and therapy is directed toward pain control
and prevention of septicemia from bacterial ingress
into the oral wounds.19 Patients are often treated with
granulocyte-colony-stimulating factor to reduce the
period of neutropenia and this has reduced the frequency of such ulcers.
Topical analgesia such as viscous lidocaine and systemic analgesia (especially narcotics) is the mainstay
of pain control. Although chlorhexidine is often used
for decontamination, its high alcohol content makes
patient compliance poor. Other oral decontamination
rinses contain nystatin and antibiotics.
DEEP FUNGAL INFECTIONS. Zygomycosis is a
broad term used to describe fungal infections caused
by organisms in the phylum Zygomycota. These
include infections caused by organisms in the family
Mucorales with organisms in the genera Mucor and
Rhizopus. These are unusual infections, seen usually
in patients who have diabetes mellitus (usually ketoacidotic) or are immunocompromised, and are often
life threatening. Organisms are inhaled and spread
into the adjacent sinuses, eroding through the bone,
sometimes presenting on the palate as a necrotic ulcer,
a condition also referred to as rhinocerebral zygomycosis.29 Aspergillus infections are seen in neutropenic
patients, especially those with leukemia and tend to
present as necrotic soft tissue and bony lesions of the
gingiva, while histoplasmosis, coccidioidomycosis,
blastomycosis, and paracoccidioidomycosis are seen
in areas where such infections are endemic such as in
South America and in patients with HIV/AIDS.3033
Clinical Findings. Unlike candidiasis, deep fungal
infections usually present as necrotic ulcers because
they are angioinvasive organisms that cause vascular
12
TABLE 76-2
Herpes Virus and Oral Lesions
HHV2 (herpes simplex-2)
May present with oral ulcers similar to HSV-1; young adults
HHV3 (varicella zoster)
Primary infection may or may not have oral ulcers; recrudescent with unilateral ulcers along
distribution of VII or VIII; adults and immunocompromised patients
HHV4 (EpsteinBarr)
Oral ulcers in infectious mononucleosis in young adults; nasopharyngeal carcinoma in older adults,
hairy leukoplakia in patients with HIV/AIDS
HHV5 (cytomegalovirus)
Oral ulcers; may be seen associated with HSV ulcers; usually in immunocompromised patients
HHV6
Unlikely to have oral manifestations
HHV7
Unlikely to have oral manifestations
HHV8
Kaposi sarcoma; usually seen in patients with HIV/AIDS
HHV 9 (simian)
Unlikely to be seen in humans

Studies. Deep fungal infections involving the palate
or maxilla are an important differential diagnosis for

the clinical entity midline destructive disease. Other
conditions that fall into this category include NKT-cell
lymphoma, other infections such as tertiary syphilis,
granulomatosis with polyangiitis (Wegener disease),
cocaine use, and epithelial malignancy of surface or
salivary gland origin.34 A biopsy readily distinguishes
among these entities.
Because these are deep infections, a swab culture
may not capture any organisms. A biopsy shows the
presence of hyphae. It is useful to submit part of the
harvested tissue in saline for speciation in a microbiology laboratory.
A biopsy shows necrosis and inflammation. The
morphology of hyphae seen on special stains, together
with culture results, confirms the diagnosis.
Treatment is
with systemic antifungal agents such as liposomal
amphotericin and triazole antifungal agents such as
fluconazole, itraconazole, and posaconazole, often
with surgical debridement.35 Mortality is often high
in poorly controlled infection. Reducing environmental exposures is a particularly important prophylactic
measure for immunocompromised patients.
WHITE LESIONS
It is important to distinguish truly white lesions
from ulcerated or necrotic lesions that usually have a
creamy-yellow color.
Many well-recognized oral lesions are white, ranging from developmental lesions such as white sponge
nevus, to infections such as candidiasis, to immunemediated disorders such as lichen planus (LP) and to
frictional keratoses such as morsicatio mucosae oris
(Table 76-3). Such lesions, with specific clinical and
histologic findings, are not properly termed leukoplakia.
True leukoplakias tend to be well demarcated at
least around part of the lesion, are frequently dysplastic at first biopsy, and carry a significant potential for
developing into SCC over time. White sponge nevus
and reactive white lesions are discussed online.
WHITE SPONGE NEVUS. White sponge nevus is

an extremely rare condition, inherited in an autosomal
dominant fashion. It affects the oral and genital mucosa,
usually in a symmetric and often multifocal pattern,
due to mutation in keratin K4 or K13 that results in
keratin instability and abnormal keratin aggregation.53
Spontaneous mutations have been reported.
thrombosis and ischemia. The most common location

for rhinocerebral zygomycosis is the palate, although
fungal infections in immunocompromised patients
may occur at any site in the mouth.
::
(a) Primary gingivostomatitis, usually in first to third decades of life

(b) Herpes labialis and recrudescent herpetic ulcers on the attached mucosa in healthy patients; in
adults
(c) Ulcers on any oral mucosal site in immunocompromised patients
Chapter 76
HHV1 (herpes simplex-1)
Clinical Findings. Patients develop poorly demar-
cated, diffuse, painless white plaques on the oral

mucosa, usually the buccal mucosa and tongue, usually within the first two decades of life.21,54

Studies. Other conditions that may appear similar
clinically include hereditary benign intraepithelial dyskeratosis, another rare mucosal disorder that occurs in
a racial isolate in South Carolina,5557 and pachyonychia
congenita.5860 Oral lesions of dyskeratosis congenita
are true leukoplakias occurring in approximately 65%
of patients and are usually dysplastic.61,62
Biopsy or exfoliative cytology is always indicated
and shows perinuclear eosinophilic condensations
(representing abnormal keratin aggregation) and distinguishes it from other mucosal disorders discussed
below.
Management and Prognosis. There is no treat-
ment for white sponge nevus, although some have
833
12
TABLE 76-3
Oral White Lesions

Developmental (Often Part of a Genodermatosis)
White sponge nevus
Hereditary benign intraepithelial dyskeratosis
Pachyonychia congenita
Section 12
::
Reactive
Frictional keratoses
Morsicatio mucosae oris
Benign alveolar ridge keratosis
Other nonspecific
Chemical injury
Leukoedema
Contact desquamation
Smokeless tobacco keratosis
Submucous fibrosis (scarring and fibrosis, not keratotic)*
Retention of secretions and debris
Hairy tongue
Retention on other surfaces
Unknown
Uremic stomatitis
Infectious
Candidiasis
Hairy leukoplakia
Immune-mediated
Lichen planus
Chronic graft-versus-host disease
Lupus erythematosus
Psoriasis
Migratory glossitis/stomatitis
Neoplastic
Leukoplakia
Verrucous leukoplakia
Proliferative leukoplakia
Verrucous carcinoma
reported resolution with antibiotics, in particular

tetracycline.63 It is postulated that tetracycline affects
the keratinization process and inhibits epithelial proliferation.
REACTIVE WHITE LESIONS. These very common conditions are caused by very mild topical injury
caused by smoking or other mild contact injury such as
strong toothpastes and alcoholic mouth rinses. The following white lesions are in ascending order of severity
of injury beginning with changes caused by intracellular edema and swelling to those resulting in keratoses.
Leukoedema. Many dentists classify leukoedema
as a developmental malformation but it is likely a
reactive lesion. It occurs in 20%70% with habits such
as using tobacco, coca, or marijuana to >90% of darkskinned individuals mainly because the whiteness
of the lesion shows up more clearly on pigmented
mucosa.54,64
834
Clinical Findings. Lesions are usually bilateral on the

buccal mucosa or ventral tongue and consist of painless, fine grayish white, opalescent reticulations. They
are not well demarcated, but diffuse. Stretching the

mucosa completely eliminates these fine lines since
this is not a keratotic lesion, but rather caused by intracellular edema of damaged superficial keratinocytes.21
Differential Diagnosis and Laboratory Findings.
Reticular LP may look similar but they are more
densely white and do not disappear on stretching the
mucosa.
A biopsy shows typical findings of keratinocyte
edema or hydropic degeneration.
Management and Prognosis. No treatment is necessary since these lesions are benign although advice on
smoking cessation may be warranted.
Contact Desquamation. This is a common oral

condition, where the injury to the tissue is slightly more
severe than in leukoedema causing actual degeneration and detachment of the superficial keratinocytes.
The offending agents are mouthwashes and toothpastes that are caustic [in particular Listerine (Pfizer
Pharmaceutical, NY) mouthwash that contains 27%
alcohol as well as eucalyptol and menthol].
Clinical Findings. This is generally a condition of
adults. Patients will often report that their mouth is
peeling. Lesions present as painless sloughs of desquamated tissue that lie in thin ribbons on the mucosa
and can be removed without pain or discomfort to
the patient, with normal-appearing, pink underlying
tissue.65 Since the keratinized tissues are somewhat
protected from the adverse effects of such topical
agents, it is generally the nonkeratinized tissues that
are involved. A helpful sign is a background of leukoedema with faint reticulations.
Differential Diagnosis and Laboratory Studies. While
some bullosing disorders may form such sloughs,
those lesions are almost always painful or sensitive,
and may bleed. Lack of symptoms is key to the diagnosis of this condition coupled with the typical history.
A biopsy shows desquamating strips of surface keratinocytes.
Management and Prognosis. Patients should discontinue the use of the offending dentrifrice, or change to
a less caustic agent.
Morsicatio Mucosae Oris (Pathominia

Mucosae Oris, Chronic Bite Injury). This
is a yet more intense local factitial injury to the oral

mucosa, caused by a chewing habit, leading to reactive
keratosis and benign epithelial hyperplasia. It occurs
in 3% of the population.66 Any other factitial injury
either from an unusual habit, or the rough edge of an
appliance may lead to a similar lesion.
Clinical Findings. MMO appears as white papules

and plaques on either side of the linea alba on the buccal mucosa, lower labial mucosa, or the lateral tongue,
usually caused by raking of the teeth over the mucosa67
Patients may or may not be aware of this habit (especially if this is a nighttime habit). Lesions have a
shaggy, rough surface, are poorly demarcated, and
A biopsy shows typical features of lichen simplex

chronicus. BARK is closely related to MMO (described
above), another frictional keratosis. It is possible that
BARK being located on the keratinized mucosa that is
closer in histology to the skin, takes on the more typical histologic characteristics of lichen simplex chronicus (LSC).
12
Management and Prognosis. No treatment is necessary once the histopathologic diagnosis has been established. If a denture is the source of frictional irritation,
this should be adjusted accordingly.
Management and Prognosis. No further management is necessary. These lesions are benign and have
no malignant potential. The use of night guards or
appliances to break the habit has not been shown to
be helpful.
Benign Alveolar Ridge Keratosis (BARK,

Oral Lichen Simplex Chronicus). BARK is
a very common condition that was recently defined

histologically. It occurs primarily on the keratinized
mucosa of the gingiva and hard palate as a reaction
to frictional trauma. It is the oral equivalent of lichen
simplex chronicus.
Clinical Findings. BARK presents as poorly demarcated, painless white papules and plaques, often with
a rough surface, usually less than 1 cm in greatest
dimension (eFig. 76-5.4 in online edition). The most
common location is the retromolar pad (at the site of
previously extracted wisdom teeth) and other areas
where teeth have been extracted.68,69 It is not necessary
for the opposing teeth to contact the mucosa, since
crushing of food against the alveolar ridge that had
been previously protected by a tooth is sufficient.
Differential Diagnosis and Laboratory Studies. Leukoplakia, especially verrucous leukoplakia is a very
important differential diagnosis and a biopsy should
always be performed if the lesion shows signs of sharp
demarcation or is extensive. More worrisome, verrucous leukoplakia, a dysplastic lesion, also has a rough
surface and is usually greater than 1 cm.

Studies. Leukoplakia and candidiasis of the palate
may both mimic nicotine stomatitis.

A biopsy shows hyperkeratosis with benign epithelial changes and importantly, inflammation of excretory salivary ducts that exhibit squamous metaplasia.
This diagnosis is difficult if the ducts are not included
in the biopsy specimen.
Differential Diagnosis and Laboratory Studies. Candidiasis, some lesions of LP, hairy leukoplakia, and
some leukoplakias and erythroleukoplakias may look
similar but a biopsy will provide a definitive diagnosis. Such factitial injury may be superimposed upon an
underlying condition such as dysplasia or LP, making
the diagnosis even more challenging.
A biopsy shows varying degrees of parakeratosis with
impetiginization and benign epithelial hyperplasia.
Clinical Findings. The palate of adult patients is

the site most often affected. It is diffusely white
with red, punctuate areas representing the openings
of salivary ducts. It is usually not a painful lesion
although severe cases may be sensitive to hot and
spicy foods, and lesions are usually symmetric and
diffuse.21,54
::
occasionally may show evidence of erythema and/or

ulceration where the chewing has been more intense
(eFig. 76-5.3A and 76-5.3B in online edition).
Chapter 76
Figure 76-5 Primary herpes simplex virus (HSV) gingivostomatitis with involvement of gingiva and left upper
labial mucosa.
Nicotinic Stomatitis. Nicotinic stomatitis is not

caused by nicotine as its name suggests but rather by
heat, usually from pipe smoking. A similar condition
may be seen in patients who reverse smoke, that is,
hold the lighted end of the cigarette in the mouth, as
is the habit in some South Indian and Southeast Asian
populations. It has also been noted in patients who
habitually drink very hot beverages.
Management and Prognosis. Lesions may resolve if

the habit is discontinued. The risk for malignant transformation has not been well documented. However,
the development of raised, indurated areas should
raise suspicion for malignant transformation.
Smokeless Tobacco Keratosis. This is a lesion
that results from a combination of direct contact toxicity of the smokeless tobacco on the mucosa (early
lesions), and from effects of carcinogens within the
snuff, namely tobacco-associated nitrosamines (late
lesions that represent true leukoplakias). Not all
smokeless tobaccos are alike. Snuff may be moist or
dry and in general moist Swedish snuff (snus) is
lower in nitrosamines than moist and dry snuff from
the United States.70 Toombak, snuff from Ethiopia,
has the highest levels of nitrosamines of all.71 In many
Asian countries, snuff and smokeless tobacco is mixed
with other substances such as spices and importantly
areca nut, which contains another potent carcinogen,
the alkaloid arecoline.72
Over the last 1015 years, there has been increased
interest in using smokeless tobacco as a risk reduction
measure in subjects who have difficulty discontinuing
cigarette smoking because the risk of developing cancer (oral and other cancers) is reduced.73,74
835
12
Section 12
::
836
Clinical Findings. The lesions are located where the

snuff is placed, usually the mandibular sulcus/vestibule, between the teeth and the buccal mucosa. The
area looks grayish white, opalescent, and wrinkled,
often with fissures.21,54
Lesions are generally painless and poorly demarcated (eFig. 76-5.5 in online edition).
Differential Diagnosis and Laboratory Studies.
The diagnosis includes leukoplakia, candidiasis, and
BARK. Aspirin is much more caustic and causes necrosis and ulceration, rather than this delicate white lesion.
Biopsy reveals thin parakeratosis, intracellular
edema, and devitalization of superficial keratinocytes.
Any other agent that is locally irritating and slightly
caustic may cause this clinical appearance.
Management and Prognosis. Most early lesions are
primarily caused by contact injury and are reversible if
the habit is discontinued. However, the development
of a dense white plaque or erythema may signal transformation to malignancy and these areas should be
biopsied. The rate of malignant transformation is only
1%2% compared with cigarette smoking.
INFECTIOUS LESIONS
Candidiasis. Fungal infections are extremely com-
mon in the oral cavity and the most common causative

agent is Candida albicans. Approximately 20%30% of
the population are carriers. In immumnocompromised
hosts, other species such as C. tropicalis, C. dubliniensis,

C. glabrata, and C. kruseii should also be considered, as
some of these may be resistant to conventional therapy. Predisposing factors include hyposalivation (see
Section Xerostomia and Hyposalivation in online
edition), immunocompromise, topical steroid therapy
(for treatment of oral lesions or as inhalers), and antibiotic therapy.
Clinical Findings. Oral candidiasis may present in
various forms (Table 76-4) (Figs. 76-6A76-6E).1,21
Lesions are almost always painful and dentures act
as fomites.75 Although C. albicans is the most common
pathogen in denture-associated candidiasis, C. glabrata
is found in 30% of cases.76
Differential Diagnosis and Laboratory Studies. An
important differential diagnosis is hairy or coated
tongue. This is not a candidal infection, although cultures may grow Candida in carriers. These lesions are
almost always painless and do not involve mucosa
other than tongue dorsum, unusual for candidiasis. It
is caused by hyperplasia and hypertrophy of the filiform papillae of the tongue, with retention of keratinaceous debris as a result of hyposalivation and poor
oral intake. Patients therefore are often ill, dehydrated,
and on antibiotic therapy, further adding to the suspicion that the lesions represent candidiasis.
Culture is not particularly useful for diagnostic purposes since many individuals are carriers. However, culture is important if speciation or sensitivity is required,
TABLE 76-4
Presentation and Management of Oral Candidiasis
Type
Clinical
Treatment
Thrush/Pseudomembranous candidiasis
Curdy yellowish-white papules or plaques;

may or may not scrape off
Often synchronously on dorsum or
tongue and palate so-called kissing
lesions
Nystatin 1:100,000 iu/mL; swish and spit

out 5 mL tid or qid
Clortrimazole trochea 10 mg; suck on 1
troche tid or qid
Ketoconazole 200 mg qd 7-14 days
Fluconazole 100 mg; take one tablet once
a day 310 days
Erythematous/Atrophic candidiasis
1. Erythematous areas under a denture

2. Linear gingival erythema in HIV/AIDS
1. Mycostatin and triamcinolone cream

on worn denture (under occlusion);
treat denture with dilute bleach
(1:10), sodium benzoate or other
antimicrobial soaks
2. See Thrush above
Hyperplastic candidiasis
Primarily white papules and plaques

with minimal erythema; associated
with mucocutaneous disease or hairy
leukoplakia
See Thrush above
Angular cheilitis
Fissured, weepy lesions at the corners

of the mouth; often associated with
Staphylococcus aureus
Mycostatin and triamcinolone cream; may

need topical erythromycin
Median rhomboid glossitis
Rhomboidal area in posterior midline

of tongue, anterior to circumvallate
papillae; maybe slightly depressed and
erythematous, or raised
See Thrush above
Troches do not dissolve well in patients with hyposalivation.
12
Figure 76-6 A. Erythematous candidiasis. B. Angular cheilitis.
Hairy Leukoplakia. EpsteinBarr virus (EBV)

infections in the oral cavity may present as a primary
infection (infectious mononucleosis). Hairy leukoplakia is an unusual presentation of recrudescent EBV
in the oral cavity, where this normally lymphotropic
virus is present within the epithelium.
Clinical Findings. This manifests as a painless, white
plaque usually located on the lateral border of the tongue
in immunocompromised patients, and in particular, those
with HIV/AIDS and after organ transplantation.77,78
Typically, these present as white linear lesions running perpendicular to the long axis of the tongue but
when more advanced, may extend onto the dorsum
and present as a plaque (Fig. 76-7). Lesions are usually
asymptomatic and usually superinfected with Candida.
Infrequently, hairy leukoplakia has been reported in
healthy individuals.79
ORAL LICHEN PLANUS

Oral LP is an immune-mediated disorder and an interface stomatitis characterized by T-cell destruction of
the basal cells of the epithelium, possibly as a result of
altered antigen presentation on these cells, mediated
by TH1 cytokines. Interferon- production is thought
to mediate lesions involving the oral cavity only while
TNF- may mediate systemic disease.80 Whether this is
a disease in and of itself or whether it represents a final
common pathway of mucosal reaction is unclear at
this time. Many local and systemic conditions predispose to the development of such lichenoid lesions
in the oral cavity. The term lichenoid used here to
describe reticulated, often erythematous and/or ulcerated lesions, usually bilateral and symmetric. Unfortunately, many erythroleukoplakias that are by definition
red and white lesions but usually without significant
reticulation are also clinically described as lichenoid
Management and Prognosis. Patients who have dry

mouths from polypharmacy or substantial damage
to salivary glands (such as from radiation) are prone
to develop recurrent candidiasis and are particularly
difficult to manage. Nystatin rinses and clotrimazole
troches contain caries-inducing sugars and should be
used long-term only with careful monitoring by the
dentist. The use of cholinergic agents such as pilocarpine or cevimeline helps to restore some secretory
function of salivary glands and may reduce the frequency of candidiasis.
AIDS, hairy leukoplakia is usually associated with a

low CD4 count and high viral load.77 Treatment with
an antifungal medication (see Section Candidiasis)
will resolve the associated candidiasis and treatment
with antiretroviral therapy results in resolution.
::
or to identify carriers prior to the start of long-term steroid therapy. A potassium hydroxide preparation using
scrapings from oral lesions is a good way to identify
infection. Biopsies show typical candidal organisms.
Chapter 76
Differential Diagnosis and Laboratory Studies.

Lesions of MMO and candidiasis often occur on the
lateral tongue and may appear similar.
Both cytologic smears and biopsies show characteristic findings and the presence of EBV can be confirmed by in situ hybridization.
Management and Prognosis. The presence of hairy
leukoplakia may be the first indication that a patient
is infected with HIV. In patients with established HIV/
Figure 76-7 Early hairy leukoplakia (Used with permission

from Dr. Mark Lerman, Harvard School of Dental Medicine).
837
12
Section 12
::
838
by some investigators, causing confusion and leading

to the concept of LP as a premalignant lesion.
Local lichenoid reactions may develop as a result
of contact injury to amalgam restorations or cinnamic
aldehyde from chewing gum. Medications implicated
in the development of oral LP include antihypertensive agents (especially hydrochlorthiazide), some
hypoglycemic agents, allopurinol, sulfasalazine, carbamazepine, and the new biological agents.8082 It is
often impossible to differentiate either clinically or
histologically, between lesions of idiopathic LP and
lichenoid hypersensitivity reactions.83
Other conditions associated with oral lichenoid
lesions include hepatitis C in Mediterranean races and
this is associated with HLA-DR684,85; chronic graftversus-host disease, and lupus erythematosus.86,87
CLINICAL FINDINGS. Oral LP occurs in 1%2% of

the population in the United States and affects females
more than males, usually those in the fifth decade
of life and older. Three clinical forms are noted(1)
keratotic/reticular, (2) erythematous/erosive, and (3)
ulcerativeand these often occur in combination.21,54
The most recognizable is the keratotic/reticular form
(Wickham striae) that is usually not painful. This is
symmetric in distribution and reticulations almost
always occur on the buccal mucosa and tongue
although any oral mucosal site may be affected (Figs.
76-8A and 76-8B). Lesions on the dorsum of tongue
tend to be subtle and more papular with atrophy of

filiform papillae giving the tongue a white cast and
smooth appearance (Fig. 76-8C). The erythematous or
erosive form is usually painful and this is particularly
common as a primary presentation on the gingiva (clinically desquamative gingivitis).88 LP on the gingiva is
also noted in the gingivalgenital syndrome.89 Ulcerative LP usually occurs in association with the other
two forms. The finding of intact blisters (bullous LP)
is rare in the oral cavity because it is a trauma-intense
environment. Concomitant skin involvement is noted
only in 10%15% of patients.
A controversial entity is the so-called plaque-type
LP. If this lesion occurs as a unilateral plaque without
reticulations, it should be considered a leukoplakia.
If it occurs within an established, typical symmetric
oral LP, it should be considered leukoplakia developing within LP. In either case, biopsy is indicated to
exclude dysplasia or malignancy.
Several scoring systems have been developed for
evaluating the severity of disease but none are universally accepted.9092
DIFFERENTIAL DIAGNOSIS AND LABORATORY STUDIES. Many conditions may result in the
development of LP and lichenoid reactions. However,

the most important is erythroleukoplakia. It can be differentiated from oral LP in that it is not usually definitively
reticulated (although it may have subtle linear areas), is
Figure 76-8 A. Reticular lichen planus (LP) of right buccal mucosa. B. Reticular, erythematous and ulcerative LP of left
buccal mucosa in same patient as 76-8A. C. LP of dorsum of tongue; D. LP of gingiva.
CLINICAL FINDINGS. Leukoplakia is more common in adult males. It presents as a painless, white
plaque that may be homogenous or nonhomogenous.97
It may occur anywhere in the oral cavity and generally shows areas that are sharply demarcated from the
surrounding mucosa (Fig. 76-9). Homogenous leukoplakia may show areas of fissuring. Nonhomogenous
leukoplakia have areas of erythema (erythroleukoplakia), rough, warty areas (verrucous leukoplakia),
or nodular areas; they have a higher association with
dysplasia and carcinoma, as do lesions on the floor of
mouth, ventral tongue, and soft palate.101,102
Proliferative verrucous leukoplakia (PVL)103,104 tends to
occur in middle-aged females and, as its name suggests,
tends to spread or proliferate over the mucosa over
time, and is usually multifocal (eFigs. 76-9.1A76-9.1C
in online edition). It is associated with smoking in less
than 30% of cases. Patients are usually diagnosed with
this condition one to two decades after the first appearance of the white lesion. Areas of it may become verrucous, although not invariably, and other areas may
appear red, in which case the term proliferative erythroleukoplakia may be appropriate. Approximately
70%100% of cases develop SCC over time.103,105 These
lesions are particularly difficult to diagnose because
patients often have had multiple biopsies over many
years, and each time, the diagnosis is one of hyperkeratosis only without evidence of dysplasia.
Oral erythroplakia, although a red lesion, will be
discussed here because of its high associated dysplasia. It is an uncommon lesion and in its pure form
12
::
MANAGEMENT AND PROGNOSIS. Management of oral LP and lichenoid lesions involves pain
control and treatment with topical steroids and other
anti-inflammatory agents (Table 76-1).95 Gingival
lesions are effectively treated with topical steroids held
in a stent. Systemic therapy with prednisone (at 1 mg/
kg for 1 week with a fairly rapid taper) or hydroxychloroquine should be instituted in severe cases and
topical therapy started concomitantly.
Localized, unliateral lesions may respond to removal
of dental restorations and a short course of topical steroids. Disease remission occurs in <10% of cases.
The rate of malignant transformation (often given
as 1% every 5 years) is controversial because some
studies do not correct for confounding factors such as
smoking, while other included erythroleukoplakias,
leukoplakias (diagnosed as plaque-type LP), and
proliferative leukoplakia in the group of lichenoid
lesions. Classic, bilaterally symmetric, reticulated LP
has a very low malignant potential.96
BARK. Because frictional injury is very common in the

oral cavity and usually presents as a hyperkeratosis,
it is likely that many so-called leukoplakias actually
represent nonspecific frictional keratoses that are not
MMO or BARK.
Leukoplakias occur in 2%4% of the population.98
Any lesion that carries a provisional diagnosis of leukoplakia must be biopsied because approximately
20%50% of these lesions are dysplastic or cancerous at
the time of biopsy.99,100
Leukoplakia is strongly associated with smoking
and/or alcohol ingestion. Other predisposing factors
are similar to those for oral cancer and will be discussed below.
Chapter 76
usually asymmetrically distributed, and often presents

at a high-risk site for cancer such as the ventral tongue
unilaterally. It is strongly associated with dysplasia and
carcinoma (see below). Other lesions include candidiasis
and contact stomatitis such as to chewing gum.
Chronic ulcerative stomatitis is an entity that
resembles erythematous/erosive LP but is associated
with antibodies directed against Np63.93 Direct
immunofluorescence studies reveal nuclear binding
of keratinocytes in the basal and lower one-third of
the epithelium. Serum immunoglobulin (Ig) G can be
detected using guinea pig esophagus as substrate and
an ELISA is now available.94
The reticulated white areas on the buccal mucosa
may sometimes resemble MMO. Erythematous LP
lesions on the gingiva are often indistinguishable from
other diseases presenting as desquamative gingivitis
such as mucous membrane pemphigoid, hypersensitivity reaction, or plasma cell gingivitis. Pure ulcerative lesions without reticulations are more likely to be
aphthous ulcers.
Diagnostic histopathologic findings for oral LP, are
squamatization of basal cells and a lymphocytic band
at the interface. Direct immunofluorescence studies
show shaggy fibrinogen and often IgM at the interface
and IgM staining of colloid bodies.
LEUKOPLAKIA AND ERYTHROPLAKIA

This is one of the more challenging diagnostic entities
of oral mucosal disease. Leukoplakia is defined as a
white plaque of questionable risk having excluded
other (known) diseases or disorders that carry no
increased risk for cancer.97 It is a clinical diagnosis
only and modified once the histopathologic diagnosis is known. For example, what may appear to be a
provisional diagnosis of leukoplakia on the buccal
mucosa may histopathologically prove to be MMO
as a final definitive diagnosis. Frictional keratosis is
NOT a leukoplakia and the only two histologically
well-defined frictional keratoses are (1) MMO and (2)
Figure 76-9 Leukoplakia of tongue (dysplasia).
839
12
presents as a painless, red, sometimes velvety plaque

of the oral mucosa (eFig. 76-9.2 in online edition). More
than 90% of cases are associated with dysplasia or carcinoma at the time of diagnosis.106,107 It is much more
common to see it in combination with leukoplakia
(erythroleukoplakia).
DIFFERENTIAL DIAGNOSIS AND LABORATORY STUDIES. The clinical differential diagnosis
Section 12
::
list for leukoplakia is long (Table 76-3). However, sharp

demarcation at least one border is a helpful finding
and usually excludes an inflammatory/reactive lesion.
A biopsy should be performed for any white lesion if
the etiology cannot be established with confidence on
clinical grounds.
Approximately 20%50% of leukoplakias are dysplasias or carcinoma at the time of biopsy.100,101,106,108
However, 5%18% of lesions diagnosed as benign
hyperkeratosis, when followed over time, transform
to carcinoma.99,102,108 This is particularly true of lesions
of proliferative leukoplakia where multiple biopsies
show benign hyperkeratosis until many years later
when overt dysplasia or carcinoma develops.
Research using microarrays and other techniques to
better characterize the genome of these lesions will shed
light on this in coming years. The concept of oral or
squamous intraepithelial neoplasia similar to cervical intraepithelial neoplasia has not received acceptance although it is likely a useful concept to adopt.
Management, prognosis, and risk of progression to
oral SCC are discussed online.
There is controversy as to whether leukoplakias
should be excised.109 Some suggest that small leukoplakias should be excised, while extensive lesions could
be managed with multistage stripping.110 While some
clinicians and pathologists believe that mild dysplasias
may just be observed since some of these regress, it is
likely that some of these regressing mild dysplasias
represent only keratotic lesions with reactive atypia.
True dysplasias are intraepithelial neoplasias that have
not yet become invasive. If such lesions can be removed
without excessive morbidity, this seems prudent.
Options for the 50%80% of cases diagnosed as
benign hyperkeratosis, include periodic rebiopsy or
excision. It is suggested that benign hyperkeratoses
that are not clearly frictional or reactive in nature and
are in high-risk sites be narrowly excised and followed
and that recurrent lesions be excised with a margin
of several mm. Because leukoplakia is a clinicopathologic entity, it is important that the clinician work with
a pathologist who is experienced in the diagnosis of
reactive and nonreactive oral keratotic lesions.
Smoking cessation counseling should always be part of
the overall management strategy for patients who smoke.
ORAL SQUAMOUS CELL CARCINOMA
840
Head and neck cancer is the 11th most commonly occurring cancer in the United States, and there are approximately 35,000 cases per year, with one-third of these
occurring in the oropharynx.111 Risk factors include
smoking cigarettes, excessive use of alcohol, chewing
areca nut, a past history of cancer and/or immunosuppression, family history of cancer, exposure to high-risk
forms of human papilloma virus (HPV) (especially for
carcinomas of the posterior oral cavity and oropharynx), age, and for lip cancer, sunlight.112,113
CLINICAL FINDINGS. Oral SCC affects males more

often than females in a 2:1 ratio and usually affects
older adults. Excluding the lip, the most common sites
are the ventral tongue, gingiva, and floor of mouth. It
may present as a leukoplakia, erythroplakia, proliferative leukoplakia, a nonhealing ulcer or ulcerated nodule, or a mass.112 The tumor may have a verrucous or
papillary surface (eFig. 76-9.3 in online edition). Pain
may or may not be present and there may be paresthesia. Advanced lesions infiltrate the underlying bone
or muscle and may lead to difficulty with movement
of the tongue, adversely affecting speech and eating.
Metastases to the submandibular and upper cervical
lymph nodes are common, and nodes should be palpated in patients with suspicious lesions.
DIFFERENTIAL DIAGNOSIS AND LABORATORY STUDIES. The differential diagnose for
leukoplakia are presented in Table 76-3. Traumatic

ulcerative granuloma (see above) may be mistaken
for oral carcinoma because it is often on the lateral/
ventral tongue, may not be particularly painful and is
often present for weeks. Benign neoplasms of soft tissue or salivary gland origin may be traumatized and
present as an ulcerated nodule, raising the suspicion
of oral carcinoma.
A biopsy shows a proliferation of malignant epithelial
cells infiltrating the stroma as single cells or in a bluntly
invasive fashion. The latter is a particular feature of verrucous carcinoma that tends not to metastasize.
MANAGEMENT AND PROGNOSIS. Management and prognosis is dependent on the stage. Most
Stage I and II lesions are treated with surgical excision
(usually en bloc resection) with an objective of obtaining clear margins.114 Some Stage II lesions are treated
with a supraomohyoid neck dissection. Studies on
sentinel node biopsy have shown metastatic lesions
in 20%30% of patients.115,116 Stage III and IV tumors
may be treated with surgery, radiation or chemoradiation (the chemotherapy being a radiation sensitizer)
for organ-sparing purposes.117 The use of cetuximab,
a monoclonal antibody against the epidermal growth
factor receptor, which is highly expressed in many oral
cancer, has resulted in improved disease control.
Five-year survival for patients with local disease
only, locoregional disease and distant metastases are
81%, 50%, and 14%, respectively.114
BULLOUS DISORDERS/RED
LESIONS
Many autoimmune bullous disorders present as erythematous and/or ulcerative lesions. It is rare for
intact bullae to be present in the oral cavity.
MUCOUS MEMBRANE PEMPHIGOID

Mucous membrane pemphigoid is a heterogeneous
group of disorders characterized by subepithelial blistering and antibodies, usually IgG or IgA, directed
against a variety of antigens such as BP230, BP-180,
laminin-332, laminin-331, Type XVII collagen, Type VII
collagen, or 1 integrin subunit,121 to name a few.
PEMPHIGUS
The oral cavity may be involved by pemphigus vulgaris and paraneoplastic pemphigus. There is a predilection for this condition among Ashkenazi Jews and
those living around the Mediterranean and South Asia
and a strong association with HLA-DR4, Drw14, and
DQB1*503.126 The antigen is desmoglein 3.
(70%75%) presenting as desquamative gingivitis,

with mucous membrane pemphigoid representing
9%14% of cases.122,123 Other conditions include hypersensitivity reactions such as plasma cell gingivitis and
less commonly other autoimmune bullous disorders
such as pemphigus vulgaris, linear IgA disease, and
epidermolysis bullosa acquisita. LP may or may not
show reticulations on the gingiva or elsewhere in the
oral cavity and pemphigus vulgaris almost always
involves mucosal sites other than the gingiva. Linear IgA disease and epidermolysis bullosa acquisita
always present with concomitant skin lesions. Granulomatosis with polyangiitis (Wegener disease) produces a granular, erythematous gingivitis.
All patients with a clinical diagnosis of desquamative gingivitis should have a biopsy both for routine
histology and for direct immunofluorescence studies.
The presence of linear IgG, IgA, and/or C3 at the basement membrane zone on direct immunofluorescence
testing is strongly suggestive of pemphigoid. The
diagnosis of linear IgA disease should not be made in
::
DIFFERENTIAL DIAGNOSIS AND LABORATORY FINDINGS. LP is the most common disease
MANAGEMENT AND PROGNOSIS. The most

effective way to treat mucous membrane pemphigoid
presenting as desquamative gingivitis is with a topical
steroid gel held in a soft stent (similar to a bleaching
or fluoride tray extended over the gingiva) for 30 minutes twice a day. Clobetasol may be used for the first
few months, switching to fluocinonide when disease is
better controlled. Application may also be reduced to
1015 minutes once a day for maintenance. Prednisone
and dapsone may be used if lesions are recalcitrant.124
Azathioprine and cyclophosphamide are also effective
in some cases.121 It is unclear whether patients with
IgA on direct immunofluorescence studies have more
recalcitrant disease. Some cases may respond to etanercept.125
This disease is chronic and the disease rarely remits
completely. Since ocular complications may be severe,
all patients with oral lesions are referred for baseline
ophthalmologic examination. Long-term topical steroid therapy may lead to hypertension, hyperlipidemia, and poor control of diabetes mellitus, so periodic
blood pressure measurements, ACTH and cortisol levels, and lipid and glucose levels are indicated.
12
Chapter 76
CLINICAL FINDINGS. This is a disease of middle

aged and older adults with a slight female predisposition. The most common presentation for mucous membrane pemphigoid is desquamative gingivitis. This
presents as a band of bright red, painful gingiva, often
denuded of epithelium, with areas that are ulcerated
or with necrotic epithelium lying on the surface (Fig.
76.10). Patients have difficult eating coarse, acidic, or
spicy foods and the gingiva bleed readily on brushing.
Oral mucosa lesions rarely cause scarring and most
patients who present with oral lesions initially do not
usually develop skin lesions. It is uncommon to see
lesions on sites other than the gingiva in the oral cavity.
patients with mucosal disease alone. Indirect immunofluorescence using salt-split skin may also be helpful.121
CLINICAL FINDINGS. Pemphigus vulgaris is

an uncommon condition, most often seen in adults.
Patients may present with lesions in the mouth before
developing skin lesions. Lesions may present as desquamative gingivitis, but almost invariably, other
mucosae are involved, in particular the hard and soft
palate. Oral lesions are denuded and erythematous,
painful, and slightly depressed. Remnants of the bullae or necrotic debris may overlie the erosion, or be
heaped up at the edges (eFig. 76-9.4 in online edition).
Some patients have lesions limited to the oral cavity
and never develop skin lesions.
In addition to the erosions and ulcers present intraorally, patients with paraneoplastic pemphigus (also
known as paraneoplastic autoimmune multiorgan
syndrome) present with hemorrhagic crusting of the
lips. It is usually associated with a lymphoid malignancy.127
DIFFERENTIAL DIAGNOSIS AND LABORATORY FINDINGS. Large ulcers of Behet disease
Figure 76-10 Mucous membrane pemphigoid.
and recurrent aphthae major may look similar to pemphigus vulgaris. StevensJohnson syndrome and the
more severe toxic epidermal necrolysis may resemble
lesions of paraneoplastic pemphigus.
841
12
Section 12
Figure 76-12 Plasma cell gingivitis.
::
CLINICAL FINDINGS. Patients may present with

erythematous and eroded mucosa, especially on the
buccal mucosa and palate with a hint of white reticulations. Ulcers may be present (Fig. 76-11).
Figure 76-11 Lupus erythematosus of buccal mucosa.

The biopsy for pemphigus vulgaris shows suprabasilar acantholysis and direct immunofluorescence
studies show intercellular deposition of IgG. Paraneoplastic pemphigus shows deposition of IgG and C3
both intercellularly and at the basement membrane
zone. Patients with only oral lesions of pemphigus
usually do not exhibit elevated serum IgG.
by well-formed reticulations of the buccal mucosa.

Patients with lupus erythematosus usually have an
established diagnosis and present for management of
painful oral lesions.
The biopsy shows an interface stomatitis with linear
IgG deposition along the basement membrane zone on
direct immunofluorescence.
MANAGEMENT AND PROGNOSIS. Treatment
MANAGEMENT AND PROGNOSIS. The mainstay of treatment is topical steroid therapy. Symptoms usually wax and wane with systemic and skin
disease.
for pemphigus vulgaris is with topical steroids in mild

cases with the use of a stent for gingival lesions. More
severe cases can be successfully treated with prednisone and mycophenolate mofetil in conjunction with
topical steroids.
LUPUS ERYTHEMATOSUS
Patients with systemic and discoid lupus erythematosus present with oral findings in up to 25% of cases.128
842
DIFFERENTIAL DIAGNOSIS AND LABORATORY FINDINGS. LP can usually be differentiated
Figure 76-13 A and B. Fibroma.
PIGMENTED LESIONS
The two most common pigments of exogenous origin
are amalgam and graphite from pencil lead. Pigmented
lesions of endogenous origin are usually caused by
melanin or hemosiderin.
12
Figure 76-14 Gingival nodule.
CLINICAL FINDINGS. This presents in adults

usually, as a discrete, nontender, slate-gray, or black
macule of the oral mucosa that is usually less than
1 cm.166168 The patient is usually unaware of the lesion.
When it is noted adjacent to a silver or amalgam restoration because of leaching out of particles, the diagnosis is straightforward. However, if it is located at a site
away from the restoration, such as the buccal mucosa,
tongue, sulcus, or palate, the diagnosis may not be as
obvious (Fig. 76-15).
DIFFERENTIAL DIAGNOSIS AND LABORATORY FINDINGS. Any other dark foreign material
such as graphite may look similar. Melanotic lesions

especially the oral melanotic macule and postinflammatory hypermelanosis may look similar although in
general these are more tan and dark brown rather than
dark blue. Dysplastic melanocytic lesions and melanoma usually have less uniform pigmentation and
irregular borders. A vascular lesion such as a varix or
MANAGEMENT AND PROGNOSIS. A biopsy is

usually not required if the lesion is adjacent to a restoration. However, if there is any doubt about the diagnosis, a biopsy is recommended.
PHYSIOLOGIC PIGMENTATION
(RACIAL PIGMENTATION)
This is very common in dark-skinned individuals of
African, South and Southeast Asian, and Mediterranean descent.
CLINICAL FINDINGS. Physiologic pigmentation

presents asymptomatic diffuse, even or patchy, brownto-black macular pigmentation of the oral mucosa and
in particular the attached gingiva (Fig. 76-16). This
usually has a symmetric distribution.21
Dental amalgam restorations are primarily composed

of silver and mercury with smaller amounts of other
elements such as tin. The silver particles stain the reticulin fibers leading to the tattoo.165
::
AMALGAM TATTOO
venous lake may look similar, although those intend to

appear as blebs or papules and blanch with pressure.
The histopathology is distinctive. Pigmentation by
other materials not containing silver such as graphite
does not cause staining of the reticulin fibers.
Chapter 76
Figure 76-16 Physiologic pigmentation.
DIFFERENTIAL DIAGNOSIS AND LABORATORY STUDIES. The patient is usually unaware of
this. Postinflammatory hypermelanosis from diffuse

and symmetric involvement by oral LP may also have
a similar appearance. However, the pigmented areas
tend to be located where the obvious white reticulations are present. Cosmetic tattooing of the gingiva is
a prevalent practice in some African cultures and this
may lead to extensive and symmetric pigmentation.
The biopsy shows the presence of melanin within
basal cells in the absence of melanocytic hyperplasia.
MANAGEMENT AND PROGNOSIS. Recognition of the condition is sufficient and a biopsy is seldom necessary.
ORAL MELANOTIC MACULE

Figure 76-15 Amalgam tattoo in floor of mouth.
The etiology of the solitary melanotic macule is unclear.

It is possible that at some of the lesions may have an
inflammatory etiology.
843
12
CLINICAL FINDINGS
The most common sites of involvement are the lower
lip vermilion, gingiva, and hard palate.169,170 They are
asymptomatic, discrete, tan, brown, or black macules,
usually less than 1 cm with even pigmentation (eFig.
76-16.1 in online edition). Unlike ephelis, they do not
darken in summer or lighten in winter. While most
lesions are solitary, multiple macules are not uncommon in dark-skinned individuals, and they may proliferate in middle age.
Section 12
DIFFERENTIAL DIAGNOSIS AND

LABORATORY STUDIES
::
Multiple oral melanotic macules are seen in idiopathic

lenticular mucocutaneous pigmentation (Laugier
Hunziker syndrome) associated with melanonychia.171
Multiple melanotic macules are often seen neurofibromatosis, McCuneAlbright syndrome, PeutzJeghers
syndrome, LAMB (lentigenes, atrial myxoma, blue
nevus) syndrome, and the associated Carney syndrome.21
The sudden onset of melanotic macules should raise
the possibility of Addison disease and ACTH levels
should be measured. History and clinical examination
usually exclude the other syndromes.
Multifocal oral melanosis is also associated with
postinflammatory conditions such as LP and the socalled smokers melanosis that occurs on the gingiva
around the canine teeth (see below).
Biopsy reveals increased melanin pigment in the
basal cells in the absence of melanocytic hyperplasia,
and many melanophages in the lamina propria.
MANAGEMENT AND PROGNOSIS

No treatment is necessary. Laser therapy may be useful in patients who are concerned with the esthetic
appearance of the macules.172
POSTINFLAMMATORY
HYPERMELANOSIS
These pigmented lesions occur in particular in darkskinned patients, similar to lesions of postinflammatory hyperpigmentation on the skin. They may
be localized or diffuse depending on the underlying
inflammatory process.
CLINICAL FINDINGS
844
LP is often associated with postinflammatory hypermelanosis and the pigmentation underlies the reticulations of the disease (Fig. 76-17). Smokers melanosis
is often described as a separate entity but likely represents a postinflammatory hypermelanosis occurring
in approximately 20% of subjects who smoke. It tends
Figure 76-17 Postinflammatory hypermelanosis from

lichen planus.
to occur on the buccal gingiva around the canine teeth

or on the buccal mucosa.173,174 Resolution of these
lesions after smoking cessation supports an inflammatory etiology.175

LABORATORY FINDINGS
Oral melanotic macules may resemble melanoacanthosis, another likely inflammatory reactive disorder in
which there is proliferation of dendritic melanocytes
throughout acanthotic epithelium.
Biopsy helps exclude a dysplastic melanocytic
lesion.

No treatment is necessary unless the patient is concerned about esthetics. Lesions generally fade over
time if the inflammation resolves.
MEDICATION-INDUCED
HYPERPIGMENTATION
The medications most commonly associated with
oral pigmentation do so via several different mechanisms.176 Minocycline and tetracycline chelate to
apatite crystals in bones and teeth and their metabolic products chelate iron and melanin in the soft
tissues.177 The latter mechanism is also seen during
therapy with antimalarial drugs. Pegylated interferon
used with ribavirin may stimulate melanin production by stimulating production of -melanocyte
stimulating factor.178,179 Heavy metals such as lead
is secreted into the gingival fluids and likely chelate
with sulfides (usually black) produced by plaque bacteria.180 Bismuth subsalicylate ingestion is also associated with pigmentation of the tongue either from
systemic ingestion and tissue deposition, or direct
conversion of the compound to bismuth sulfide from
oral bacteria.181,182
CLINICAL FINDINGS
The most common site of pigmentation caused by
minocycline and antimalarial medications is the palatal mucosa, which assumes a slate-gray to blue diffuse
macular discoloration that is generally bilateral and
symmetric. The lesions are asymptomatic.
Tongue pigmentation caused by pegylated interferon accentuates the papillae in a punctate configuration; this has been reported mainly in dark-skinned
individuals.178 Heavy metals deposit on the gingiva in
linear fashion (Burton line in plumbism).180
Depending on the length of exposure, discontinuation

of the drug may or may not result in eventual complete
resolution of the lesion.
MELANOACANTHOSIS
This is an uncommon inflammatory condition of the
oral mucosa. Although this condition is also reported
under the term melanoacanthoma, melanoacanthosis is preferred because this is a macular lesion, may be
multifocal and is not a tumor-like lesion. Many cases
of multifocal melanoacanthoma and melanoacanthosis
reported in the literature represent either multiple melanotic macules or postinflammatory hypermelanosis.
This raises the question as to whether oral melanotic
macules and melanoacanthosis are just two manifestations of postinflammatory hypermelanosis.
CLINICAL FINDINGS
Black females in the second to fourth decades are most
often affected. The lesion starts as a brown macule, usually on the buccal mucosa, that over days and weeks
spreads rapidly, but still in a macular fashion.183,184

LABORATORY STUDIES
While dysplastic nevi and melanoma may grow rapidly, the rate of expansion of the lesion is so fast that an
inflammatory condition is more likely.
A biopsy shows acanthosis with benign melanocytes
throughout the full thickness of the epithelium.
NEVOMELANOCYTIC NEVI
CLINICAL FINDINGS
The most common is the intramucosal nevus that
accounts for two-thirds of cases, followed by the compound nevus and the blue nevus (17%) each; junctional
nevus constitute only 3% of lesions.168 The most common location is the palate (40%) followed by the buccal
mucosa (19%).185 Most were identified in the third and
fourth decades of life.
Intramucosal and compound nevi tend to be nodular,
while junctional and blue nevi tend to be macular. Most
nevi are pale-tan to dark-brown or black while blue
nevi are slate-blue in color. Approximately 15%20% of
intramucosal nevi are nonpigmented clinically.185

LABORATORY STUDIES
Intramucosal and compound nevi may be mistaken
for fibromas or any other benign mesenchymal tumor.
Blue nevi resemble melanotic macules, amalgam tattoo, or even a varix. Intraoral Spitz nevi are rare but
have been reported.
A biopsy shows the presence of nevomelanocytic cells
in nests in the lamina propria and/or the epithelial
connective tissue interface. Blue nevi consist of spindled melanocytes in the lamina propria.
No treatment is necessary; this condition regresses

over time.
::
The history of ingestion of the drug followed by the

appearance of a diffuse pigmentation of the oral
mucosa and sometimes skin after several months or
years is diagnostic.
Biopsy shows pigment granules that stain for both
iron and melanin.
12
Chapter 76

LABORATORY FINDINGS

In general, nodular lesions are excised or shaved.
MELANOMA
Intraoral melanomas constitute 0.7% of all melanomas
and occur on average 20 years later than cutaneous
melanomas.186,187 The etiopathogenesis in this UVprotected site is unknown and lesions behave similarly
to acral lentiginous melanoma.
CLINICAL FINDINGS
Oral melanomas are tumors of adults in the fifth to
seventh decades of life with a male predilection and
usually evolve from preexisting dysplastic melanocytic lesions.188,189 They are more frequent in black and
Japanese patients and the most common site is the
palate or maxillary gingiva. By the time they are diagnosed, they are fairly large, asymmetric, and unevenly
pigmented. Areas of ulceration and bleeding may be
present. Approximately 40% are amelanotic.188
845
12

LABORATORY FINDINGS
Kaposi sarcoma tends to be purple or bluish-red,
while melanomas tend to be brown-to-black. A large
pyogenic granuloma or other vascular lesion with a
dark coloration may resemble a melanoma, although
a surrounding macular dysplastic melanocytic lesion
would be absent.
A biopsy shows an invasive proliferation of melanocytes from an intraepithelial component.
Section 12
::
Five-year survival is approximately 20%30%.190,191

Excision with clear margins is the treatment of choice
and survival is closely related to the depth of invasion.192 Surgery with radiotherapy greatly reduces
local relapse and metastasis to lymph nodes, although
it may not improve survival.190,193
Disorders of the Lips

Disorders of the lips including actinic cheilitis, orofacial granulomatosis,200,204 angular cheilitis, and lip nodules are discussed online.
ACTINIC CHEILITIS
Some use the term actinic cheilitis to encompass atrophy of the lips caused by actinic damage without evidence of dysplasia. Here, it will be defined as actinic
keratosis of the lip, a dysplastic lesion.
CLINICAL FINDINGS
Because the etiology is related to sun-damage,
patients are generally adults in the sixth decade and
beyond.194,195 There is usually a background of chronic
actinic damage and atrophy of the lip with blurring of
junction of the vermilion and the skin, predominantly
involving the lower lip. Actinic cheilitis presents as
single or multiple crusted or scabbing, slightly scaly
lesions and plaques on the vermilion of the lip, usually
several millimeters in size, that heal and then break
down. These occur on a whitish, keratotic background.
Fissuring and erosions of the vermilion may be present. Discomfort is variable.

LABORATORY STUDIES
846
An early SCC, traumatized adnexal or salivary gland

tumor, or recrudescent herpes simplex infection should
be considered in the differential diagnosis.
A biopsy is diagnostic and shows keratinocytic dysplasia.

Several treatment options are available depending on
the size of the lesion and patient preference. Lesions may
be surgically excised, treated with cryotherapy or carbon
dioxide laser,196 or managed with topical agents such as
5-fluorouracil or 5% imiquimod for 46 weeks.197,198 In
patients prone to herpes simplex recrudescence, antiviral
prophylaxis should be considered. More recently, the use
of photodynamic therapy with 5-aminolevulinic acid has
shown complete clinical response in two-thirds of cases
and partial response in one-third; follow-up revealed
recurrence in approximately one-third of cases.199
CHEILITIS GRANULOMATOSA
(OROFACIAL GRANULOMATOSIS)
This is the best known of the noninfectious granulomatous diseases that affects the orofacial region. Like
other granulomatous disease, it likely represents a
delayed-type hypersensitivity reaction to antigens.200
Elimination diets and removal of amalgam restorations
have resulted in complete remission of some cases, but
no obvious etiologic agents is identified in many cases.
There may be a genetic predilection and the reaction is
mediated via Th1 pathways.201,202
Patients with orofacial granulomatosis who present
only with lip involvement have cheilitis granulomatosa.
The term MelkerssonRosenthal syndrome refers to the
triad of fissured tongue, facial palsy, and cheilitis granulomatosa, but it is rare to see the triad fully expressed
clinically. It is also unclear whether fissured tongue, a
fairly common condition, is truly part of the syndrome.
CLINICAL FINDINGS
Most patients are young adults and the presentation
is variable. Some present with unilateral, soft (early
lesions), or firm-rubbery (more established lesions)
painless swelling of the lip, and others present with
symmetric swelling of the upper or lower lips or, less
frequently, both (eFig. 76-17.1 in online edition). Periorbital or zygomatic swelling are atypical presentations.203 The swelling is originally relapsingrecurring
and then becomes persistent, often with fissuring of the
lips. There may also be a history of facial swelling, VII
nerve palsy (uncommon), and gingival involvement.
The last presents as nodular swellings on the gingiva or
a cobblestoning of the buccal mucosa. While some also
include linear ulcers in the maxillary and mandibular
vestibule/sulcus as part of orofacial granulomatosis,
such ulcers are more typical of Crohn disease (see Section Differential Diagnosis and Laboratory Findings).

LABORATORY FINDINGS
Early Crohn disease and sarcoidosis are indistinguishable from lesions of orofacial granulomatosis, both
ANGULAR CHEILITIS
In most cases, this represents a form of candidiasis
(see Section Candidiasis) often with concomitant S. aureus infection.21 The prevalence is approximately 1% in the general adult population and 28%
in denture wearers.211,212 Drooping of the corners of
the mouth with drooling and retention of saliva in
the creases leading to candidiasis, often associated
with wearing of full dentures that do not provide
adequate soft tissue support is a major predisposing
factor. Patients with hematinic deficiencies or who are
immunocompromised are also prone to developing
this condition.213
CLINICAL FINDINGS
There is painful, usually bilateral maceration of the corners of the mouth with ulceration, crusting, cracking,
and, in severe cases, fissuring.214 Lesions may heal and
recur within days or weeks. Some patients develop a
diffuse cheilitis due to candidiasis.215
Recrudescent HSV infection in immunocompromised

patients may lead to bilateral ulcers and maceration of
the corners of the mouth, although usually other intraoral sites are also involved. A culture or direct fluorescent antibody testing will establish the diagnosis.
Patients should have bloodwork to rule out a hematinic deficiency.

Antifungal creams with topical steroid therapy (see
Table 76-4) are particularly useful in the treatment of this
condition. The usual anticandidal regimens employing
nystatin, clotrimazole, and chlorhexidine are also effective.216 If lesions only partially resolve, S. aureus infection should be suspected and treatment with topical
erythromycin usually resolves the residual lesion.217,218
If there is a hematinic deficiency, repletion should
be undertaken and dentures may need to be relined or
remade to better support the soft tissues.
EXFOLIATIVE CHEILITIS
This is a rare inflammatory condition of the lip and some
cases are associated with factitial injury and lip licking or
picking, sometimes associated with psychological distress;
however, many cases are of unknown etiology. It is seen in
approximately 25% of patients with HIV infection.219
CLINICAL FINDINGS
Topical and intralesional steroid injections are the

mainstay of treatment.204 The dose depends on the
severity of swelling and usually patients are treated
every week for 23 weeks.205 Systemic therapy in
recalcitrant or severe disease includes the use of
prednisone (1 mg/kg), thalidomide, minocycline,
and more recently, monoclonal antibodies against
TNF-.206,207
Less than 50% of patients are in remission on followup.204 In long-standing cases, fibrosis from the inflammation may lead to cosmetic problems that can only be
corrected with cheiloplasty.
12
::

LABORATORY STUDIES
Chapter 76
clinically and histopathologically. Therefore, patients

should be questioned regarding gastrointestinal
symptoms such as cramping, diarrhea, and blood in
stools. Endoscopy is often uninformative in asymptomatic patients since gastrointestinal manifestations
may occur years later. Patient should be made aware
that this may represent early Crohn disease so that
they can self-monitor for gastrointestinal symptoms.
In sarcoidosis, angiotensin-converting enzyme levels
are often elevated and hilar lymphadenopathy may be
present.
Angioedema is never persistent, but rather shows
complete resolution between acute episodes; and
patients may show increased levels of C1 esterase
inhibitor. Cellulitis from infections of the anterior
teeth may lead to lip swelling, but these are acute
and painful and the offending tooth is always
identified.
Biopsy reveals the presence of nonnecrotizing granulomas without foreign material or identifiable infectious agent.
The lip is covered by fine or thick scales and crusts that

can be peeled away, leaving an erythematous, raw area
(eFig. 76-17.1 in online edition). Patients will report that
within a few hours, a new scale or crust forms.220,221 The
lips may also appear cracked, fissured, and chapped.
Some patients admit picking at the lesions while others deny this.222 Cultures in patients with HIV disease
yield Candida in 50% of cases.219

LABORATORY STUDIES
Actinic keratosis is an important consideration and
this also causes scaly plaques but these do not tend to
peel and recur as quickly. Plasma cell cheilitis should
be considered although this presents as an erythematous rather than scaly lesion.223,224
A biopsy shows parakeratosis, acanthosis, and
chronic inflammation, either somewhat consistent
with factitial injury or nonspecific in nature.
MANAGEMENT
Some patients have been at least partially successfully
treated with antidepressants, suggesting that factitial
847
12
injury associated with psychological distress plays a

role.221,225 Other treatment modalities include mupirocin and tacrolimus.222
LIP NODULES
On the lower lip nodules usually result from trauma and
include bite or irritation fibromas and mucoceles (both
discussed above under Nodular Lesions). The upper lip
is traumatized much less frequently and mucosal nodules at this site usually represent one of the following:
1. Benign salivary gland neoplasm (such as
Section 12
pleomorphic adenoma or canalicular adenoma)
2. Malignant salivary gland neoplasm (such as
::
mucoepidermoid carcinoma)
3. Benign nerve sheath tumor (such as solitary
circumscribed neuroma)
4. Benign vascular tumor (such as pyogenic
granuloma)
5. Nasolabial cyst, a developmental malformation
All require excisional biopsy. Histopathology is
diagnostic for each condition.
TONGUE
ATROPHIC GLOSSITIS
Atrophy of the filiform and fungiform papillae of the
tongue leads to a bald shiny, erythematous tongue
dorsum. Such atrophy is often seen in hematinic deficiencies and in patients with prolonged hyposalivation
such as those with Sjgren syndrome or after head and
neck radiation therapy.213
CLINICAL FINDINGS. The tongue presents with

a smooth, bald appearance and papillae are atrophic
(Fig. 76-18). Patients often complain of a burning sensation and experience sensitivity when eating acidic,
salty, or crunchy foods.21 They may have associated
angular cheilitis if there is a hematinic deficiency.
Patients who develop malabsorption after intestinal
surgery are prone to developing atrophic glossitis.226
LABORATORY STUDIES AND DIFFERENTIAL DIAGNOSIS. Patient should have blood work
to rule out hematinic deficiencies, in particular iron

and vitamins B6 and B12 deficiency. For the last, assay
of methyl malonic acid may be more sensitive than just
a B12 level alone.
MANAGEMENT AND PROGNOSIS. Treatment

is with repletion of deficient elements. Topical anesthetics help to control symptoms.
HAIRY TONGUE (BLACK HAIRY
TONGUE, COATED TONGUE)
This is an extremely common condition that causes
much confusion. There is generally an antecedent history of illness and antibiotic use, leading to a common
misdiagnosis of candidiasis. There are usually no other
lesions on other oral mucosal sites and no pain, which
would be highly unusual for candidiasis. To further
add to the confusion, a small number of such patients
will grow Candida on culture because they are carriers.
Hairy tongue is caused by retention of keratinaceous
debris on the tongue dorsum resulting from two factors acting alone or in combination: (1) dehydration
(leading to more sticky and mucous rather than serous
saliva) and (2) poor oral intake (eating a soft diet or
one low in fresh fruits and vegetables).54 Since most
patients have an antecedent history of illness or are
hospitalized, they often are dehydrated and have
poor appetite. Chromogenic bacteria that reside in the
tongue produce metabolic by-products that sometimes
stain the tongue, as do food dyes.
CLINICAL FINDINGS. The tongue presents with a

matted or coated appearance that is usually symmetric (Fig. 76-19). If located on the posterior midtongue,
patients may experience gagging if the hairs are
long. The thickened matte of keratin on the tongue
leads to increased bacterial colonization and their
metabolic products (often sulfides) may lead to a foul
or stale breath. Such metabolic products may stain the
tongue a variety of colors such as brown or black.
DIFFERENTIAL DIAGNOSIS AND LABORATORY STUDIES. Candidiasis involving the dorsum
of the tongue is an important differential diagnosis,

but has more patchy distribution of the curdy plaques,
associated erythema, a less symmetric distribution,
and involvement of other parts of the oral cavity by
similar candidal papules and plaques. Ingestion of
bismuth subsalicylate may transiently lead to a black
tongue.182
There is no test that is useful. Rare cases have been
biopsied and show only elongated filiform papillae. Cultures for Candida are positive in 20%30% of
patients and likely indicate carrier status.
848
Figure 76-18 Atrophic glossitis.
MANAGEMENT AND PROGNOSIS. Vigorous hydration and return to a normal diet with fresh
fruits and vegetables generally resolve the lesions.
12
Chapter 76
The tongue may be brushed as part of the daily oral

hygiene regimen to help to dislodge loose keratin
squames and reduce discoloration. Hairy tongue is not
harmful to the patient.
FISSURED TONGUE
tongue with spicy or acidic foods, although in general, this condition is asymptomatic.21 Approximately
one-third of patients with migratory glossitis (see
below) have concomitant fissured tongue.
DIFFERENTIAL DIAGNOSIS AND LABORATORY STUDIES. The clinical presentation is striking
This is a common condition that occurs in 1%2% of

the population and is generally believed to be developmental in etiology.211
and a biopsy is not useful. The presence of sensitivity

should prompt a careful examination for the presence
of migratory glossitis, atrophic glossitis, or even candidiasis within the fissures.
CLINICAL FINDINGS. It is fairly uncommon in

the first and second decade of life and usually seen in
adults. Some believe that Candida reside within the fissures and cause symptoms.
There are two main patterns. The first consists of
a central fissure, either alone or with smaller fissures
radiating from it at right angles (Fig. 76-20A). The second pattern is one of short fissures distributed evenly
throughout the tongue without the central fissure (Fig.
76-20B). Some patients report some sensitivity of the
MANAGEMENT AND PROGNOSIS. Most

lesions are noted on routine examination, are asymptomatic and do not require therapy. Some patients who
are symptomatic show resolution of symptoms with a
short course of antifungal therapy, but predisposing
factors for candidiasis must be addressed or the lesions
will recur.
In general, fissured tongue is a permanent condition. However, some patients report that fissures are
evanescent.
Figure 76-19 A. Hairy tongue. B. Brown hairy tongue.
::
Figure 76-20 A. Fissured tongue. B. Fissured tongue with migratory glossitis on right.
849
12
candidal hyphae via cytology distinguishes the two.

LP and MMO on the lateral tongue are white lesions
that are sometimes mistaken for this condition, but
biopsy showing a psoriasiform pattern with many
spongiotic pustules in the absence of candidal hyphae
is diagnostic.
Section 12
Figure 76-21 Typical migratory glossitis.
::
BENIGN MIGRATORY GLOSSITIS/

STOMATITIS (GEOGRAPHIC TONGUE)
CLINICAL FINDINGS. This occurs in 1%2% of the
population and is associated with a fissured tongue in

about 30% of cases.211,227 There is an area of atrophy of
the tongue dorsum leading to loss of filiform papillae
and a slightly depressed erythematous area that is usually sensitive or painful, especially when acidic foods
come in contact with it (Figs. 76-21 and 76-22A and
B). Such demarcated areas rimmed by a raised white
border that is circinate or serpiginous are diagnostic.228
Waning lesions are often merely well-demarcated erythematous patches. A history of atopy is often elicited
from such patients or from immediate family members.227 Approximately 13% of patients with psoriasis
develop this tongue condition.229 Flare-ups are associated with both physical and psychological stress.
Infrequently, other mucosal sites such as the palatal mucosa, floor of mouth or buccal mucosa may be
involved. In such cases, the term migratory stomatitis should be applied.230
DIFFERENTIAL DIAGNOSIS AND LABORATORY STUDIES. Erythematous candidiasis may
cause depapillation of the tongue dorsum and cause

some soreness and sensitivity.231 Identification of
850
MANAGEMENT AND PROGNOSIS. Patients

should be reassured that this is not infectious in etiology, a common concern. Diphenhydramine used as
a swish and spit preparation or 2% viscous lidocaine
may reduce symptoms. If severe, topical steroids
(especially dexamethasone) are helpful. However,
patients need to realize that this is an evanescent lesion
that tends to recur.
Macroglossia, hyperplastic lingual tonsil, papillitis of the tongue, and tongue nodules are discussed
online.
CLINICAL MACROGLOSSIA
Macroglossia refers to the diffuse enlargement of the
tongue that may be symmetric or asymmetric. Patients
report that the tongue seem enlarged and is more readily traumatized by biting since it may now overly the
mandibular teeth. Mild symmetric enlargement is usually caused by loss of muscle tone such as in aging or
with some systemic conditions such as amyloidosis.
Loss of muscle tone (flabby tongue) is particularly
obvious in older patients who have lost all their teeth
so that there is concomitant loss of bone height in the
mandible. The tongue appears to spread over the
edentulous mandibular ridge and this also makes it
difficult for the lower denture to stay in place. Patients
with trisomy 21 often have such flabby tongues.
Asymmetric enlargement is usually caused by the
presence of a tumor, in particular a vascular malformation of either lymphatic (lymphangioma) or blood
vascular origin (venous malformation) that tends to
insinuate between the muscle fibers rather than produce an encapsulated mass.
DIFFERENTIAL DIAGNOSIS AND LABORATORY STUDIES. In cases of amyloid deposits or a
Figure 76-22 A. Migratory glossitis presenting with mostly erythema and atrophy. B. Subtle migratory glossitis.
12
HYPERPLASTIC LINGUAL TONSIL

The lingual tonsil is located on the posterolateral aspects of the tongue bilaterally and is part of
Waldeyer ring. In its healthy form, it lies below the
foliate papillae (Fig. 76-23). Inflammation of this tissue
from trauma or upper respiratory tract infection leads
to hyperplasia. Although the term foliate papillitis is
often used for this condition, the more accurate term is
hyperplastic lingual tonsil.
CLINICAL FINDINGS. The hyperplastic lingual

tonsil, when inflamed, protrudes as a fleshy, soft area
with a slightly irregular surface (because of the crypts
in the overlying foliate papillae), which then becomes
more readily traumatized that then makes it even more
inflamed and protuberant.21
DIFFERENTIAL DIAGNOSIS AND LABORATORY FINDINGS. This posterolateral tongue is a
common site for SCC and the fairly rapid appearance

of this lesion may mimic cancer. Lymphomas may also
develop in this area.
Biopsy shows benign hyperplasia of lymphoid tissue.
MANAGEMENT AND PROGNOSIS. Excision

is curative. Intralesional steroid injections may reduce
the size of the lesion so that it is no longer traumatized.
There are several forms of papillitis and they represent irritation of the tongue papillae either from local
trauma, dryness, or a hypersensitivity reaction (possibly to a contactant).
CLINICAL FINDINGS. One form is transient lingual papillitis that presents as multiple enlarged white
papillae scattered over the surface of the tongue that
tends to be relapsingrecurring.232234 Another form
presents as reddened and enlarged fungiform papillae
on the dorsum of the tongue (Fig. 76-24). A rare form
is eruptive papillitis with intrafamilial transmission.235
MANAGEMENT AND PROGNOSIS. Dexamethasone mouth rinse reduces inflammation. However,
the inciting factor must be addressed to prevent recurrence.
MANAGEMENT AND PROGNOSIS. The diagnosis relies on a careful clinical history and examination, with biopsy as necessary. For symmetric lesions,
there is no treatment unless the patient resorts to a surgical recontouring of the tongue.
For patients with amyloidosis, a work-up for
plasma cell dyscrasia is indicated. For patients with
other tumors, excision with/out the use of embolization in the case of vascular tumors is the treatment of
choice.
PAPILLITIS OF TONGUE
::
neoplasm, a biopsy is diagnostic. An MRI study is usually helpful for soft tissue tumors in the tongue that
present with asymptomatic enlargement.
Figure 76-24 Fungiform papillitis.
Chapter 76
Figure 76-23 Hyperplastic lingual tonsil.
TONGUE NODULES
As with the lip, nodules on the lateral tongue tend to
have a traumatic etiology and include fibromas (and
its variant giant cell fibroma) and traumatic neuroma.
More common tumors of the tongue include benign
nerve sheath tumors, granular cell tumors, oral lymphoepithelial cyst, vascular lesions such as pyogenic
granulomas or venous malformations, and osseous
and cartilaginous hamartomas.
All require excisional biopsy and have diagnostic
histopathology.
KEY REFERENCES
1. Bruch JM, Treister NS: Clinical Oral Medicine and Pathology, 1st edition. New York, Humana Press, 2009
2. Jurge S et al: Mucosal disease series. Number VI. Recurrent aphthous stomatitis. Oral Dis 12(1):1-21, 2006
83. Thornhill MH et al: The role of histopathological characteristics in distinguishing amalgam-associated oral
lichenoid reactions and oral lichen planus. J Oral Pathol
Med 35(4):233-240, 2006
851
12
88. Casiglia J, Woo SB, Ahmed AR: Oral involvement in

autoimmune blistering diseases. Clin Dermatol 19(6):737741, 2001
93. Solomon LW: Chronic ulcerative stomatitis. Oral Dis
14(5):383-389, 2008
97. Warnakulasuriya S, Johnson NW, van der Waal I: Nomenclature and classification of potentially malignant disorders
of the oral mucosa. J Oral Pathol Med 36(10):575-580, 2007
121. Chan LS et al: The first international consensus on
mucous membrane pemphigoid: Definition, diagnostic
criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol 138(3):370-379, 2002
184. Fornatora ML et al: Oral melanoacanthoma: A report
of 10 cases, review of the literature, and immunohisto-
Section 12
::
Chapter 77 :: D
iseases and Disorders of the
Male Genitalia

:: Christopher B. Bunker
DISEASES AND DISORDERS OF THE
MALE GENITALIA AT A GLANCE
Men with genital skin problems can
present to physicians who are not trained
or experienced in the diagnosis and
management of these problems.
Skin problems of the male genitalia may be
any of the following:
Normal variants.
Manifestations of sexually transmitted
diseases.
Dermatoses that may be generalized or
found at extragenital sites but that have a
predilection for the genitalia.
Dermatoses that are specific to the
genitalia.
Much dermatologic disease of the male
organ can be linked to the causes or
consequences of preputial dysfunction.
The guiding philosophy behind diagnosis
and management is to exclude sexually
transmitted disease and to minimize or
abolish sexual and urinary dysfunction and
the risk of cancer of the penis.
Circumcision is controversial, but it is
indispensable in the management of some
diseases of the penis and foreskin.
852
chemical analysis for HMB-45 reactivity. Am J Dermatopathol 25(1):12-15, 2003

190. Mendenhall WM et al: Head and neck mucosal melanoma. Am J Clin Oncol 28(6):626-630, 2005
193. Meleti M et al: Head and neck mucosal melanoma: Experience with 42 patients, with emphasis on the role of
postoperative radiotherapy. Head Neck 30(12):1543-1551,
2008
200. Grave B, McCullough M, Wiesenfeld D: Orofacial granulomatosisa 20-year review. Oral Dis 15(1):46-51, 2009
204. Al Johani KA et al: Orofacial granulomatosis: Clinical
features and long-term outcome of therapy. J Am Acad
Dermatol 62(4):611-620, 2010
EPIDEMIOLOGY
The incidence and prevalence of male genital dermatoses are not known with accuracy, but most, like sexually transmitted diseases, are more common and more
severe in the uncircumcised; these include psoriasis,
seborrheic dermatitis, and lichen planus (LP).1 The
global prevalence of circumcision is estimated at 25%
33% and in the United States, 85%.15 Religious and
cultural practices and medical intervention account for
these rates. Circumcision has been adopted as a measure to reduce human immunodeficiency virus (HIV)
transmission.617 Neonatal circumcision is a topic that
evokes controversy, but some benefits are accepted
(Table 77-1).1,2,3,10,1841 Although there is little evidence
of significant adverse effects on health and psychosexual function, circumcision can have side effects
and complications, especially when performed ritually.3,5,1719,4247 Although views of circumcision range
from prophylaxis to child abuse, the rational stance
is that nontherapeutic circumcision of male infants
should be left to parental discretion.3,4850

Etiologic and pathogenetic factors have to be understood in relationship to structure, function, and micro-
TABLE 77-1
Benefits of Circumcision
Reduced or abolished risk of penile cancer
Decreased risk of cervical cancer in partners
Protection from sexually transmitted infections, including
human immunodeficiency virus infection (controversial)
Reduced risk of urinary tract infections (controversial)
Reduced risk of inflammatory genital skin diseases
ecology.3 Obviously the genital area differs between the

sexes, but it also provides a good example of regional
human variation.
Although the whole organ of the skin is concerned
with sexual expression and activity, the penis is the
male structure most intimately involved in sexual intercourse. It is also the conduit for urinary excretion. The
scrotum is the extracorporeal sack that maintains the
testes at the ideal temperature for spermatogenesis. The
essential structures of the penis and its important landmarks are illustrated in Figure 77-1.3 As at other sites,
topographical and regional anatomic nomenclature is
an essential part of the vernacular for a dermatologist.
The anatomic position is that of full penile erection.
The perineal area is abundant in eccrine and apocrine (some functionless) sweat glands and holocrine
sebaceous glands, usually in association with hair follicles as pilosebaceous units but also occurring as free
glands at some sites such as the anal rim or around
the coronal sulcus (Tyson glands). Adnexal secretions
lubricate the hinge between limb and torso, lubricate
hair, lubricate the mucocutaneous junctions to assist
in the voiding of excreta, and protect the epithelia
from irritation and lubricate the penis for the retraction of the foreskin during sexual activity. The pattern
of keratinization differs throughout the male genital
tract area, most markedly so at the mucosal junctions,
the prepuce and distal penile shaft, and especially the
Chapter 77
Anatomy and landmarks of the penis
Glans penis
Dorsal artery
Dorsal nerve
Tunica albuginea
Corpus
cavernosum
Septum penis
Corpus
spongiosum
Urethra
Meatus and
navicular fossa
Corpus
cavernosum
Corpus
spongiosum
Corpus
cavernosum
Diseases and Disorders of the Male Genitalia
Fascia penis
::
Superficial dorsal vein

Deep dorsal vein
12
Corpus
spongiosum
Frenulum
Meatus
Crus penis
Prepuce
Glans
Frenulum
Sulcus
Bulb of
penis
Interior layer of
urogenital diaphragm
(perineal membrane)
Figure 77-1 Anatomy and landmarks of the penis. (Adapted from Bunker CB: Male Genital Dermatology. London,
Saunders, 2004.)
853
12
Section 12
::
854
glans in the circumcised individual. The detritus of

mucosal turnover combines with adnexal secretions
to produce smegma that can accumulate in the preputial sac of the uncircumcised individual, especially if
hygiene is poor. There is wide normal variation in the
anatomy of the penis (particularly the urethral meatus)
and its relationship to the prepuce, which perhaps
reflects susceptibility to minor embryologic anomalies;
the embryogenesis of the anogenital structures is complex.3 The foreskin is a delicate, busy tissue that is in
close contact with urine and exposed to sexual secretions, detergents, and infectious agents, especially
opportunistic organisms and those that are sexually
transmitted. Of the latter, human papillomavirus
(HPV) is the most important known from the point of
view of precancerous dermatoses and invasive squamous carcinoma. All these congenital and acquired
factors can conspire to produce a dysfunctional foreskin,51 often clinically expressed as male sexual dysfunction in the form of male dyspareunia. The genitals
may be a site of predilection or exclusive manifestation of disorders often encountered extragenitally (e.g.,
vitiligo, psoriasis, and LP), in part due to the Koebner
phenomenon.3
CLINICAL FINDINGS
The algorithm shown in Box 77-1 emphasizes the need
to obtain a complete history, perform an adequate
examination, and construct a differential diagnosis.
Initiating investigations to exclude sexually transmitted disease or performing a biopsy may be indicated.
Occasionally, a trial of treatment may help crystallize
a diagnosis.
The responsibility for the elucidation of anogenital
symptoms may need to be shared with the genitourinary
physician, pediatrician, urologist, or colorectal surgeon.
HISTORY
Although classic dermatologic symptoms (itch, rash,
lumps or bumps, or ulceration) may be present, the
physician must be alert to symptoms of sexually transmitted disease (e.g., discharge, dysuria), urologic disease (e.g., pain, hematuria, dysuria), and male sexual
dysfunction. Symptomatic male sexual dysfunction
equates with male dyspareunia, that is, painful or
Box 77-1 CLINICAL Approach to Male Genital DERMATOLOGY

HISTORY
EXAMINATION
Age
Job
Symptoms
Itchiness, soreness, pain
Rash
Lump, bump, ulcer, blister
History of presenting complaint
Time and space relationships, especially
to sexual activity
Personal and family history
Circumcision
Atopy
Psoriasis
Drugs and allergies
Systemic medication
Topicals
Over-the-counter medication
Sexual history
Single/married
Heterosexual/homosexual/bisexual
Regular partner
Last sexual activity
When
How (vaginal, oral, anal)
Contraception
Partner symptomatology
Urologic history and symptomatology
Smoking
Complete
Mucous membranes
Hair, nails, and teeth
Inguinal folds and nodes
Scrotum and contents
Perineum and anus
Prepuce
Circumcised/uncircumcised
Retractibility
Phimosis, paraphimosis
Penis
Navicular fossa
Glans
Coronal sulcus
Frenulum
Shaft
Signs
Pigmentary change
Purpura
Red patches
Balanitis/posthitis/intertrigo
Scaly patches
Eczematous/psoriasiform/lichenoid
Erosions/blisters/ulcers
Papules/nodules
Swelling
Urinalysis
Normal variant
Sexually transmitted disease
Systemic disease (e.g., diabetes)
Genital manifestation of extragenital
dermatosis
Primary genital dermatosis
Precancer (penile carcinoma in situ:
PCIS)
Cancer
12
Chapter 77
::
difficult sexual intercourse. Many men will not volunteer such information, so specific inquiry should be
tactfully made. The components of normal male sexual
function are libido, erection, ejaculation, and orgasm.
CUTANEOUS LESIONS
A systematic approach to the penis and prepuce is
summarized in the algorithm (see Box 77-1). The
foreskin (if present) should be gently retracted, the
gluteal and crural folds and the meatal lips parted,
and the rectum examined digitally. Site, distribution,
and morphology of lesions should be conventionally noted and analyzed. Specific male genital signs
include phimosis (nonretractable foreskin; Fig. 77-2),
paraphimosis (foreskin fixed in retraction; Fig. 77-3),
balanitis (inflammation of the glans penis), posthitis
(inflammation of the prepuce), and dorsal perforation of the prepuce (glans and shaft of penis ulcerated
through the prepuce, which lies ventrally as an empty
sleeve). Phimosis should be regarded as a sinister situation and impedes complete inspection and palpation
of the glans and coronal sulcus. The causes of phimosis are listed in Table 77-2. Paraphimosis is rarer and
is usually an acute emergency presentation caused by
vigorous sexual activity, acute contact urticaria, acute
allergic contact dermatitis, and lichen sclerosus (LSc).
Chronic paraphimosis is increasingly recognized in
India and is due to chronic inflammation and fibrosis
of the foreskin in the retracted state. Balanitis and posthitis xerotica (obliterans) can be confusing terms, used
to signify the end stage of all chronic cases of balanitis and posthitis (e.g., scarring dermatoses such as LP
and cicatricial pemphigoid), but these conditions are
usually due to LSc and are therefore considered syn-
Figure 77-3 Paraphimosis. Foreskin fixed in retraction.

(From Bunker CB: Male Genital Dermatology. London,
Saunders, 2004. Medical Illustration UK.)
onymous by some. Dorsal perforation of the penis is
very rare and is caused by gross penile disease such
as hidradenitis suppurativa, pyoderma gangrenosum,
florid condylomata, chancroid, herpes simplex, idiopathic balanoposthitis, and podophyllin misuse.3,53,54
Figure 77-2 Phimosis. Foreskin unretractable. Lichen

sclerosus. ( Medical Illustration UK.)
The algorithm (see Box 77-1) underlines the necessity

to examine patients conventionally, systematically, and
completely, because important signs will be found at
nongenital sites.
LABORATORY TESTS
The most commonly required special investigational
procedures are taking a swab or smear for microbiologic
TABLE 77-2
Causes of Phimosis
Lichen sclerosus
Nonspecific balanoposthitis (e.g., in diabetes)
Lichen planus
Hidradenitis suppurativa
Crohn disease
Chronic penile lymphoedema
Kaposi sarcoma
855
12
Section 12
::
or virologic analysis, obtaining scrapings for fungal

microscopic examination and culture, taking scrapings
for mite identification, and performing a skin biopsy.
Woods light examination is helpful in the clinical
diagnosis of vitiligo, erythrasma, and fungal infections. The investigations pertinent to the diagnosis of
sexually transmitted disease are discussed in Section
32 (see Chapters 200, 202, 203, 204 and 205).
A genital skin biopsy is informative under selected
clinical conditions. It is important to obtain the right
specimen from the right site at the right time (the
most floridly inflamed areas may not be the best
from which to obtain a specimen and histologically
often show nonspecific or zoonoid features) and to
provide the pathologist with a differential diagnosis. Examination of biopsy specimens should not be
regarded as a substitute for clinical diagnosis. It is
safe and helpful to use small amounts of adrenalinethe region is highly vascular. Knowledge of
anatomy is crucial: ventrally, the urethra can lie very
close to the surface in the coronal sulcus. It is not
often necessary to suture a preputial punch biopsy
site.3,55
SPECIAL TESTS
Diagnostic imaging of the penis, scrotum, and
perineum by ultrasonography or magnetic resonance
can be helpful under some circumstances.5658 Patch
testing is sometimes indicated.3
The principal presenting scenarios are tabulated in Box
77-2.
NORMAL VARIANTS
PEARLY PENILE PAPULES
(ANGIOFIBROMAS)
856
Pearly or pink penile papules,3 which may be found

in between 15% and 48% of men, are flesh-colored,
smooth, rounded papules (13 mm) occurring predominantly around the coronal margin of the glans,
rarely on the glans. Often there are rows or rings of
the papules. They are commoner in the uncircumcised male and regress with age.59 Ectopic lesions,
for example, on the penile shaft, have been reported.
They are frequently mistaken for warts or Tyson
ectopic sebaceous glands (of Tyson) and sometimes cause anxiety in adolescents. The histologic
findings are those of angiofibroma, and the lesion
is analogous to other acral angiofibromas such as
adenoma sebaceum, subungual and periungual
fibromas, fibrous papule of the nose, acquired acral
angiofibroma, and oral fibroma. Reassurance should
suffice, but cryotherapy and laser treatment have
been used.3
SEBACEOUS GLAND PROMINENCE

Sebaceous gland prominence, Tyson glands, sebaceous
hyperplasia, and ectopic sebaceous glands (Fordyce
condition) are all essentially equivalent, common, normal variants of the skin of the scrotal sac and penile
shaft, analogous to the situation on the vermillion of
the lips. Nevoid linear lesions on the penile shaft and
lesions on the glans have been reported. Reassurance
is usually adequate, but patients can be inordinately
distressed.3
MELANOCYTIC NEVI
It is possible that nevi on the penis occur more frequently in patients with the atypical nevus syndrome.3
A divided or kissing nevus is a lesion with one-half
located on the glans and the other half located on the
distal penile shaft separated by uninvolved skin across
the coronal divide; an analogous nevus affects the eyelids.60 Epithelioid blue nevus of the genitals is very
rare.61
PROMINENT VEINS
Prominent veins are common and very occasionally
give rise to concern but very rarely cause complications.3
ANGIOKERATOMA
Angiokeratomas are more common in white men
and are common on the genitalia (where, confusingly, together with prominent sebaceous glands
they have attracted the eponymous epithet of Fordyce
spots). Angiokeratomas are blue to purple, smooth,
25-mm papules on the scrotum, penile shaft, or
glans. They generally appear and multiply during
life but occasionally present as singletons. They may
bleed after trauma and may be mistaken for a nevus,
melanoma, or Kaposi sarcoma. The angiokeratomas of Fabry disease (see Chapter 136) are smaller
than common angiokeratomas, presenting as less
hyperkeratotic pinhead lesions, and are found more
extensively around the lower limb girdle and upper
thighs from the navel to the knees. Angiokeratoma
circumscriptum very, very rarely may affect the
penis (see Chapter 172).
Electrocautery or laser ablation can be offered, but
the lesions may recur.
CONGENITAL ABNORMALITIES
The complicated embryogenesis of the anogenital
region involving sexual differentiation and pubertal determination of secondary sexual characteristics
means that congenital and developmental anomalies
are common. Consequent anatomic and functional
12
Box 77-2 Differential Diagnosis of Male Genital Dermatoses

MALE GENITAL PRURITUS
Most Likely
Eczema/dermatitis
Psoriasis
Lichen sclerosus
Lichen planus
Herpes simplex
Candidosis
Scabies
Pediculosis
Dysesthesia syndromes
Consider
Insect bite/papular urticaria
Hirsutism
Hyperhidrosis
FoxFordyce disease
Urticaria and dermatographism
Trichosporosis
Larva currens/cutaneous larva migrans
Onchocerciasis
Drugs and foods
Always Rule Out

Squamous hyperplasia
Mycosis fungoides
::
Consider
Always Rule Out
Tattoos
Purpura
Acral lentiginous melanoma
Addison and Nelson syndromes
LaugierHunziger syndrome
PeutzJeghers syndrome
LAMB (lentigines, atrial myxoma, blue nevi)
syndrome
LEOPARD (multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism,
pulmonary stenosis, abnormalities of the
genitalia, growth retardation, deafness)
syndrome
RuvalcabaMyhreSmith syndrome
Pseudoacanthosis nigricans
Drugs and metals
MALE GENITAL POSTINFLAMMATORY HYPOPIGMENTATION

Most Likely
Consider
Postcryotherapy
Contact dermatitis
Electrotherapy
Condom leukoderma
Chemocautery
Systemic sclerosis
Lichen sclerosus
Lichen planus
Gonococcal dermatitis
Herpes simplex
Pityriasis versicolor
Onchocercal leopard skin
Peyronie disease
MALE GENITAL POSTINFLAMMATORY HYPERPIGMENTATION
Most Likely
Consider
Posttraumatic
Fixed drug eruption
Lichen planus
Herpes simplex
MALE GENITAL PURPURA
Most Likely
Physical (e.g., from suction)
Zoon balanitis
Lichen sclerosus
Consider
HenochSchnlein purpura
MALE GENITAL HYPERPIGMENTATION

Most Likely
Hyperpigmentation of median raphe
Postinflammatory hyperpigmentation
Lentigines
Melanosis
Chapter 77
MALE GENITAL HYPOPIGMENTATION/LEUKODERMA/PLAQUES

Most Likely
Consider
Scar
Biers spots
Vitiligo
Striae
Postinflammatory
Lichen sclerosus
Viral warts
Always Rule Out

Sexually transmitted diseases
Bowen disease
Erythroplasia of Queyrat
Always Rule Out

Leprosy
Syphilis
Leukodermapostsecondary
syphilide gumma
Pseudoepitheliomatous and
micaceous keratotic balanitis
Always Rule Out

Bowenoid papulosis
Always Rule Out

Amyloidosis
(continued)
857
12
Box 77-2 Differential Diagnosis of Male Genital Dermatoses (Continued)

MALE GENITAL RED SCALY PATCHES
Most Likely
Eczema/dermatitis
Psoriasis
Lichen sclerosus
Lichen planus
Erythrasma
Candidosis
Scabies
Bowen disease
Section 12
::
MALE GENITAL RED PLAQUES

Most Likely
Psoriasis
Lichen planus
Bowen disease and bowenoid papulosis
Fixed drug eruption
BALANOPOSTHITIS AND INTERTRIGO
Most Likely
Eczema/dermatitis
Contact, seborrheic
Psoriasis
Zoon balanitis
Nonspecific balanoposthitis
Lichen sclerosus
Candidosis
MALE GENITAL EROSIONS

Most Likely
Trauma
Excoriated pruritic dermatoses
(e.g., scabies)
Inverse pattern psoriasis
Zoon balanitis
Lichen sclerosus
Lichen planus
Herpes simplex
Candidosis
858
Consider
Inflammatory linear verrucous nevus
Reiter syndrome
Pityriasis rosea
Acrodermatitis enteropathica
Darier disease
Kawasaki syndrome
Primary and secondary syphilis
Tinea
Porokeratosis
Fixed drug eruption
Always Rule Out

Psudoepitheliomatous and micaceous keratotic balanitis
Mycosis fungoides
Consider
Giant lichen simplex (of Pautrier)
Inflammatory linear verrucous nevus
Leishmaniasis
Always Rule Out

Kaposi sarcoma
Carcinoma erysipeloids
Consider
Reiter syndrome
Darier disease
Crohn disease
Streptococcal dermatitis
Staphylococcal cellulitis
Nonsyphilitic spirochetal ulcerative
balanoposthitis
Tinea
Amebiasis
Myiasis
Scabies
Eccrine syringofibroadenomatosis
Chronic lymphatic leukemia
Fixed drug eruption
Always Rule Out

Sexually transmitted disease
Gonorrhea
Syphilis
Chancre with balanitis
Human papillomavirus
infection
Herpes simplex
Mycoplasma infection
Trichomonas vaginalis
infection
Lymphogranuloma venereum
Leprosy
Squamous carcinoma
Carcinoma erysipeloides
Kaposi sarcoma
Consider
Pemphigus
Bullous pemphigoid
Cicatrizing pemphigoid
Streptococcal dermatitis
Gonorrhea
Secondary syphilis
Herpes zoster
Acute primary human immunodeficiency
virus (HIV) infection
Cytomegalovirus in HIV infection
Tinea
Paracoccidioidomycosis
Pediculosis
Porokeratosis
Topical steroids
Fixed drug eruption
Always Rule Out

Kaposi sarcoma
12
MALE GENITAL VESICLES AND BLISTERS

Most Likely
Erythema multiforme/StevensJohnson
syndrome
Lichen sclerosus
Bullous impetigo
Herpes simplex
Fixed drug eruption
Consider
Chronic renal failure
Diabetes mellitus
Thrombocytopenia
Polycythemia
Cryoglobulinemia
Vasculitis
Calciphylaxis
Ecthyma gangrenosum
Herpes simplex
Always Rule Out

Fournier gangrene
Leukemia
Consider
Spontaneous scrotal ulceration
Crohn disease
Sarcoid
Behet disease
Bullous pemphigoid
Necrobiosis lipoidica
Hypereosinophilic syndrome
Gonorrhea
Tuberculosis and tuberculids
Leprosy
Yaws
Nonsyphilitic spirochetal ulcerative balanoposthitis
Herpes simplex (e.g., in HIV)
HIV giant aphthae
Deep fungal infections
Histoplasmosis
Blastomycosis
Cryptococcosis
Actinomycosis
Leishmaniasis
Amebiasis
Filariasis
Porokeratosis
Drug reaction
Always Rule Out

Embolization
Penile necrosis
Necrotizing vasculitis
Granulomatosis with
polyangiitis (Wegener)
Systemic lupus erythematosus
Polyarteritis nodosa
Idiopathic systemic vasculitis
Hereditary spherocytosis and
vascular necrosis
Degos malignant atrophic
papulosis
Calciphylaxis
Pseudomonas infection
Ecthyma gangrenosum
Necrotizing anorectal ulcer in
leukemia
Fournier gangrene
Sweat gland carcinoma
Kaposi sarcoma
Leukemia
Lymphoma
Always Rule Out

Amyloidosis
Amelanotic malignant melanoma
Malignant schwannoma
(continued)
MALE GENITAL FLESH-COLORED PAPULES AND MICROPAPULES

Most Likely
Consider
Scrotal calcinosis
Median raphe cyst
Lichen nitidus
Mucoid cyst
Viral warts
Tick bite/tick in situ
Secondary syphilis
Sclerosing lymphangitis
Mollusca
Lichen nitidus and lichen planus
Acrochordons (skin tags)
Mucinous syringometaplasia
Angiofibroma (pearly penile papules)
Demodicidosis
::
MALE GENITAL ULCERS

Most Likely
Trauma
Aphthae
Erythema multiforme
Ulcerative sexually transmitted disease
Chancre of primary syphilis
Chancroid
Donovanosis
Syphilis
Squamous carcinoma
Acute contact dermatitis (e.g., phytophotodermatitis)

Lichen planus
Bullous pemphigoid
Linear IgA disease
Herpes zoster
Chapter 77
PENILE NECROSIS
Most Likely
Decubitus ulcer
Spider bite
Strangulation/tourniquet syndromes
Vacuum erection device use
Priapism
Embolism
Coagulopathy
Warfarin
Consider
859
12

MALE GENITAL FLESH-COLORED PAPULES AND MICROPAPULES
Most Likely
Consider
Fordyce spots (ectopic sebaceous
glands)
Seborrheic keratosis
Epidermold cyst
Section 12
::
MALE GENITAL RED OR PIGMENTED PAPULES AND MICROPAPULES

Most Likely
Consider
Always Rule Out
Angioma/angiokeratoma
Tick bite/tick in situ
Amyloidosis
Lichen planus and nitidus
Insect bite
Angiokeratoma corporis diffu Inflamed viral wart
Granuloma annulare
sum
Secondary syphilis
Sarcoid
Carcinoma erysipeloids
Inflamed mollusca
Primary granuloma inguinale (donovanosis) Kaposi sarcoma
Melanocytic nevus
Primary lymphogranuloma venereum
Malignant melanoma
Tuberculide (lichen scrofulosorum)
Scabies
Leprosy
Xanthoma disseminatum
Venous varicosities
Early chancre of primary syphilis
Metastases
Bowenoid papulosis
Superficial phaeohyphomycosis
Schistosomiasis
Inflamed epidermoid cyst
Dermatofibroma
Nevus comedonicus
Syringoma
(Juvenile) xanthogranuloma
Pseudo-Kaposi sarcoma
MALE GENITAL PUSTULES
Most Likely
Penile acne
Candidosis
Folliculitis (e.g., occlusional)
Gonorrhea
Herpes simplex
MALE GENITAL PLAQUES
Most Likely
Lichen sclerosus
Confluent condylomata
Secondary syphilis
Bowen disease and bowenoid papulosis
MALE GENITAL LYMPHEDEMA

Most Likely
Idiopathic penile edema
Postinfectious
Cellulitis and erysipelas
Chancroid
Granuloma inguinale
Syphilis
860
Always Rule Out
Syringoma
Leiomyoma
Genital smooth muscle hamartoma
Neurofibroma
Lymphangioma circumscriptum
Lipoid proteinosis
Consider
Herpes zoster
Steroid acne
Always Rule Out

Behet disease
Tuberculide (acne
scrofulosorum)
Consider
Halogenoderma
Granuloma inguinale
Atypical mycobacterial infection
Yaws
Leprosy
Herpes simplex (e.g., in HIV infection/
immune restoration disease)
Candidosis
Deep mycoses (e.g., blastocytosis)
Epidermal nevus
Verruciform xanthoma
Always Rule Out

Secondary syphilis
Squamous carcinoma
BuschkeLowenstein tumor
Xanthoma disseminatum
Consider
Always Rule Out
Idiopathic congenital lymphedema (Milroy

disease)
Lipogranuloma and silicone granuloma
Iatrogenic
Radical abdominopelvic surgery
Radiotherapy
Granulomatous lymphangitis
Tuberculosis
Leprosy
Filariasis/onchocerciasis
Strangulation of the penis

Carcinomatosis
Lymphatic involvement
Lymphatic blockage
Lymphoma
Fournier gangrene

MALE GENITAL CYSTS OR NODULES
Most Likely
Median raphe cysts
Scrotal calcinosis
Sclerosing lymphangitis
Crohn disease
Scabies
Epidermoid cyst
Pilar cyst
Idiopathic congenital lymphedema

Giant hemangioma
Urethral diverticulum
Segmental urethral hypospadias
Accessory scrotum
Herniation of scrotal contents into penile
shaft
Foreign body
Lipogranuloma/silicone granuloma
Scrotal fat necrosis
HenochSchnlein purpura
Familial Mediterranean fever
Acute hemorrhagic edema of childhood
Granulomatous lymphangitis
Sarcoid
Infected cyst
Tuberculosis
Giant scrotal tumor (e.g., neurilemoma)
Epithelioid hemangioma
Epithelioid hemangioendothelioma
Drugs (e.g., angioedema due to lisinopril)
Consider
::
Paraphimosis
Foreign body
Strangulation of the penis
Iatrogenic
Continuous ambulatory peritoneal
dialysis
Raised right heart filling pressure in
intensive therapy unit
Postsurgery
Postradiotherapy
Varicocele
Hydrocele
Priapism
Peyronie disease
Epididymitis and orchitis
Cellulitis
Idiopathic penile edema
Testicular tumors
Chapter 77
PENOSCROTAL SWELLING
Most Likely
Consider
Always Rule Out
Segmental urethral hypospadias
BuschkeLowenstein tumor/
Urethral/mucoid cysts
giant condyloma
Hernias and herniation
Extramucosal anorectal carci Foreign body
noma
Lipogranuloma
Malignant melanoma
Keloid
Merkel cell carcinoma
Scrotal fat necrosis
Malignant eccrine poroma
Sarcoid
Sarcoma
Amyloid
Malignant schwannoma
Granuloma inguinale
Kaposi sarcoma
Penile acne
Chronic lymphocytic leukemia
Bacillary angiomatosis
Leprosy
Metastases
Histoplasmosis
Schistosomiasis
Onchocerciasis
Benign appendageal tumors
Myxoma
Dermoid cyst
Granular cell tumor
Giant cell fibroblastoma
Connective tissue nevus
Fibrous hamartoma of infancy
Leiomyoma
Neurofibroma
Hemangioma
Masson tumor (intravascular papillary endothelial hyperplasia)
Epithelioid hemangioma
Angiolymphoid hyperplasia with eosinophilia/Kimura disease
Solitary reticulohistiocytic granuloma
Penile horn
Keratoacanthoma
12
Always Rule Out

Aortic aneurysm
Abscess of corpus cavernosum
Kaposi sarcoma
Lymphoma
Sarcoma
Fournier gangrene
861
12
abnormality may increase the vulnerability of the area

to dermatoses (such as LSc) and infections.
Common abnormalities include meatal pit, hypospadias, median raphe cysts, canals and sinuses, and
ambiguous genitalia. Rarer anomalies include hypospadias variants, meatal stricture, mucoid or urethral
cysts, dermoid cysts, buried penis, urethral atresia,
penoscrotal transposition, congenital lymphedema,
giant preputial sac, megaprepuce, accessory scrotum,
hemangiomas, strawberry nevus, os penis, and true
aposthia. These entities may be features of congenital
syndromes.3
Section 12
SEXUALLY TRANSMITTED
DISEASES
VENEREAL DISEASES
::
The clinical manifestations on the male genitals of

syphilis, chancroid, lymphogranuloma venereum,
granuloma inguinale, gonorrhea, and other venereal
diseases as well as their pathogenesis, diagnosis, treatment, and complications are discussed in depth in
Chapters 200, 202205). Here it may suffice to remind
the physician that any inflammatory, papulonodular,
or ulcerative genital presentation requires consideration and exclusion of sexually transmitted diseases.
PEDICULOSIS
Figure 77-4 Viral warts. Condyloma acuminata. ( Medical

Illustration UK.)
grounds (Figs. 77-4 and 77-5). Morphology is described
in Chapter 196. Clinically inapparent penile warts may
present as balanoposthitis.6264
DIFFERENTIAL DIAGNOSIS. Disorders from

which viral warts must be differentiated are listed in
Box 77-3.
COMPLICATIONS. HPV infection is a risk factor
for anogenital cancer, particularly of the cervix and
anus. HPV is associated with the clinical expressions
of penile carcinoma in situ (PCIS), or Bowen disease of
the penis, erythroplasia of Queyrat (EQ), or bowenoid
papulosis (BP) and approximately 50% of cases of
(See Chapter 208)

Pediculosis pubis, or lice infestation (crabs), can
cause severe genital itching with few physical signs
unless the hairs are examined assiduously for nits and
the base of individual hairs is scrutinized with a hand
lens for the crab lice (12 mm), which will be tightly
adherent to the skin because their mouth parts are
embedded in perifollicular blood vessels. Sometimes
grayblue macules (tache bleu, maculae caeruleae) are
seen on the affected sites.
SCABIES
(See Chapter 208)
Scabies is a cause of intense itching that characteristically keeps patients awake at night. Usually there is a
rash of diagnostic distribution and morphology. Some
patients with scabieswho may have been infested for
a long time, have had it before, have been inadequately
treated, or have been adequately treated but develop
secondary eczema or nodulesmay have itch in the
anogenital region only.
VIRAL WARTS
(See Chapter 196)
862
CLINICAL FINDINGS.
Genital HPV infection

can usually be diagnosed with certainty on clinical
Figure 77-5 Viral warts. Confluent plaque. No histologic

dysplasia. Patient with diabetes. ( Medical Illustration
UK.)

of Viral Warts
Box 77-4 Treatment for

Genital Warts
Most Likely
Pearly penile papules
Seborrheic keratoses
Nevi
Mollusca
Cryotherapy
Always Rule Out

Condylomata lata (secondary syphilis)
Squamous carcinoma (and variants)
Chapter 77
Consider
Lichen planus
Lichen nitidus
Bowenoid papulosis
Surgical/scissor excision
Electrocautery/electrotherapy
Loop electrosurgery
Laser surgery
Interferons
Intralesional
Systemic
Topical
Podophyllin/podophyllotoxin
Trichloroacetic acid
5-Fluorouracil
Imiquimod
12
::
TREATMENT.
Patients presenting with warts, as

well as their sexual partners, should be counseled and
screened for HPV, other sexually transmitted diseases
including HIV infection, and cervical neoplasia.
HPV infection may be very difficult to treat. Subclinical infection is very common, difficult to detect, and
virtually untreatable, so there is divergence between
ambitions for treatment and achievability. The principles of management are based on diagnosing and
treating relevant lesions that are causing personal genital morbidity or psychosexual stress or long-term risk
to the patient or his partner. Reasonable goals include
(1) inducing cure or wart-free periods, (2) relieving or
improving symptoms such as dyspareunia, (3) ensuring that side effects or complications of the treatment
are no worse than the symptoms or risks of the warts,
(4) minimizing morbidity and mortality from cervical cancer in female partners, (5) minimizing mortality and morbidity from PCIS and frank cancer in the
patient especially those with HIV.62,69,72,73
Treatments are listed in Box 77-4.3,62,69,76,77
MOLLUSCA
(See Chapter 195)
Mollusca may be sexually acquired, as in adult
men, but genital lesions caused by autoinoculation are
common in children. Classically small, flesh-colored,
monomorphic, dome-shaped papules indented by
a central dell or umbilicus are seen. Multiple lesions
are usually present. Giant and polypoidal lesions may
occur in the setting of HIV infection. Inflammation and
purulence may be due to infection but are a common

phenomenon when individual lesions spontaneously
involute. Condylomata lata (secondary syphilis) and
LP enter the differential diagnosis of mollusca, as do
simple HPV infection and BP. Treatment may not be
necessary especially in children. Options are similar to
those for viral warts.3,77
DERMATOSES WITH A
PREDILECTION FOR THE MALE
GENITALIA
VITILIGO
(See Chapter 74)
Vitiligo commonly affects the genitalia in men and
may be the only site to be affected. Perianal involvement is also common.3 Other organ-specific autoimmune diseases should be excluded. Vitiligo has been
reported after treatment of genital warts with imiquimod.78,79 An important rare differential diagnosis is
depigmented extramammary Paget disease (EMPD).80
Phototherapy of vitiligo might lead to squamous cell
carcinoma (SCC).81
squamous carcinoma of the penis.65,66 Infection with

HIV may alter and worsen the expression and consequences of anogenital HPV infection: high-grade
dysplasia associated with high-risk HPV types have
been found in the urothelium and genital warts from
HIV-positive individuals and the penis cancer risk is
increased three- to sixfold (the anal cancer risk may be
increased by as much as 100).3,6775
SEBORRHEIC DERMATITIS
(See Chapter 22)
A diagnosis of seborrheic dermatitis is made when
a nonspecific psoriasiform or eczematous balanitis or
balanoposthitis is found in conjunction with classic
symptoms and extragenital manifestations of the diathesis.3
No treatment other than reassurance may be
required. However, treatments that diminish the commensal pityrosporum load and reduce irritation and
eczematization can be very successfully and safely
used long term. These include topical antifungals
(such as clioquinol, nystatin, and imidazoles) in the
863
12
Section 12
::
864
Figure 77-6 Psoriasis. Circumcised glans penis. ( Medical

Illustration UK.)
form of ointments, creams, lotions, or shampoos and
mixtures of the same agents with mild and moderately
potent topical corticosteroids used alongside emollients and soap substitutes. In severe cases, such as
with concomitant seborrheic folliculitis or in acquired
immunodeficiency syndrome (AIDS), treatment with
an oral imidazole might be indicated.
Figure 77-7 Psoriasis. Uncircumcised glans penis and

prepuce. ( Medical Illustration UK.)
Usually the diagnosis of psoriasis is clinical. Soreness
might indicate superinfection, especially with Candida.
Inordinate itch would make one suspect another dermatosis such as an eczematized dermatitis or tinea. A biopsy
PSORIASIS
(See Chapter 18)
Psoriasis is probably the most common dermatosis
of the male anogenitalia, either in isolation or in association with frank or mild, subtle extragenital disease.3
The Koebner phenomenon is a likely factor in site predilection. Drugs such as lithium, blockers, antimalarials, and angiotensin-converting enzyme inhibitors may
be responsible for the onset or exacerbation of psoriasis.
In circumcised men, genital psoriasis presents with
variably itchy, silvery-scaled, erythematous patches or
plaques (Fig. 77-6). On the glans or in the preputial sac
of the uncircumcised patient, scale is absent from the
patches or plaques because of the mucosal site (Fig.
77-7). The scalp, ears, umbilicus, and face (in sebopsoriasis) may be involved, and there may be variable
additional anogenital involvement, especially of the
sacrum, buttocks, intergluteal cleft, pubic mound and
groin, perianal skin, and, less commonly, the scrotum.
Psoriatic balanoposthitis can be part of the spectrum of
inverse-pattern psoriasis and may be associated with
intertriginous disease of the axillae, intergluteal cleft,
gluteal folds, and groin.
Patients with the reactive arthritis syndrome (see
Chapter 20) may sometimes have involvement of the
penis with circinate balanitis or small, flat pustules.
These penile lesions have the same histopathology and
ultrastructure as psoriasis. Sometimes this morphology is seen clinically with no background urethritis,
gastroenteritis, or arthritis (Fig. 77-8).
Figure 77-8 Circinate balanitis. HLA-B27 positive. No background urethritis, gastroenteritis, or arthritis. ( Medical
Illustration UK.)
Figure 77-9 Lichen planus. Annular plaque. Circumcised

glans penis. Coronal rim. (From Bunker CB: Male Genital Dermatology. London, Saunders, 2004. Medical Illustration
UK.)
Just as extragenital disease, for example, on the

palms and soles, may be erosive in rare cases, occasionally an erosive form of genital disease is encountered
(Fig. 77-10). A male equivalent of the vulvovaginal
syndrome of Hewitt with chronic erosive gingival and
genital lesions (genito-gingival syndrome) has been
described.82 Bullous penile LP has also been reported.83
Although LP is self-limiting, some patients experience relapses and remissions. Adhesions can form.
Postinflammatory hyperpigmentation can persist for
months or years.
Chronic mucosal erosive LP is associated with a risk
of SCC, although most reports linking the two concern
oral LP. SCC may complicate chronic hypertrophic LP
of the lower leg but has also occurred in the context of
hypertrophic LP of the glans penis.3,84,85
A biopsy is frequently necessary for diagnostic purposes but, more importantly, is performed in following
up the rare cases of chronic anogenital disease in which
the appearance of ulcero-erosive or verrucous features
leads to concern about the development of SCC. The
classic histologic findings are discussed in Chapter 114.
Potent or very potent topical corticosteroids usually produce remission. Patients should be warned
about postinflammatory hyperpigmentation. Systemic
corticosteroids are sometimes indicated for severely
symptomatic disease, erosive orogenital involvement,
and scarring of the scalp and nails. Topical and systemic cyclosporin has been used. Circumcision may be
necessary if there is phimosis and should be seriously
considered in cases of refractory disease, especially the
erosive form, because the removal of koebnerizing
influences may allow the LP to remit. The toxicity and
the lack of efficacy of systemic therapy in treating this
distressingly symptomatic situation are other powerful arguments in favor of circumcision.3,86
(See Chapter 26)

LP has a particular predilection for the mucosa, which
is perhaps partly explained by the Koebner phenomenon. LP can present in, and remain focalized to, the pelvic girdle, the genital area including the groin, and the
perianal skin. Alternatively, symptoms and morphology
of the classic diseaselilac papules and plaques with
white lacy scalemay be present at other sites (Fig.
77-9). However, it may affect the penis (like the mouth,
vulva, and anus) in isolation as the cause or consequence
of foreskin dysfunction (by koebnerization) and so
present as dyspareunia and a nonspecific dermatosis.3
The differential diagnosis includes eczema, psoriasis,
seborrheic dermatitis, nonspecific balanoposthitis, ZB,
LSc, drug eruption, porokeratosis, viral warts, penile
precancer, and frank SCC. LP can cause phimosis; the
differential diagnosis of phimosis is given in Table 77-2.
Figure 77-10 Lichen planus. Erosions on glans penis and

prepuce. Severe dyspareunia. ( Medical Illustration UK.)
::
LICHEN PLANUS
12
Chapter 77
may be necessary if there are solitary mucosal lesions in

the uncircumcised to exclude Zoon balanitis (ZB), LP, EQ,
and Kaposi sarcoma. Bowen disease and EMPD may be
misdiagnosed as psoriasis when there are single or several foci on the penile shaft and/or in the groin.
Topical treatment is based on the use of emollients,
soap substitutes, corticosteroids combined with antibiotic and antifungal agents, or weak tar solutions.
Atrophy is a risk with long-term use of potent topical
steroids, and anogenital skin has a heightened tendency
to absorb topical agents. Strong crude tar preparations
should also therefore be avoided at this site because
of the risk of genital cancer. Dithranol application may
lead to burning and so is usually avoided in this region.
Vitamin D analogues and calcineurin inhibitors seem
safe, but with the latter, the prescriber must be certain
of the absence of PCIS. Severe anogenital inverse psoriasis can be an indication for systemic treatment. Phototherapy is conventionally contraindicated because of
the risk of anogenital cancer. It is possible that chronic
anogenital psoriasis and its treatment may create a risk
for anogenital squamous cancer.
LICHEN NITIDUS
(See Chapter 27)
865
12
Lichen nitidus is sometimes held simplistically and

controversially to be a micropapular variant of LP. It
has an affinity for the penis and can be difficult to diagnose because the signs may be subtle, even when the
lesions are widespread. Also, when the lesions are very
pruritic, the signs due to excoriation and eczematization may eclipse those due to the lichen nitidus.3
GRANULOMA ANNULARE
Section 12
(See Chapter 44)

Erythematous smooth, ovoid nodules of granuloma
affecting the penis have been described. They are perhaps related to trauma and koebnerization, because
circumcision can be curative.87
NECROLYTIC MIGRATORY ERYTHEMA
::
Necrolytic migratory erythema can be focalized to the

male genitalia as a sore or painful annular erythematous eruption with a central glassy appearance and
serpiginous border surrounded by scaling. It is a characteristic cutaneous manifestation of the glucagonoma
syndrome (see Chapter 153).88
APHTHAE
The diagnosis of aphthous ulceration of the genitalia
requires the exclusion of sexually transmitted diseases
and other causes of genital ulceration, especially Behet
disease. This is in contradistinction to oral ulceration, in
which a clinical diagnosis is acceptable practice.3 The
causes of aphthae are obscure. The histologic findings of
idiopathic aphthous ulceration are nonspecific. Aphthae
and idiopathic orogenital ulceration are more common
and are worse, symptomatically and morphologically, in
HIV-infected individuals. In patients with AIDS, biopsy
must be performed on all mucocutaneous ulcers and
specimens must be cultured; several pathologies may
coexist. Treatment of simple aphthae is with topical
corticosteroid/antibiotic/anticandidal combinations. In
patients with AIDS, thalidomide may be efficacious.
BEHET DISEASE
866
(See Chapter 166)

The genital ulcers in men are painful, sometimes very
painful, and this distinction may be helpful. They occur
anywhere on the anogenitalia, including the scrotum
and perianal skin. They are said to be bigger, deeper,
fewer, and less recurrent than those in the mouth.
To diagnose Behet disease according to strict diagnostic criteria, oral ulceration must be present; then
patients must also either manifest genital ulceration
and ophthalmic involvement or genital ulceration and
skin signs (or a positive pathergy test result). In practice, there are many patients who have an incomplete
syndrome. Although their disease does not satisfy
these rigid diagnostic criteria, possible or probable Behet disease is an acceptable label for everyday
practical purposes. Essentially, Behet disease is a systemic vasculitis that may involve many organs, so that
protean presentations and complications are possible.
Patients with relapsing polychondritis (see Chapter
159) and Behet disease have been reported, and the
term MAGIC (mouth and genital ulcers with inflamed
cartilage) syndrome applied.89,90 Histologic findings are
usually nonspecific and do not distinguish idiopathic
aphthae, although sometimes necrotizing vasculitis can
be seen. Topical treatment with corticosteroid/antimicrobial combinations may suffice. Topical interferon
lozenges have been advocated.91 However, some
patients will require systemic treatment with colchicine,
prednisolone, azathioprine, cyclosporin, thalidomide,
infliximab, or etanercept.3,92,93 (See Chapter 166).
MUCOUS MEMBRANE PEMPHIGOID

(See Chapter 57)
Mucous membrane (cicatricial) pemphigoid is a rare
disease that must be in the differential diagnosis of blistering, erosions, ulcers, transcoronal adhesions, scarring, and phimosis.3,94 These manifestations can occur
in isolation, but ophthalmic, oropharyngeal, and cutaneous lesions are more common than genital involvement. Direct immunofluorescence usually yields
positive results, but indirect immunofluorescence does
not. Topical and oral steroids may be ineffective. Dapsone, sulphamethoxypyridazine, mycophenolate, and
biological therapies may be used.
PYODERMA GANGRENOSUM
(See Chapter 33)
Pyoderma gangrenosum is a rare event but is frequently misdiagnosed or diagnosed late while infections and cancer are pursued diagnostically (Fig. 77-11).
It may represent a pathergic reaction after urologic
surgery or complicate inflammatory bowel disease or
leukemia. Treatment must be aggressive to avoid permanent damage to the urethra and erectile tissues.3
DRUG ERUPTIONS
(See Chapter 41)
The penis is a classic site of predilection for fixed
drug eruptions.3 Clinically, fixed drug eruption is characterized by the acute eruption of itchy, painful, swollen plaques, sometimes with central blister formation,
erosion, and ulceration. Postinflammatory hyperpigmentation can be persistent. On first exposure to the
drug the eruption can take 12 weeks to appear but
subsequently appears just a few hours after administration. Recurrence is at the same site(s) each time the
drug is encountered, and rechallenge/provocation can
be used as a diagnostic test. For causes, see Chapter 41.
Ulceration due to papaverine can occur when the
drug is inadvertently injected subcutaneously for the
treatment of erectile impotence.95 Heparin and warfarin have induced skin necrosis of the genitalia.3 Alltrans retinoic acid has been reported to induce genital
Painful, grouped, crusting, vesicopustular lesions may

be found unilaterally on the buttock, in the perineum,
on the scrotum and penis, in the groin, and on the
upper thigh. Hospitalization, urologic assessment,
observation, possibly catheterization and sigmoidoscopy, and possibly assisted fecal extraction are indicated. Treatment should be with intravenous acyclovir.
12
TINEA
Chapter 77
(See Chapter 188)

Tinea of the penis or scrotum is not common, and
when it occurs it is usually associated with crural disease. Rarely encountered is tinea that occurs on the
glans penis as a seat of itch or pain and produces an
erythematous patch or a crop of scaly papules.3 In
India, it is associated with penile lesions due to the
wearing of a langota, an occlusive T-shaped loincloth.99
::
Figure 77-11 Pyoderma gangrenosum. Most of the

shaft of the penis, but not the glans, has been destroyed.
( Medical Illustration UK.)
ulceration in patients with hematologic malignancy.96
Foscarnet can create genital ulceration in HIV-infected
patients due to the high urinary concentrations of the
drug.97 Nicorandil is a newly-appreciated cause of anogenital and peristomal ulceration.
Lisinopril has been associated with genital angioedema.98 The cutaneous side effects of topical steroids
are well known: striae, atrophy, erythema, telangiectasia, erosion, and modification of cutaneous, bacterial,
viral, and fungal infections occur commonly. Drugs
can also cause pruritus and urticaria.
STREPTOCOCCAL DERMATITIS
(See Chapter 176)
Streptococcal dermatitis causing a perianal cellulitis
is a recognized syndrome in children, but a similar clinical situation occasionally occurs in adults and might
affect the genitalia alone.3 It is much more common in
boys, and if the penis is involved, there may be dysuria, erythema, swelling, and balanoposthitis. Group
A -hemolytic streptococci can be isolated, and the
lesions may be associated with streptococcal infection
of the upper respiratory tract in other members of the
family. Treatment is generally with systemic penicillin.
HERPES ZOSTER (SHINGLES)

(See Chapter 194)
Sacral herpes zoster is relatively rare but can be associated with severe morbidity due to nocturia, dysuria,
acute urinary retention, constipation, and fecal retention.3 When the pain precedes the rash, the differential
diagnosis of an acute surgical emergency is evoked.
(See Chapter 207)

Perineal granulomatous lesions are a rare manifestation of schistosomiasis (infection with Schistosoma
haematobium).3,100 Rarely genital skin lesions may lead
to the diagnosis. They occur because of ova shed by
worms that have entered the perineal vessels from the
pelvic venous plexuses. Papules and nodules may be
itchy; may be skin-colored, pink, or brown; may be
scattered or grouped; and may affect the penis and
scrotum. They can spread onto the perineum and
around the anus and may develop into soft, warty,
vegetating lesions but remain relatively asymptomatic.
Ulceration is rare and carcinoma even rarer. Diagnosis
is by biopsy (see Chapter 207). Ova may be recovered
from urine or stool.
SCHISTOSOMIASIS
ONCHOCERCIASIS
(See Chapter 207)
The dermatologic genital consequences of onchocerciasis are pruritus, leopard skin hypopigmentation
(on shins and scrotum), nodules (on ileal crests, scrotum, and ribcage), dermatitis, including lizard skin
lichenification, hanging groin, and scrotal enlargement.3 The differential diagnosis of the scrotal enlargement includes bancroftian filariasis. The diagnosis is
made by demonstrating microfilariae in skin snips.
POROKERATOSIS
Genital porokeratosis of Mibelli (see Chapter 52) is
rare.3,101 Annular raised (double-rimmed) lesions have
been found in the intergluteal cleft, on the scrotum, and
on the penis, including the glans. Rarely lesions may be
ulcerative. Porokeratosis may be misdiagnosed clinically as psoriasis, Bowen disease, granuloma annulare,
or LP but histologic examination of the margin shows
the characteristic cornoid lamella. Cryotherapy and
topical 5-fluorouracil can be used for treatment.
867
12
KAPOSI SARCOMA
Section 12
(See Chapter 128)

Solitary Kaposi sarcoma of the penis was recognized, if rarely, before the HIV epidemic, and cases are
still occasionally seen in HIV-negative patients.3 AIDSrelated Kaposi sarcoma is usually multicentric and
often involves the face, oral mucosa, palate, and penis
(20%). A solitary lesion is not unusual. It can present as
a dull red patch or plaque on the glans penis or in the
preputial sac and can also affect the penile shaft, scrotum, and perianal skin in one of its more classic manifestationsnamely, purple, slightly scaly patches or
plaques, nodules, and ulcerative lesions. An engorged,
hypervascular presentation has been described, as
has penile lymphedema, acute phimosis, and rectourethral fistulation. Odd morphology should arouse suspicions of mixed pathology.
::
LYMPHOMA, LEUKEMIA, METASTASES

Ulceration of the penis in chronic lymphocytic leukemia and scrotal ulceration in acute myelogenous
leukemia due to leukemic infiltration have been
reported.3 Pyoderma gangrenosum, Pseudomonas
infection, and Fournier gangrene can be associated
with hematologic malignancy. Although the groin is
a classic site of involvement in Langerhans cell histiocytosis (see Chapter 147), involvement of the penis is
very rare. Metastases to the penis and scrotum occur
uncommonly.102 They are usually secondary to cancer
of the urogenital tract or gastrointestinal system (e.g.,
rectum) or complicate other common cancers such as
those of the lung. They may present with pain, swelling, priapism, urinary symptoms, or hematuria. A
cutaneous nodule or nodules may be seen or infiltration of the deeper penile structures palpated.
PRIMARY MALE GENITAL

DERMATOSES
PENILE MELANOSIS AND
LENTIGINOSIS
868
Several terms have been coined to describe benign pigmented macules of the penis such as penile melanosis, penile melanotic macules, and atypical pigmented
penile macules: penile melanosis, vulvovaginal melanosis, and the predominantly oral mucosal hyperpigmentation of LaugierHunziker syndrome (see Chapter
75) may be grouped under the umbrella of essential
melanotic hyperpigmentation of the mucosa.3,103 Some
if not all cases may represent postinflammatory hyperpigmentation from previous disease or insult [e.g.,
phimosis, balanoposthitis, topical treatment, LSc (Fig.
77-12), LP, circumcision]. It has been suggested that
adjacent depigmentation is an essential element of the
condition.104 Although penile melanosis is a good term for
lesions without lentiginous hyperplasia on histologic
examination, there may be increased basal epidermal
Figure 77-12 Penile melanosis. Glans penis. Postlichen

sclerosus. ( Medical Illustration UK.)
pigmentation with or without benign lentiginous melanocytic hyperplasia, including ultrastructurally. The
possibility of Addison or Nelson syndrome should be
entertained, as should the possibility of a lentiginosis
syndrome [PeutzJeghers, LAMB (lentigines, atrial myxoma, blue nevi), LEOPARD (multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism,
pulmonary stenosis, abnormalities of the genitalia,
growth retardation, deafness), or BannayanRileyRuvalcaba syndrome (see Chapter 75)], although idiopathic
lentigines of the penis are recognized.
If lesions are large or enlarging, with irregular edges
and multifocal and variegated pigmentary patterns,
concern may be raised about atypical melanocytic proliferation and acral lentiginous melanoma.
Despite being benign, penile melanosis can be cosmetically disturbing. Laser treatment may be helpful.
ZOON BALANITIS
ZOON BALANITIS AT A GLANCE
Zoon plasma cell balanitis (ZB; properly
balanoposthitis) affects the middle-aged and
older uncircumcised male.
ZB is a chronic, reactive, irritant mucositis.
ZB is characterized by silent
symptomatology and florid signs.
Zoonoid inflammation is a common
corollary of other dermatoses that cause
a dysfunctional prepuce. Asymmetric,
atypical, or unusual morphology should be
viewed with suspicion.
Circumcision is the definitive treatment in
the majority of cases.
ETIOLOGY AND PATHOGENESIS. The evidence

indicates that ZB is a chronic, reactive, principally
12
Chapter 77
::
irritant mucositis that causes, or is due to, a dysfunctional foreskin.3,51 Irritation is induced by retention of
urine and squames between two tightly apposed and
infrequently and inadequately separated and/or infrequently or inappropriately bathed, commensally hypercolonized, desquamative, secretory epithelial surfaces.
CLINICAL FINDINGS. An asymptomatic presentation with little or no dyspareunia is classic. Conversely,

the signs can be florid. Well-demarcated, glistening,
moist, shiny, bright red, or autumn brown patches
symmetrically involve the glans and inner prepuce,
sparing the keratinized penile shaft or foreskin (Fig.
77-13). Other signs include dark red stippling or cayenne pepper spots due to hemosiderin deposition and
solitary or multiple lesions of differing sizes (guttate
or nummular), characteristically kissing. Rarely, erosive and vegetative presentations have been reported,
but lesions with asymmetric, atypical, or unusual
morphology should be viewed with great suspicion
and the organ inspected diligently for other, less florid
signs. ZB may be secondary and may thus conceal
more subtle evidence of underlying preputial disease
such as LSc, precancer, or frank cancer that might have
induced the manifest zoonoid changes. Overt cases of
other dermatoses such as contact dermatitis, psoriasis,
LSc, LP, penis precancer, and penile cancer may appear
to have zoonoid changes on clinical and histologic
examination (Fig. 77-14). It is possible that some of the
clinical and histologic variants that have been reported
and the dubious claim that ZB per se is a premalignant
condition are a consequence of this phenomenon.105
LABORATORY TESTS.
On histologic examination
the epidermis is attenuated with absence of the granular
and horny layers, sparse dyskeratosis and spongiosis,
and diamond- or lozenge-shaped basal cell keratino-
Figure 77-14 Zoonoid inflammation. Florid zoonoid balanoposthitis complicating lichen sclerosus. ( Medical Illustration UK.)
cytes. In the dermis there are variably seen a band of
plasma cells infiltration, extravasated erythrocytes,
hemosiderin, fibrosis, and vascular proliferation.106

which ZB must be differentiated are listed in Box 77-5.
TREATMENT. Although the condition may be ameliorated by improvement in washing habits and micturition
Figure 77-13 Zoon balanitis. Symmetric red patches.

Glans penis and prepuce. ( Medical Illustration UK.)

of Zoon Balanitis
Most Likely
Psoriasis
Lichen sclerosus
Consider
Contact dermatitis
Erosive lichen planus
Viral warts
Herpes simplex
Fixed drug eruption
Always Rule Out
Kaposi sarcoma
869
12
practices and by the intermittent application of mild or

potent topical corticosteroids (with or without antibiotics and anticandidals) and topical tacrolimus, ZB usually
persists or relapses. Definitive curative treatment is surgical circumcision.3,107,108
LICHEN SCLEROSUS
Male genital lichen sclerosus (LSc) is an
idiopathic inflammatory fibrosing dermatosis.
Section 12
It is principally a disease of uncircumcised

men, although it can persist or recur after
circumcision.
::
LSc can be the cause of significant morbidity

expressed as preputial dysfunction and male
dyspareunia.
Between one-fourth and one-half of cases of
squamous cell carcinoma (SCC) of the penis
may be preceded by LSc. SCC complicating
LSc carries a high mortality.
TABLE 77-3
Symptoms and Signs of Male Genital

Lichen Sclerosus
Asymptomatic
Spontaneous
Itching, burning, soreness, pain, adhesions,
blisters, white patches, purpura, balanoposthitis, phimosis
Dyspareunia
Itching, burning, soreness, pain, bleeding, tearing, splitting,
Effacement of normal architectural features
Phimosis, narrow meatus, dissolution of frenulum, short
frenulum, broad frenulum, bunched frenulum, white
papules and patches, loss of coronal definition, adhesions,
telangiectasia, scarring, fibrotic band (waisting or
bunching), constrictive posthitis
Posthitis and balanitis xerotica
Dysuria, voiding difficulties, urinary retention
Renal failure
Cancer
LSc are summarized in Table 77-3 and partially illustrated in Figs. 77-15 and 77-16. The principal presentation in men is of dyspareunia. The classic genital
morphologic manifestations of LSc are of atrophic
white patches or plaques or lilac, slightly scaly patches
with telangiectasia and sparse purpura, like those of
(See Chapter 65)
EPIDEMIOLOGY. Genital LSc is more common

than extragenital disease, but there may very occasionally be involvement in both areas. In adults, anogenital LSc is said to be about ten times more common in
women than in men. Perianal disease is very rarely, if
ever, encountered in the male. LSc may be much more
frequent than is generally supposed in young boys.
In boys, persistent primary phimosis or the secondary development of phimosis in a previously retractable foreskin should be viewed with suspicion: some,
many, or most of such cases will be due to LSc.3,51,107,109
ETIOLOGY AND PATHOGENESIS. The pathogenesis of LSc, particularly the role of autoimmunity,
is discussed in Chapter 65. Antiextracellular matrix
protein 1 antibodies have been found in the sera of
male and female patients with genital LSc.110,111 In male
genital LSc, roles seem likely for trauma (as suggested
by cases in which the development of LSc was related
to injury or surgery112) and contact with urine (as suggested by the association of genital LSc with anatomic
abnormality, particularly hypospadias,113 and the striking differences in the pattern of distribution between
the sexes) but not for infection (men with genital LSc
rarely if ever have sexual partners with LSc3,107). It is
likely that chronic exposure of susceptible epithelium
to urine due to a dysfunctional naviculomeatal valve
accounts for most cases in men.114
870
CLINICAL FINDINGS. LSc is discussed in detail in
Chapter 65. The symptoms and signs of male genital
Figure 77-15 Lichen sclerosus. Constrictive posthitis

and tight fibrotic band causing waisting or bunching.
12
Dorsal pit
Urethra
COMPLICATIONS.
The urological morbidity due

to urethral disease can be severe.116 The psychological consequences of sexual dysfunction for men and
their partners are frequently overlooked. SCC of the
penis is the most worrying complication of LSc: the
published risk is 2%12.5% and the latent period may
be 1030 years.3,51,117126 Involvement of the glans with
LSc is a significant risk.126 Carcinoma complicating
LSc constitutes approximately 25%50% of all cases of
penile cancer.3,107,120,127130 LSc is histologically associated with differentiated PCIS, basal epithelial atypia
and usual or verrucous (rarely pseudohyperplastic)
SCC.131

of Lichen Sclerosus
Most Likely
Lichen planus
Consider
Always Rule Out
Child sexual abuse
Squamous carcinoma
cussed in Chapter 65. The aims in male genital disease

are to minimize or abolish male sexual dysfunction (dyspareunia), urinary dysfunction, and the risk of penis
cancer.114 Avoidance of contact with soap and urine are
essential. Very potent topical steroids acheive remission in 50%60% and the majority of the remainder are
cured by circumcision.133 Topical steroids are safe but
occasionally HPV may be reactivated.134,135 Topical calcineurin inhibitors should not be used.136,137 Some men
require sophisticated urethromeatal surgery.116,125,138
NONSPECIFIC BALANOPOSTHITIS
Nonspecific balanoposthitis is viewed either as a
diagnosis of exclusion or as a descriptive term that
indicates the limitations of diagnostic acumen.3,51,107,
Sexually transmitted disease, immunosuppression,
and diabetes or an identifiable primary dermatosis
such as psoriasis, seborrheic dermatitis, ZB, LSc, LP,
warts, or carcinoma in situ must be sought. A biopsy is
essential. When patients present with symptoms and
signs of balanoposthitis, nonspecific histopathologic
features are found in approximately 10% of biopsy
specimens.139 Genitourinary physicians frequently
diagnose candidosis, but dermatologists believe that
Candida infection may complicate any inflammatory
mucocutaneous dermatosis and is found as a secondary opportunistic phenomenon rather than as a primary cause of disease.3 Phimosis may be the end stage
situation including in diabetes.140 Preputial dysfunction is the cause or consequence ofprobably all cases of
nonspecific balanoposthitis, and many patients probably have LSc as the underlying morbid state. Treatment141 can be very difficult, and the disease may fail to
respond to local hygienic measures, soap substitution,
topical steroids, and topical and systemic antibiotics.
The ultimate recourse is circumcision, which is curative in most instances. Histologic examination of the
whole prepuce may substantiate the presence of an
underlying genital dermatosis such as LSc. However,
in a significant number of patients the circumcision histologic findings will be nonspecific, even after review

which LSc must be differentiated are listed in Box 77-6.
TREATMENT. Treatment of extragenital LSc132 is dis-
::
the classic clinical manifestations of extragenital LSc,

may be seen. A constrictive lichenoid posthitis is commonly seen associated with a fibrotic preputial band
causing hourglass waisting of the penile shaft.3
Urethral involvement may be more common and
extensive than hitherto supposed.115,116
Most cases of LSc can be diagnosed clinically. If there
is clinical doubt, then a biopsy should be performed.
The histologic findings are discussed in Chapter 65.
Chapter 77
Figure 77-16 Lichen sclerosus affecting the glans penis. Etiolation (washed out appearance) is apparent. A. Apparent
partial hypospadias. B. Meatal lips parted to reveal the deep navicular fossa with dorsal pit. This naviculomeatal architecture leads to an incompetent valve and urinary dribbling postmicturation. ( Medical Illustration UK.)
871
12
Section 12
::
872
with the pathologist for early signs of LSc and even if

there had been either hard or soft signs of an underlying dermatosis such as LSc on clinical evaluation on
one or more occasions. These observations imply that
such patients have nonspecific preputial dysfunction
due to nonspecific irritation, trauma, and secondary
candidosis such that a genuine nonspecific balanoposthitis ensues, with the pace of normal preputial repair
and regeneration being exceeded by the pace of dayto-day attrition or wear and tear.3,51,107
DERMATOLOGIC NONDISEASE,
DYSESTHESIA, AND CHRONIC PAIN
SYNDROMES
Dermatologic nondisease142 should be considered
when florid symptomatology is accompanied by a paucity or complete absence of any primary dermatologic
signs.143 Patients with symptoms of itching, burning,
redness, and pain focalized to the penis or scrotum,
in some cases so severe as to prevent the patient from
sitting down, are not uncommonly encountered. The
chronic urogenital and rectal pain syndromes are
described by the terms penodynia, scrotodynia, orchialgia, prostatodynia, coccygodynia, proctalgia fugax, perineal
pain, descending perineum syndrome, and vulvodynia.144147
The red or burning scrotum syndrome has been
defined as persistent redness of the anterior half of the
scrotum that may involve the base of the penis... usually
accompanied by a persistent itching or burning sensation and hyperalgesia.148 Accompanying the erythema
there may be telangiectasia. It is a chronic condition that
is resistant to treatment and its cause is unknown.143,148
The neuroanatomy of the pelvis is complicated, and
the neuropathophysiologic basis of these syndromes
is poorly understood. They seem to share features of
neurogenic inflammation and neuropathic pain.149
Although their clinical presentations are well recognized by physicians in many specialties, these diagnoses should be arrived at after comprehensive clinical
assessment, contemplation of the differential diagnosis,
and a process of exclusion based on suitable investigations and response to treatment.150 Localized dermatographism should be sought by stroking the inside
of the thigh. Contact urticaria, irritant and contact
dermatitis, and scrotal rosacea due to topical steroid
application should be considered. Tinea and candidosis must be excluded. Intercurrent herpes simplex or
postherpetic neuralgia might mislead. Angiokeratoma
corporis diffusum and multiple sclerosis are causes of
odd sensory symptoms. Zinc deficiency and migratory necrolytic erythema could be entertained. Penile
sensitivity is reduced in diabetic patients, and this may
correlate with erectile dysfunction in some of these
men.151 The drug chart should be reviewed. Some men
with idiopathic anogenital pruritus may be found to
have lumbosacral radiculopathy if investigations such
as plain radiography, nerve conduction studies, computerized tomography, and needle electromyography
are performed, and significant improvement may be
obtained by paravertebral injections of triamcinolone
and lidocaine.152
A diagnosis of a chronic pain syndrome carries the

possibility of considerable psychological morbidity.
Dysmorphophobia, depression, and psychosis may be
present, and attempted or completed suicide is a real
risk in such patients.14
Scrotal rosacea (see Chapter 81) should be treated
with oral tetracyclines and these (e.g., doxycycline)
may be effective in the red scrotum syndrome.153
If anogenital dermatographism and/or urticaria is
suspected, oral antihistamines can be prescribed.
Prednisolone and antidepressants such as doxepin,
amitriptyline, and paroxetine can afford some relief.
Neuromodulation by sacral root stimulation might be
tried.96 However, treatment is generally problematic
and at best only empiric. Invasive and irreversible procedures should be avoided if at all possible. Multidisciplinary management is the ideal.3,107
PENILE ACNE
Penile acne is an poorly-documented entity occasionally encountered in clinical practice.3 Young men complain of penile spots or boils or blackheads and on
examination have comedones, papules, pustules, and
inflammatory nodules of the proximal penile shaft. An
important differential diagnosis of acneiform disease
presenting at any site is chloracne caused by occlusion
of the skin with machine oil. Conventional treatment
for acne is prescribed in a hierarchical manner: topical
keratolytics, antibiotics, and retinoids; oral antibiotics;
and isotretinoin (see Chapter 80).
CHRONIC IDIOPATHIC
PENILE EDEMA
Chronic idiopathic penile edema is a rare, illunderstood condition.3,154 It is the cause of significant
morbidity, sexual dysfunction, and phimosis. Patients
present with swelling and intercurrent attacks of cellulitis and lymphangitis of the penis, scrotum, and
pelvic girdle. Recurrent sexually transmitted diseases,
a chronic dermatosis, and hypoplastic lymphatics are
sometimes incriminated. The antistreptolysin-O titer
may be elevated, and a biopsy specimen may show
granulomatous lymphangitis, and Crohn disease
(Fig. 77-17) should be sought even if the patient has
no gastrointestinal symptoms. Sarcoidosis should be
excluded. Treatment has to be aggressive to prevent
intercurrent infection and further lymphatic damage
and scarring. Long-term treatment with oral antibiotics such as erythromycin, clarithromycin, clindamycin,
trimethoprim, cotrimoxazole, or ciprofloxacin is advocated. Occasionally, a short cause of oral prednisolone
is helpful. The goal should be to reduce the preputial
edema to allow circumcision.
SPONTANEOUS SCROTAL ULCERATION

Rare cases of spontaneous scrotal ulceration in young,
previously fit men have been described.155 Histologic examination showed nonspecific vasculitis and

of Fournier Gangrene
12
Most Likely
Trauma
Herpes simplex
Cellulitis
Gonococcal balanitis and edema
(See Chapter 179)

Fournier gangrene is a medical and surgical emergency.3 Patients present with systemic upset and painful erythematous swelling of the genital, perianal, or
lower abdominal skin and may be in urinary retention.
An ominous black spot may appear on the scrotum.
There is gross systemic toxicity (peculiarly, sometimes
absent in children) and no suppuration. Necrosis of
skin and deeper tissues rapidly supervenes and death
ensues (the mortality may be higher than 50%) unless
diagnosis is prompt and radical management is instituted. In its clinical picture Fournier gangrene overlaps
with necrotizing fasciitis and Meleney gangrene. Risk
factors are presented in Table 77-4.
The process probably begins with appendageal or
urethral infection, and polybacterial infection develops. Most of the organisms isolated from cases prove to
be resident urethral or lower gastrointestinal flora, and
most patients have mixed infections. What then follows is a necrotizing cellulitis, perhaps exotoxin mediated that affects skin, subcutis, fascia, and musclethe
TABLE 77-4
Risk Factors for Fournier Gangrene

Debilitation
Diabetes mellitus
Alcoholism
Anogenital infection
Chemotherapy
AIDS
Postinstrumentation
Postsurgery (urologic and colorectal)
Heroin addiction
Trauma
Unconventional sexual practices
human counterpart of the local Shwartzman phenomenon. In children, the most commonly isolated pathogens are staphylococci and streptococci. Radiologic
studies may show soft tissue gas.
Disorders from which Fournier gangrene must be
differentiated are listed in Box 77-7.
If the clinical diagnosis of Fournier gangrene is
entertained, then drastic emergency management is
required. Surgical and microbiologic expertise, often in
an intensive care setting, may be required. Radical surgical dbridement of all affected tissue is undertaken
and broad systemic antibiotic therapy initiated. If the
patient survives, then plastic surgical repair can be
performed.157 Hyperbaric oxygen treatment has been
advocated, as has high-dose systemic corticosteroid
treatment. Children can be treated with more conservative surgery, and the mortality rate is lower.158
In adults, the mortality is around 25% and is highest in disease of anorectal rather than urogenital origin, which likely reflects a less typical presentation and
longer delay in diagnosis.3
FOURNIER GANGRENE
Always Rule Out

Vascular occlusion syndromes
::
spontaneous resolution occurred. A related entity may

be idiopathic scrotal panniculitis and fat necrosis,156
because trauma, extreme cold, and Fournier gangrene
were excluded.
Chapter 77
Figure 77-17 Chronic penile edema. Crohn disease. Histologic examination showed a granulomatous lymphangitis. ( Medical Illustration UK.)
Consider
Migratory necrolytic erythema
Allergic vasculitis
Polyarteritis nodosa
Ecthyma gangrenosum
Warfarin necrosis
NONSYPHILITIC SPIROCHETAL
ULCERATIVE BALANOPOSTHITIS
Nonsyphilitic spirochetal ulcerative balanoposthitis is
recognized in the tropics and South Africa and presents
as large, serpiginous, foul-smelling ulcers in uncircumcised men, associated in some with nontender inguinal
lymphadenopathy.159 Treatment is with penicillin or
metronidazole.
SCROTAL CALCINOSIS
Scrotal calcinosis is a relatively common, benign
idiopathic disorder presenting as rock-hard smooth
white papules or nodules on the scrotum, multiple or
873
12
solitary.3 Occasionally, the lesions may become secondarily inflamed or infected after trauma. Rarely,
a lesion or lesions occur on the penis. The differential diagnosis includes epidermoid cyst. Indeed, it is
debatable whether the lesions are indeed idiopathic or
whether they arise from epidermoid cysts, eccrine duct
milia, eccrine epithelial cysts, dystrophy of the dartos
muscle, trauma, or foreign bodies (e.g., thorn or even
Onchocerca organisms). Cold, trauma, and the thinness
and specialization of scrotal skin are thought to be etiologic factors. Treatment is by surgical excision, but the
lesions recur.
Section 12
SCLEROSING LYMPHANGITIS
::
Nonvenereal sclerosing lymphangitis [there are a

confusing number of synonyms: penile venereal edema,
Mondor phlebitis, localized penile (venereal) lymphedema,
penile lymphocele] is increasingly recognized.3 Patients
present with a serpiginous mass in the coronal sulcus,
spreading sometimes onto the dorsal penis. The lesion
may appear for the first time or become tender and
enlarge after prolonged or frequent sexual intercourse.
In circumcised men the circumferential scar may be a
predisposing factor. It has not been established whether
this entity represents a posttraumatic lymphangitis or
phlebitis. The problem may resolve spontaneously or
surgical excision may be required.
True thrombophlebitis of superficial penile and
scrotal veins is analogous to Mondor phlebitis of the
chest wall. Herpes simplex virus infection, polyarteritis nodosa, and thromboangiitis obliterans may initiate
it. Penile thrombophlebitis has been seen as the initial
presentation of a paraneoplastic migratory thrombophlebitis caused by pancreatic cancer.
VERRUCIFORM XANTHOMA
Verruciform xanthoma is a rare entity that principally
involves the mouth. Genitalia are the next most frequently affected area, where it presents as a painless,
yellowbrown or red, verrucous, sessile, or papillary
plaque.3 Histologically there is hyperkeratosis, focal
parakeratosis, and irregular epidermal acanthosis.
Rete ridges are lengthened and extend into the dermis,
forming areas called dermal papillae and which enclose
capillary vessels surrounded by foam cells that are
CD68+ but S100. It is thought that the lesion results
from epidermal degeneration and that keratinocyte
lipid is taken up by dermal macrophages or fibroblasts
to form the foam cells. HPV-6 DNA has been found in
one case. SCC may arise within the lesion. Treatment is
by surgical excision.
PENILE CARCINOMA IN SITU AND

SQUAMOUS CELL CARCINOMA
AT A GLANCE
Erythroplasia of Queyrat (EQ), Bowen
disease of the penis (BDP), urethral
disease and bowenoid papulosis (BP) are
synonymous in describing clinical situations
in which histologically carcinoma in situ
(CIS) is present.
Penile carcinoma in situ (PCIS) is a better term
than penile intraepithelial neoplasia or PIN
(corresponding to cervical intraepithelial
neoplasia, vulval intraepithelial neoplasia,
and anal intraepithelial neoplasia) because
of the potential for confusion with prostatic
intraepithelial neoplasia.
and 400 cases are seen per year in the United Kingdom.161,162 It is estimated that penile SCC represents
10%20% of tumors seen in males in the developing
world, where neonatal or infantile circumcision is not
part of the culture.163 However, in developed countries
such as Japan and Denmark where circumcision is not
routinely practiced, penile cancer incidence is falling
and is approximating that in the United Kingdom and
United States.164,165 The epidemiology of PCIS is not
well established; it is probably underdiagnosed and
underreported.161,166
ETIOLOGY AND PATHOGENESIS. (See Chapters 114). The precise causes of the different types of
PCIS and SCC of the penis are unknown. Acknowledged risk factors for SCC are presented in Table 77-5.
HPV (high-risk and mixed infections), LSc, and
immunoincompetency are the most important considerations.65,66,74,75,107,129,130,167169
CLINICAL FINDINGS. EQ manifests as bright red,
shiny patches, or plaques of the mucosal sites, the
glans, and prepuce of the uncircumcised (Fig. 77-18
PENILE CARCINOMA IN SITU

AND SQUAMOUS CELL CARCINOMA
874
EPIDEMIOLOGY. SCC of the penis accounts for

0.3%0.6% of cases and less than 1% of cancer deaths
in the United States.3,51,65,107,160 One hundred deaths
Figure 77-18 Erythroplasia of Queyrat. ( Medical Illustration UK.)
12
TABLE 77-5
Risk Factors for Penile Cancer
DIFFERENTIAL DIAGNOSIS (Box 77-8).
biopsy is indicated in most instances.
Figure 77-19 Bowen disease. ( Medical Illustration UK.)
(Fig. 77-20). BP is pigmented in keratinized sites, and

lesions are multiple and more inflamed in mucosal
sites; lesions are more polymorphic, more coalescent,
less papillomatous, and smoother topped than common
genital viral warts. BP is seen in younger, sexually active
men. Pseudoepitheliomatous micaceous and keratotic
balanitis is probably not a separate entity but a clinical
variant of PCIS, probably associated with LSc and conferring a risk of development of invasive SCC.3,65
In SCC irregular nodular and ulcerative morphology is encountered (Fig. 77-21). Clinically, there may
be evident background PCIS and/or LSc (or even LP).
Inguinal lymphadenopathy may be present, although
in penile cancer only 50% of enlarged glands will be
found to contain tumor. Verrucous carcinoma, warty
carcinoma, BuschkeLowenstein tumor (BLT), and
giant condyloma may be dramatic clinical lesions,
often polypoid or cauliflower-like. Although locally
deeply invasive, they are well demarcated from surrounding tissue. These terms are often used synonymously to describe rare, low-grade, well-differentiated
squamous carcinomas.170177 The potential for aggressive behavior, mortality risk, and clinical, histologic,
and virologic differences may distinguish them. Giant
condyloma and BLT are thought likely to have their
origin from common genital warts. BLT has also been
associated with LSc.178
::
and eFig. 77-18.1 in online edition). Bowen disease of

the penis (BDP) is characterized by red, scaly patches
and plaques of the keratinized penis (Fig. 77-19 and
eFig. 77-19.1 in online edition). Both affect the older
male. BP presents as multiple warty lesions rather
than as erythematous patches or red, scaly plaques
Figure 77-20 Bowenoid papulosis. Red papules, distal

penile shaft. ( Medical Illustration UK.)
Chapter 77
Uncircumcised state
Phimosis
Poor hygiene
Chronic irritation and inflammation
Scarring
Smoking
Alcohol
Lichen sclerosus
Lichen planus
Bowen disease of the penis
Bowenoid papulosis
Warts and Human papillomavirus infection
Other sexually transmitted diseases
Age of first sex
Multiple sexual partners
Oral sex
Never having used a condom
Human immunodeficiency virus infection
?Psoriasis
Photochemotherapy
Iatrogenic immunosuppression
Figure 77-21 Squamous carcinoma. HIV-positive patient.

875
12

of Penile Carcinoma In Situ and
Squamous Cell Carcinoma
BOWEN DISEASE OF THE PENIS/ERYTHROPLASIA
OF QUEYRAT
Most Likely
Psoriasis
Zoon balanitis
Nonspecific bowenoid papulosis
Lichen sclerosus
::
Always Rule Out

Section 12
Consider
Kaposi sarcoma
BOWENOID PAPULOSIS
Most Likely
Viral warts
Lichen planus
Consider
Mollusca
Nevi
Always Rule Out
Condylomata lata
SQUAMOUS CELL CARCINOMA
Most Likely
Ulcerative sexually transmitted disease
Lichen sclerosus
Consider
Artifact
Behet disease
Always Rule Out
Fournier gangrene
876
HISTOLOGY. The histopathology of mucosal PCIS is

generally that of a bowenoid pattern of dysplasia with
dysmaturation and atypical cells and increased mitoses at different levels of the epithelium. This is often
accompanied by HPV-related cytopathic changes in
the upper layers of the epithelium, but there is as yet
no formal consensus on clinicopathologic classification and clinical utility. Increasingly encountered are
the terms squamous hyperplasia and squamous intraepithelial lesion of squamous, basaloid, or warty type and
low or high grade to describe the histologic findings of
epithelial lesions associated with penile SCC.179,180 Differentiated PCIS and basal epithelial atypia are associated with LSc and full thickness, undifferentiated
bowenoid dysplasia with HPV.131
In SCC, tongues of invasive atypical keratinocytes
invade the lamina propria or deeper structures and
contain foci of aberrant and ectopic keratinization
(squamous pearls). Penile SCC is morphologically and
histologically heterogenous.65,128,131,181186 The frequency
of occurrence of different types in 61 U.S. cases was
59% usual (squamous), 15% papillary (not otherwise
specified), 10% basaloid, 10% warty (condylomatous),
2% verrucous, and 2% sarcomatoid.181 Usual or verrucous (rarely pseudohyperplastic) SCC are associated
with LSc whereas warty, basaloid or mixed types are
associated with HPV.131
Suspected verrucous carcinoma demands a deep
surgical biopsy. Verrucous carcinoma has different
pathologic features from typical squamous carcinoma, showing well differentiated and maturing
squamous epithelium with very little atypia or pleomorphism and few mitoses. The diagnosis of verrucous carcinoma in biopsy specimens may be difficult
to establish because it relies very much on the depth
of invasion of the lesion in relation to surrounding
epidermis, and the growth pattern is of a pushing
margin rather than infiltration. Warty carcinoma, BLT,
and giant condyloma differ further in having marked
squamous proliferation with HPV-related changes;
they are not associated with bowenoid dysplasia but
do have more atypia and mitoses than classic verrucous carcinoma.
PROGNOSIS. Quantifying the malignant potential

of BDP/EQ/BP/PCIS is not easy. EQ is probably more
dangerous than BDP in terms of risk of progression to
invasive SCC. BP may remit spontaneously and probably has less malignant potential than EQ or BDP.3,14,16
The prognosis of established, thick, invasive SCC
remains poor, but that of early thin disease is much
better. HPV status does not correlate with survival.187
In the United States, previously or currently married
men present earlier and have increased survival overall; African-Americans present later and do less well.188
In India late presentation is common.189
The histologic type of SCC has a bearing on prognosis: low mortality risk is associated with mixed, papillary, and warty types, intermediate risk with usual and
basaloid types and high risk with sarcomatoid cancers.65,181,182,185,186,190,191 The prognosis is also related to
the depth of invasion of crucial anatomic landmarks.
Features imparting a poor prognosis include perineural invasion and vascular invasion and high histological grade.192
The role of SCC antigen as a biomarker for penile
cancer remains speculative.193,194
TREATMENT. There are several approaches to the
treatment of PCIS, summarized in Box 77-9. The guiding principle is to be conservatively ablative.65,107,161 A
rational initial step is to recommend circumcision.
Patients presenting with these conditions (and their
sexual partners) should be counseled and screened
Box 77-9 Treatments for Penile

Carcinoma In Situ
Circumcision
Cryotherapy
Salicylic acid
Podophyllin/podophyllotoxin
Curettage and cautery
Simple excision
Mohs micrographic surgery
Laser therapy
Photodynamic therapy
Radiotherapy (not advised)
5-Fluorouracil
Imiquimod
MELANOMA
(See Chapter 124)
(See Chapter 121)

EMPD3 presents as an irritating, itchy, burning, red
scaly patch or plaque and may be multicentric. It can be
found anywhere around the anogenital area, including
the glans penis. An underpants pattern of erythema
has been described in some patients. EMPD is frequently misdiagnosed as an inflammatory dermatosis,
such as psoriasis, eczema, or Bowen disease. Subclinical EMPD disease occurs, in which the skin looks normal macroscopically but is involved microscopically.
The disease behaves indolently, spreading by local
extension and metastasis. The combination of genital
and extragenital EMPD is rare but overt, and latent
axillary EMPD disease may coexist. Axillary macular
lesions that changed shape and color daily have been
reported in association with penile and pubic Paget
disease. Very rarely, depigmented EMPD disease presents as a pale patch in the genital area, evoking a differential diagnosis of vitiligo, hypopigmented mycosis
fungoides, and LSc.80
EMPD has been treated with cryotherapy and topical 5-flurouracil, but wide excisional surgery (e.g.,
Mohs), with plastic repair if needed, is probably the
treatment of choice. Radiotherapy is controversial.
Photodynamic therapy is under evaluation. Topical
imiquimod holds promise.196
KEY REFERENCES
PREVENTION. Chronic disease and dysfunction of

the foreskin confer a significant risk of PCIS or frank
SCC. The field changes due to LSc and HPV create situations of multifocality or multicentricity and a
temporal dynamic, contributing to long-term risk even
if corrective treatments have been initiated. Feasible
measures for penile cancer prophylaxis are treatment
of chronic inflammatory conditions such as LSc, LP,
and nonspecific balanoposthitis; prevention of phimosis; limitation of psoralen and ultraviolet A treatment;
smoking cessation; and prophylaxis for HPV infection.165,195
EXTRAMAMMARY PAGET DISEASE
::
for HPV and other sexually transmitted diseases,

including HIV infection. Smoking should be discouraged. Follow-up should be long term, and the focus
should include the whole perineum, anus, and perianal skin.
For SCC, adequate surgical excision is required.
This may need to be radical (i.e., penile amputation),
depending on location and extent, but the trend is
toward tissue-conserving techniques for functional
and cosmetic reasons.107,162 Mohs micrographic surgery
and laser procedures have their proponents. Local
staging to inform management decisions is achieved
by clinical evaluation, histologic analysis, sonography,
and magnetic resonance imaging. The histologic grade
helps predict proximal histologic extent beyond grossly
visible tumor margin. Sentinel node biopsy has been
advocated, but the management of ilioinguinal lymphadenopathy is controversial. Established lymphatic or
hematogenous dissemination requires individualized
multidisciplinary management. Combination chemotherapy has been used for palliation and proposed for
adjuvant treatment but is of uncertain value. Brachytherapy or external beam radiotherapy and chemoradiotherapy have their proponents.
12
Chapter 77
Melanoma is a rare neoplasm of the penis, but the

prognosis is poor because of late diagnosis and early
lymphovascular invasion. It should always enter the
differential diagnosis of penile melanosis and lentiginosis as well as genital papules, nodules, and ulcers.3

1. Mallon E et al: Circumcision and genital dermatoses.
3. Bunker CB: Male Genital Dermatology. London, Saunders,
2004
51. Porter WM, Bunker CB: The dysfunctional foreskin. Int J
STD AIDS 12:216, 2001
65. Micali G et al: Penile cancer. J Am Acad Dermatol 54:369,
2006
107. Bunker CB: Management of penile dermatoses. Expert
Rev Dermatol 1:241, 2006
114. Bunker CB et al: Re: Lichen sclerosus: Review of the
literature and current recommendations for management. Pugliese JM et al. J Urol 178:2268-2276, 2007. J Urol
181:1802-1803, 2009
132. Neill SM et al: Guidelines for the management of lichen
sclerosus. Br J Dermatol 147:640, 2002
139. Alessi E, Coggi A, Gianotti R: Review of 120 biopsies performed on the balano-preputial sac. From Zoons balanitis to the concept of a wider spectrum of inflammatory
non-cicatricial balanoposthitis. Dermatology 208:120, 2004
161. Bunker CB: Diagnosis and management of penile precancer: Combined clinics and topical chemotherapy.
In: The Effective Management of Urological Malignancies,
edited by J Anderson, RTD Oliver, A Miles. London, Aesculapius Medical Press, 2005
877
12
Chapter 78 :: D
iseases and Disorders of
the Female Genitalia

:: Lynette J. Margesson & F. William Danby
VULVOVAGINAL DISEASES
AT A GLANCE
Common problems, including the following:
Infections
HISTORY
Section 12
The approach to the patient with vulvar complaints

requires directed history taking, as outlined in Box
78-1.
Inflammatory dermatoses
Bullous and erosive diseases
::
Ulcers
Vulvodynia
Evaluation, diagnosis, and management are
challenging because:
Normal vulvar anatomy is often
unfamiliar to the physician.
Morphology and histologic features of
dermatoses are often nonspecific.
Causes are often multiple and complex.
Patient anxiety and depression are often
severe and can worsen symptoms.
EPIDEMIOLOGY
The incidence and prevalence of dermatoses affecting
the female genitalia are generally not well established.
The vulva has been referred to as the forgotten pelvic organ. Despite being the visible female genital
structure, it is least described in the medical literature.1
Teaching about vulvar conditions and even the normal
vulva is sadly lacking for most medical practitioners,
so it is not surprising that vulvar conditions are both
underreported and underdiagnosed. Approximately
16% of women report undiagnosed chronic vulvovaginal pain at some time in their lives.2,3
878
CLINICAL FINDINGS
The etiology and pathogenesis of many diseases of

the female genitalia are likewise not well understood.
Those that also affect other areas of the body are better characterized, but the environment of the vulva
strongly affects the course of disease.
CUTANEOUS LESIONS AND

SYMPTOMS
The warm moist environment of the vulva often alters
disease morphology or symptomatology. For example,
usually scaling dermatoses may lack clinically obvious scale, and in diseases that usually exhibit welldemarcated plaques, the lesions may be less distinct. In
addition, diseases that normally do not produce scarring
of keratinized skin or oral mucosa can induce resorption of the labia minora, narrowing of the introitus, and
Box 78-1 Elements of History

Taking for Patients with
Vulvovaginal Complaints
Symptoms: onset, initial trigger, duration, alleviating, and exacerbating factors
Previous treatments: duration and effectiveness
Copies of previous physicians evaluations, culture,
and biopsy reports
Daily cleansing and care practices
Contactants: tampons, pads, lubricants, deodorants, fragrances
Gynecologic history
Menstruation/menopause/estrogen and other
hormone replacement
Pap test results
Contraception
Pregnancy
Sexual activity
Sexually transmitted diseases
Surgeries
Urologic history
Continence/incontinence
Surgery
Gastrointestinal history
Diarrhea
Constipation
Psychiatric history
12
Normal vulva
Mons pubis
Clitoris
Prepuce clitoris
Frenulum of clitoris
Labium major
Labium minor
Hymenal ring
Bartholins duct openings

Posterior commissure
Posterior vestibule
scarring of the clitoral hood. Vulvar scarring can occur

from any inflammatory condition.4
When examining the vulva, it is important to make
sure there are no physical abnormalities, particularly,
that all normal anatomy is present. Using a diagram
can help and this also can be shared for patient education (Fig. 78-1). Unimpressive physical findings are
sometimes associated with severe itching and vulvar pain. Lichenification manifested only by a slight
change in texture can present with severe pruritus
deserving of and responsive to aggressive therapy.
Finally, a complete mucocutaneous examination is
crucial, because extragenital findings can assist in the
diagnosis of several genital conditions.

Skin disease affecting the vulva more often has a multifactorial etiology, compared to other areas of the
body. The primary skin disease is often accompanied
by and driven by a secondary yeast infection, bacterial
colonization, or lack of estrogen, even in the absence of
obvious clinical findings. The infection can be purely
cutaneous, purely vaginal, or both. Irritant contact dermatitis from topically applied agents often exacerbates
both signs and symptoms. Such contributors need to
be constantly sought.
Vulvar symptoms cannot be divorced from vaginal
abnormalities. Irritating or infected vaginal secretions
are a common cause of vestibular (introital) symptoms,

which makes a speculum examination highly advisable in many instances.
LABORATORY TESTS
Skin biopsy specimens for hematoxylin and eosin
staining and direct immunofluorescence testing may
be required. Sometimes multiple biopsy samples are
required to establish a specific histologic diagnosis.
When previously well-controlled dermatoses flare,
repeat biopsy may be needed to rule out squamous cell
carcinoma or a second disease process. When doing a
vulvar biopsy, preanesthetizing the area with a topical
anesthetic can be very helpful.
Culture of cutaneous swab samples, for Candida
and bacteria, is indicated when concurrent infection is
considered. Infection can complicate treatment at any
point in the course of a disease.
A microscopic evaluation of vaginal smears allows
inspection for yeast (see Chapter 189), Trichomonas, and
bacterial vaginosis (see Chapter 205). Abnormalities
such as an increased number of white blood cells or
the presence of immature epithelial cells may be seen
as well and may be markers for inflammatory skin diseases, estrogen deficiency, foreign body, or pyogenic
bacterial infection. Vaginal cultures, done in addition,
can identify infection caused by a nonalbicans Candida
Diseases and Disorders of the Female Genitalia
Figure 78-1 Normal vulva.
::
Perineum
Chapter 78
Vestibular duct openings
Urethral meatus
879
12
organism, a pathogen difficult to see on microscopic

smears but occasionally a cause of significant symptoms.
Patch testing is important if allergic contact dermatitis is suspected (see Chapter 13). Consultation
with specialists in gynecology, urology, or urogynecology may be necessary to assist with diagnosis,
management, or treatment. This is particularly true
in the setting of multifactorial processes (e.g., incontinence as a contributing factor) or diseases requiring surgical intervention (e.g., posterior fourchette
fissuring).
Women with vulvovaginal symptoms assume they

have a curable, infectious disease. Patients need to
be counseled that many genital dermatoses are controllable but not curable. These women cannot be
evaluated and treated in a 10-minute office visit; they
require adequate time for education and reassurance.
Frequently they need to be followed long term.
Section 12
::
TREATMENT
Because of the varied morphologies and frequent

multifactorial presentations, the differential diagnosis of a vulvar condition can be quite broad (Box
78-2). Normal variants can be confusing as well.
The diseases discussed in this chapter are grouped
into the categories of inflammatory dermatoses,
bullous and erosive diseases, ulcers, abscesses, and
vulvodynia.
Several factors need to be considered when treating

most dermatoses of the female genitalia.
Many women are unfamiliar with their genital
anatomy and do not have the vocabulary to accurately
discuss their problem or follow instructions for applying topical medications. Diagrams and/or a use of a
hand-held mirror are extremely helpful for patient
education. The vulvar diagram (Fig. 78-1) can be very
important here.
An ointment is generally the most comfortable vehicle for delivering medication to the modified mucous
membranes of the vulva. Ointments spread easily,
require very small volumes per application, are less
sensitizing and generally cause less burning.
Irritant contact dermatitis is a common complicating
factor in any genital dermatosis. Aggressive washing
and use of soaps, topical medications, and home remedies are the most common offenders. Because soaps,
douches, disinfectants, and very hot or cold water
often are not considered relevant by patients, information regarding their use is often not volunteered, and
very careful questioning is warranted. Gentle cleansing of the area can be accomplished by flushing once a
day with water (or mild cleanser and water) and patting dry. Washcloths for washing and towel rubbing
while drying must be avoided.
Superpotent glucocorticoids such as clobetasol propionate are often required to treat dermatoses of the
female genitalia. Fortunately, glucocorticoid atrophy
is surprisingly uncommon on the modified mucous
membranes of the vulva. Nonetheless, patients should
be reevaluated monthly during periods of daily use
and warned about side effects due to spread of medication to the surrounding areas where atrophy is more
likely to occur such as the inguinal crease, proximal
medial thighs, and perianal skin. Limit the amount of
topical steroid prescribed.
Tacrolimus or pimecrolimus can be used as steroidsparing medications on vulvar skin. Stinging or burning frequently occurs with initial application. This is
especially true for very inflamed or eroded areas. These
agents are often less effective than glucocorticoids and
their long-term safety is still in question. Despite these
issues they are a useful second line option.5 (For efficacy and side effects, see Chapter 221.)
Warmth and moisture of the genital area are unavoidable and promote infection and maceration. Bacterial

of Vulvovaginal Disorders
INFLAMMATORY DERMATOSES


Psoriasis
Lichen sclerosus
Vulvar fissures
BULLOUS AND EROSIVE DISEASES

Lichen planus
Erythema multiforme major
Pemphigus vulgaris
Fixed drug eruption
Herpes simplex
Vulvar carcinoma
ULCERS

Aphthous ulcers
Crohn disease
Syphilis
Chancroid
Other in sexually transmitted diseases
ABSCESSES
880

COURSE
Bartholin gland abscess

12
superinfection can be treated with oral antibiotics.

Yeast infections are especially common, particularly
when patients are treated with topical glucocorticoids
and/or oral antibiotics. The identification of infection
on red, scaling, and often exudative skin can be difficult and should be pursued actively in patients with
recalcitrant symptoms.
COMMON NORMAL VARIANTS
Chapter 78
There is great variety in normal vulvovaginal anatomy.

Vulvar and vaginal erythema of varying degrees is present in most asymptomatic premenopausal women, but
this redness is rarely noticed before the onset of discomfort. Architecturally, the labia minora exhibit a wide
range of asymmetry and sizes. Normal but very small
labia minora may be difficult to differentiate from scarring produced by inflammatory skin disease. Sebaceous
glands may be prominent on the inner labia minora.
Harmless, soft, finger-like, skin-colored, monomorphous papules called vulvar papillomatosis can be seen
around the hymenal ring. (See eFig. 78-1.1 in online edition) These can be confused with genital warts.
::
Clinically subtle inflammation of the vulva sometimes

produces remarkable symptoms. Therefore, a very
careful examination with a high index of suspicion for
a dermatosis is required.
LICHEN SIMPLEX CHRONICUS

(See Chapter 15)
Vulvar lichen simplex chronicus is most often seen
in atopic individuals with sensitive skin. It can complicate other vulvar dermatoses, especially contact
dermatitis, lichen sclerosus and, less frequently, lichen
planus.
The morphologic manifestations of lichen simplex
chronicus when it occurs on the vulva vary from minimal hyperpigmentation and dullness of texture of the
modified mucous membranes to remarkable lichenification and edema (see Fig. 78-2 and eFigs. 78.2.178.2.5
in online edition). Erythema can be subtle on the labia
majora because hair obscures the skin. Excoriations
and fissures within skin folds are common but heal
quickly and may not be seen in the office. Sometimes
hydrated, thickened lichen simplex chronicus appears
white, mimicking lichen sclerosus, or the leukoplakia
of intraepithelial neoplasia.
Although the histologic findings, differential diagnosis, and therapy are similar for lichen simplex chronicus affecting the vulva as for that involving other parts
of the body, there are several notable modifications.6
Contact dermatitis needs to be recognized and treated
as it frequently confounds management. Women overwash and especially scrub the area and also may apply
topically whatever they can find. Topical glucocorticoid therapy is a mainstay, but prompt alleviation of
Figure 78-2 In this case of lichen simplex chronicus of

the vulva there is thick dramatic whitening bilaterally and
symmetrically around the vulva and perianal area.
symptoms often requires a higher potency preparation
than is standard for intertriginous skin. Those with
significant lichenification do well with a superpotent
preparation such as clobetasol propionate for the first
few weeks. The potency or frequency can be decreased
as the patient improves. Nighttime sedation is often
required to interrupt the itchscratch cycle.7 Skin and
vaginal infections, often subclinical, are extremely
common and often drive lichen simplex chronicus.
Therefore, skin and vaginal cultures for yeast, and
especially to rule out methicillin-resistant Staphylococcus aureus (MRSA), should be performed, especially
since treatment will normally require potent topical
glucocorticoid therapy for control. Treat bacteria and
Candida infections orally because topical treatment
can irritate and intensify pruritus. Proper hydration
is essential for healing. Patients with lichen simplex
chronicus that is intensely inflamed, excoriated, or
eroded generally require medications in an ointment
base, to avoid additional sensitizers and the drying
effects of cream and lotion bases. A plain water soak in
a tub for 5 minutes three times a day, followed by gentle patting of excess moisture and the application of a
Class 31 corticosteroid ointment is the best approach
for initial therapy, and must be done under cover of an
appropriate oral antibiotic and fluconazole. Sedation is
very helpful initially to stop scratching, with hydroxyzine or doxepin at night to tolerance. Systemic corticosteroids should be used for short periods of time
for severe pruritus. Follow-up to prevent and manage
relapse is essential.
INFLAMMATORY DERMATOSES
881
12
IRRITANT AND ALLERGIC CONTACT

DERMATITIS
Section 12
::

Vulvar skin is thin, damp, and permeable. It is
exposed to a wide range of insults from washcloths
and vigorous scrubbing to caustic, irritating or allergenic cleansers, and topical products applied to alleviate symptoms. Irritant vulvar dermatitis is common,
ranging from the diaper dermatitis seen in infants and
elderly incontinent ladies to the chapped, sore vulva of
the overzealous scrubbers. Allergic vulvar contact dermatitis is less common, with relevant allergens found
in 30% of those tested.8
Irritant and allergic contact dermatitis of the vulva
can be either a primary or secondary diagnosis, acute or
chronic. Either or both may commonly complicate any
vulvar dermatosis. A patient with acute irritant contact
dermatitis experiences burning on contact with the
offending substance. Deep erythema is common. Vesiculation, rare, can occur on keratinized skin, whereas
erosion is usual on modified mucous membranes
(Fig. 78-3). Therapies such as fluorouracil, imiquimod,
podophyllin resin, benzocaine, some topical antifungal
creams, and topical gentian violet can produce a brisk
reaction.9 Chronic irritant contact dermatitis is characterized by poorly demarcated erythema or hyperpigmentation that can be difficult to appreciate because the
vulva normally is pink or dusky (eFig. 78-3.1 in online

edition). Lichenification and scale, when present, make
diagnosis easier. Pruritus can be intense.
Although the British have found allergic contact dermatitis to be a common finding on the vulva, American
physicians report few relevant positive results on patch
tests for patients with eczematous vulvar skin.811
Nevertheless, women with refractory vulvar symptoms should be evaluated clinically and a thorough history taken to identify allergic contact dermatitis. In acute
allergic contact dermatitis of the genital area, vesicles
erode as quickly as they form, producing painful exudative erosions and plaques. Chronic allergic contact
dermatitis is manifested more often by mild erythema
and subtle edema. Notable scale is infrequent. Scratching in more severe and chronic cases induces lichenification. Common allergens include diphenhydramine,
neomycin, polymyxin, sulfonamides, benzocaine, some
antifungal creams, spermicides, glucocorticoids, some
antiseptics, fragrances, and preservatives (see Chapter
13). As can occur with eyelid dermatitis, allergens can be
carried inadvertently from fingertips to the vulva during
the course of scratching or wiping. In addition, the habits
of sexual partners can be important (consort dermatitis).
The therapy for vulvar contact dermatitis is the same
as for this disease occurring in other areas and hinges
most importantly on avoidance of irritants and allergens. Irritant, and to a lesser extent allergic, contact
dermatitis can be a complicating factor in most vulvar
conditions.12 It can also obscure underlying disease.
Women with chronic symptoms often are well served
by discontinuing all topical therapies (eFigs. 78-3.2 and
78-3.3 in online edition). For a severe or extensive eruption, use systemic steroids, avoiding topicals except
for a bland emollient like petrolatum. Be sure to stop
all offending hygiene practices and control secondary
infection and pruritus. For a mild-to-moderate eruption a Class IIIV topical steroid ointment applied twice
daily can hasten improvement. Reevaluation 1 or 2
weeks later may reveal an underlying primary process.
PSORIASIS
882
Figure 78-3 Patchy erythema, superficial desquamation,

and small erosions are often seen with an irritant contact
dermatitis such as this eruption caused by benzocaine and
resorcinol.
(See Chapter 18)

Vulvar psoriasis is too often missed. Women are
embarrassed to mention it to their dermatologist. They
show it to the gynecologist, unfamiliar with skin conditions, who cannot help with recognition and management. Dermatologists need to ask female psoriatics
if they have genital rashes. Although vulvar psoriasis
generally is accompanied by psoriasis in other typical
locations, the vulva is a common site of Koebnerization. Vulvar psoriasis usually affects only fully keratinized skin, sparing the modified mucous membrane
of the inner labia majora and the labia minora. Vulvar
psoriasis typically exhibits dusky red, well-demarcated
plaques. Rather than thick, silvery scale, the moistness
of inverse psoriasis or a glazed, shiny surface texture is
seen (Fig. 78-4, eFigs. 78-4.178-4.3 in online edition).
Genital psoriasis often responds well to topical therapy. A mid- or high-potency glucocorticoid ointment
generally is required for significant clinical or symp-
LICHEN SCLEROSUS
12
(See Chapter 65)

Lichen sclerosus is the commonest cause of chronic
vulvar dermatosis. The prevalence is 1:3001:1,000.
The onset is bimodal in premenarchal girls and perimenopausal women.
::
tomatic improvement. Calcipotriene ointment, tacrolimus ointment, or pimecrolimus cream can be tried
as well, but some patients find these too irritating. For
extensive psoriasis, methotrexate, oral retinoids, cyclosporine, or the newer biologics are required.
Chapter 78
Figure 78-4 Psoriasis of the vulva with symmetrical, papulosquamous, scaling, and erythema typically seen on the
hairy area of the labia majora with a thin pink plaque extending to the perianal area.
CLINICAL FINDINGS. Lichen sclerosus begins

asymptomatically in most patients. Women often tolerate their disease comfortably until they develop a
superimposed complicating event, such as candidiasis
or atrophic vaginitis that produces itching, followed by
scratching, and the process becomes self-perpetuating.
At presentation, the most common symptom of lichen
sclerosus is pruritus (mild or severe). Because vulvar
skin affected by lichen sclerosus is fragile, scratching
often produces painful erosions. Many women, by
the time they come for treatment, exhibit late signs
of lichen sclerosus, including remarkable textural
changes and scarring with loss of normal vulvar architecture. Scarring and narrowing of the introitus may
make intercourse painful, even intolerable.
Lichen sclerosus begins with white papules or
plaques that often occur first on the anterior vulva and
periclitorally. Although these papules and plaques are
sometimes smooth and somewhat waxy, especially
when they occur on moist skin, the classic presentation is one of a hypopigmented, well-demarcated
plaque with a shiny, crinkled cellophane-like surface
Inflammatory condition of the vulva

occurring at any age.
Most symptomatic in childhood and
postmenopausal years (low estrogen levels).
Cellophane paper-like texture to the white
plaques classically.
Chronic, long-term disease leads to scarring
and resorption.
Chronic active disease increases risk of
vulvar squamous cell carcinoma.
Treatment is with superpotent steroid
(clobetasol propionate) ointment.
Maintenance therapy is needed for long-term
control.
Figure 78-5 Hypopigmentation, crinkled texture, and

purpura are classically seen in lichen sclerosus.
883
12

of Lichen Sclerosus of the Vulva
Most Likely
Lichen planus
Vitiligo
Consider
Contact dermatitis
Section 12
Always Rule Out

::
cell carcinoma in the natural course of lichen sclerosus.4,15 Squamous cell carcinomas occurred primarily
in patients with chronic hyperkeratosis or erosions.
With effective topical therapy, this risk is understood
to be lower.
Figure 78-6 Occasionally, the texture of lichen sclerosus

can be waxy or even thin and smooth, as seen here, rather
than crinkled. The loss of labia minora and midline agglutination of the clitoral hood are also seen commonly in late
lichen sclerosus.
(Fig. 78-5 and eFigs. 78-5.178-5.4 in online edition).
Generally, the skin is quite thin and fragile, with erosions and purpura being common manifestations.
Some women, particularly those who experience intolerable itchiness, exhibit thickened hyperkeratotic skin
with extensive secondary changes, including fissuring,
crusting, and even bleeding (eFig. 78-5.5 in online edition). Many patients with lichen sclerosus experience
progressive scarring (eFig. 78-5.6 in online edition).
Resorption of the labia minora and scarring of the clitoral hood, which buries the clitoris, are common in
long-standing disease (Fig. 78-6). Extragenital lichen
sclerosus of keratinized skin occurs in a minority of
women with vulvar lichen sclerosus and is most often
located on the upper trunk and arms (see Chapter 65).
Usually, extragenital lesions are asymptomatic.
An association of lichen sclerosus with circulating
autoantibodies has been reported, but the only association with autoimmune disease sufficient to justify
laboratory testing is with hypothyroidism.13
DIFFERENTIAL DIAGNOSIS. Fully developed

lichen sclerosus with hypopigmentation and distinctive shiny or crinkled textural changes is easily recognized. Unfortunately, lichen sclerosus is sometimes
subtle or mimics other diseases (Box 78-3).
884
COMPLICATIONS. Sexual dysfunction results

from scarring and introital narrowing. Four to five
percent of patients are reported to develop squamous
TREATMENT. Although topical glucocorticoids

reduce symptoms, they do not always normalize the
skin texture or prevent scarring. The application of a
superpotent topical preparation once or twice a day
alleviates symptoms within a few days, but several
months of therapy is required for resolution of the
clinical findings.14,15
Most patients require 35 months of once- or twicedaily application to achieve maximal improvement.
Patients should be followed monthly during periods
of daily treatment to monitor the skin for steroid side
effects and for improvement so that the frequency of
application can be decreased.16 As an adjunct therapy
for the first week or two to control scratching and hasten healing, sedating dosages of an antihistamine or a
tricyclic antidepressant are helpful. Any infection must
be controlled.
Lichen sclerosus usually is not eliminated permanently by therapy. One survey showed an 84% recurrence rate among patients off therapy.17 Despite the
frequent requirement for long-term maintenance
therapy, however, there is no proven optimal schedule.
Most patients do well with two to three carefully localized weekly applications of a superpotent glucocorticoid on an ongoing basis.
No other treatments for lichen sclerosus produce the
striking and prompt benefit of a topical superpotent
glucocorticoid. Intralesional triamcinolone is used in
resistant areas. In addition, other medical therapies
generally have shown benefit only in open-label series.
Tacrolimus and pimecrolimus (see Chapter 221) have
been reported effective.18
Beneficial effects have also been described historically with topical testosterone, progesterone, and
estrogen, but the benefit is minimal and equivalent to
that of vehicle or lubrication alone.1921
Topical tretinoin 0.025% and calcipotriol sometimes
produce improvement, but their usefulness is limited
because they can cause irritation.22,23
Oral retinoids have been reported to be helpful for

some.24 The Chinese literature abounds with reports of
benefit from traditional Chinese herbs and acupuncture for lichen sclerosus.25
Surgical therapies, including cryotherapy, vulvectomy, carbon dioxide laser vaporization, pulsed dye
laser therapy, and photodynamic therapy have been
advocated for the treatment of lichen sclerosus.2630
VULVAR FISSURES
BULLOUS AND EROSIVE DISEASES

LICHEN PLANUS
CLINICAL FINDINGS. Vulvovaginal lichen planus

has a wide variety of clinical manifestations. Erosive
vulvovaginal lichen planus is most common and is
generally very symptomatic. It presents with burning,
rawness, and dyspareunia with variable itching. Nonerosive lichen planus of the vulva may appear bland with
mainly itching and irritation, but it can be very symptomatic and be accompanied by serious accompanying
erosive vaginal disease. Irritating inflammatory vaginal
secretions can produce symptoms of introital burning
and stinging. Disease may be restricted to the vagina
with no vulvar manifestations. Rectal and perianal disease is common and often produces pain.
White, lacy, reticulate striae resembling papular oral
lichen planus sometimes occur on the modified mucous
membranes of the vulva (Fig. 78-8 and eFig. 78-8.1 in
online edition). Less easily recognized are solid, uniformly hypopigmented, flat white plaques that mimic
lichen sclerosus except for the absence of crinkled cellophane paper-like texture (eFig. 78-8.2 in online edition).
Erosive lichen planus is manifested by a glazed erythema
and variable red, painful erosions that are either nonspecific or surrounded by typical white, often scalloped, epithelial changes (eFigs. 78-8.3 and 78-8.4 in online edition).
Erosive vulvovaginal lichen planus is often accompanied
by erosive buccal and gingival oral disease.34,35
Lichen planus, especially when erosive, produces
remarkable scarring (eFig. 78-8.5 in online edition).
Resorption of the labia minora and obliteration of the
clitoris under an agglutinated clitoral hood are very
common. Narrowing of the introitus occurs more often
and more severely than with lichen sclerosus, and
vaginal adhesions can close the vagina, preventing
both intercourse and introduction of a speculum (eFig.
78-8.6 in online edition).
Vaginal erosions are often obvious, appearing as
bright red, often raw, patches, but sometimes equally
painful disease can be subtle and show only mild erythema on a speculum examination. Scarring may vary
from a minor synechia, slight narrowing or vaginal
(See Chapter 26)

Vulvovaginal lichen planus is much less common
than vulvar lichen sclerosus with a likely prevalence
of 1 in 2,5004,500. It is often misdiagnosed as lichen
sclerosus.33
::
Figure 78-7 Recurrent fissuring of the posterior fourchette with intercourse is a commonly recognized phenomenon of unknown cause that often requires perineoplasty, a type of excisional surgery.
12
Chapter 78
Small, linear fissures on the vulva are common causes

of itching, stinging, and dyspareunia.31 Sometimes
these fissures present clinically as painful, erythematous lines in skin folds and at other times they present
as obvious linear erosions.
Most well recognized are fissures at the posterior
fourchette that split during intercourse (Fig. 78-7 and
eFig. 78-7.1 in online edition). These produce tearing pain initially, followed by burning and stinging
when alkaline semen touches the area. The skin heals
quickly, but splits recur with intercourse. The cause
is unknown. The condition usually occurs suddenly,
after years of comfortable coitus. Adequate lubrication
and positioning of the woman on top can minimize
tearing. Otherwise, surgical excision (perineoplasty) is
required, with the vertical fissure excised and the skin
closed front to back with advancement of the vaginal
mucosa to cover the area.32
Recurrent fissuring within skin folds, especially in
the interlabial sulci of the vulva, is a common cause of
stinging and irritation of the vulva. Women typically
complain of a sensation of paper cuts. Intercourse
and tight clothing are often precipitating events. Isolated acute fissuring is associated most often with Candida colonization or infection. Skin fold fissures can
result from any inflammatory dermatosis, including

psoriasis, lichen sclerosus, and lichen simplex chronicus. When one of these factors is identified, treatment
is directed toward its correction. When no specific
underlying cause is found, a topical glucocorticoid
ointment combined with an oral antibiotic and anticandidal medication often eliminates the fissuring.
However, almost immediate recurrence is common,
and prolonged therapy may be required to break the
cycle.
885
12

of Vulvar Lichen Planus
Most Likely
Lichen sclerosus
Consider
Fixed drug eruption
Contact dermatitis
Section 12
Always Rule Out

::
Figure 78-8 Although these white, well demarcated

linear papules are typical for papular lichen planus, they
are often accompanied by nearby erosive disease.
shortening to vaginal obliteration. Vaginal discharge

can be light to heavy and bloody. An examination of
vaginal smears is a sensitive test for the presence of
vaginal inflammation. Large, flat, cuboidal, mature
desquamated vaginal epithelial cells are replaced by
smaller, rounded basal cells shed from erosions and
rapidly proliferative inflamed vaginal epithelium and
sheets of leukocytes are seen. Up to 77% of patients
with oral lichen planus have vulvovaginal lichen planus, but are often unaware and should be examined
for asymptomatic involvement.36,37
The diagnosis of lichen planus is made either by
biopsy or by the identification of classic lacy lesions
in association with other typical mucous membrane
lesions. Biopsies are often nonspecific and a negative
biopsy does not rule out this diagnosis.
DIFFERENTIAL DIAGNOSIS. When lichen planus presents classically and involves oral and genital
mucosa, it is easy to diagnose. Unfortunately, lichen
planus on the vulva alone can be indistinguishable
from other diseases (Box 78-4).
886
COMPLICATIONS. The inflammation, pain, and

scarring commonly cause sexual dysfunction, and at
times, anger and depression. Vulvar squamous cell
carcinoma has been well described in patients with
erosive genital lichen planus. The magnitude of this
risk is not known, but patients should be evaluated for
this condition regularly.
TREATMENT. The aggressive treatment of vaginal

lichen planus is crucial for patient comfort. Meticulous
local care with early treatment of infection, minimization of external irritants, and attention to any underlying atrophy of estrogen deficiency are important
measures. A vaginal dilator should be used daily to
prevent adhesions of the vaginal walls. Emotional support and careful patient education regarding the nature
of the disease, its prognosis, and its therapy are vital.
Pruritic, noneroded vulvar lichen planus is usually
quite well managed simply by the application of a
potent topical glucocorticoid ointment. Severe erosive
vulvovaginal lichen planus can present a difficult therapeutic problem. A superpotent glucocorticoid ointment applied to the vulva is standard first-line therapy.
For mild-to-moderate disease, a gram of the glucocorticoid ointment can be inserted into the vagina as well,
or hydrocortisone acetate 25 mg rectal suppositories
can be inserted nightly into the vagina.38
For severe disease, use a compounded 100-mg/g
hydrocortisone acetate vaginal cream, 35 g nightly
for 2 weeks, decreasing to three times a week as maintenance. Systemic steroids are also used and the least
toxic is deep intramuscular triamcinolone 1 mg/kg
up to 80 mg/dose. This may be repeated monthly
for 3 months and limited to four doses per year (personal experience). Patients are warned about adrenal
suppression and given fluconazole 150 mg weekly to
prevent candidiasis. Any patient with vulvar disease
receiving an intravaginal glucocorticoid should be told
of her increased risk for yeast infection. There is little
tendency for erosive vulvovaginal lichen planus to
remit, but it can be well controlled. The severity tends
to wax and wane, sometimes as a result of secondary
infections, exposure to irritants, or stress but more often
for no identifiable cause. Bursts of oral predniso(lo)ne
or intramuscular triamcinolone can be helpful for flares.
Topical tacrolimus and pimecrolimus have been
reported to be useful in the treatment of vulvar lichen
planus, but these medications are irritating.39,40 They
can be used as steroid sparers once the inflammation
is controlled.
Other medications that have been reported primarily in open trials as useful for the treatment of erosive
mucous membrane lichen planus include hydroxy-
chloroquine, methotrexate, retinoids, azathioprine,

cyclophosphamide, mycophenolate mofetil, and thalidomide.4145
ERYTHEMA MULTIFORME MAJOR,

STEVENSJOHNSON SYNDROME, AND
TOXIC EPIDERMAL NECROLYSIS
EXTRAMAMMARY PAGET DISEASE

(See Chapter 121)
VULVAR CARCINOMA
ULCERS
APHTHAE
Aphthae, canker sores, common in the oral cavity, are often misdiagnosed on the vulva where they
occur more frequently than the few literature reports
would suggest. These are acute, painful ulcers that can
be single or multiple (Fig. 78-9).
They typically affect girls 919 years of age and present with the sudden onset of painful, punched-out,
(See Chapter 57)

Cicatricial pemphigoid regularly produces multiple
mucosal erosions. The nonspecific, painful erosions of
the vulva and surrounding epithelium can be clinically indistinguishable from lichen planus and lichen
sclerosus. Vulvar erosions generally are accompanied
by nonspecific vaginal erosions that can result in significant vaginal scarring. Management consists of both
local glucocorticoid therapy and systemic treatments.47
Vaginal treatment is the same as for erosive vaginal
lichen planus. Again, local care, the use of vaginal dilators, and secondary infection control are important factors in management.
(See Chapter 193)
::
CICATRICIAL PEMPHIGOID
HERPES SIMPLEX
12
Chapter 78

Erythema multiforme major, StevensJohnson syndrome, and toxic epidermal necrolysis all lead to erosive vulvar disease. One retrospective survey of 40
women with toxic epidermal necrolysis revealed that
28 had vulvovaginal involvement with severe erosions, of whom five experienced permanent scarring.46
These patients were unable to engage in intercourse,
even after corrective surgery. Local care during the
serious phase of the illness can prevent long-term dysfunction due to scarring. Prompt treatment of secondary bacterial or Candida infection may be important. In
addition, daily insertion of a vaginal dilator (such as
an inexpensive syringe cover) is important to ensure
patency.
rates, and furosemide.48,49 Lesions are most often located

in the vestibule or on the modified mucous membranes
of the labia minora or medial labia majora. Unlike the
classic, round, edematous plaques or blisters seen on
keratinized skin, the erosions of a fixed drug eruption on the vulva are often irregular, sometimes with a
slightly shaggy border. Often there are one or a few typical lesions on keratinized skin, or there are oral erosions.
The deepening hyperpigmentation seen on keratinized
skin affected by recurrent fixed drug eruptions is usually absent on the modified mucous membranes of the
vulva (Fig. 78-8.7 and eFig. 78-8.8 in online edition).
PEMPHIGUS VULGARIS
(See Chapter 54)
Pemphigus vulgaris often presents with mucosal
erosions on the vulva. Although pemphigus vulgaris is
usually considered to be a nonscarring disease, vulvovaginal involvement can lead to scarring, with vaginal
adhesions and obliteration of vulvar architecture. As
with cicatricial pemphigoid, a high index of suspicion
and confirmatory biopsies are important in reaching
the correct diagnosis. For treatment, see Chapter 54.
FIXED DRUG ERUPTION

(See Chapter 41)
Erosions due to fixed drug eruption sometimes
occur on the vulva. Common offenders include acetaminophen, hydrochlorothiazide, nonsteroidal anti-
inflammatory medications, oral contraceptives, sulfa
drugs, penicillin, tetracyclines, allopurinol, barbitu-
Figure 78-9 Aphthae of the vulva are characterized by

large size, punched-out borders, and a white fibrin base
as seen on the medial labium minus of this patient with
concomitant vaginal candidiasis.
887
12
Section 12
::
well-demarcated vulvar ulcers, usually less than

a centimeter (range 0.55 cm). The ulcers are most
often found on the vulvar trigone, the labia, and less
frequently the lower vagina. Typically there is a prodrome with flu-like symptoms of mild fever, headache,
and malaise. There may be a past history of oral aphthae. The ulcers last 13 weeks and resolve. Scarring is
variable. Usually there is just one episode but these can
recur. The pathogenesis probably involves the interaction of genetic factors with infection as a trigger. The
hypothesis is that microbial antigens with molecular
mimicry induce a reactive process directed at host antigens. Commonly the antigenic agent is unknown, but
a number of cases have been associated with Epstein
Barr virus, a few cases with Mycoplasma pneumoniae,
HIV, or cytomegalovirus5052 (eFig. 78-9.1 and 78-9.2
in online edition). The combination of recurrent oral
plus genital ulcers is complex aphthosis.53 This pattern is seen most commonly with inflammatory bowel
disease, Crohn disease and ulcerative colitis and, less
commonly with, celiac disease. It also can occur infrequently with medications, myeloproliferative diseases,
neutropenia, lymphopenia, and some rare syndromes
like FAPA syndrome (fever, aphthae, pharyngitis, and
adenitis). Rarely, in North America, these ulcers are
associated with Behets disease. This is a frequent
association in the Middle East.
Diagnosis is one of exclusion. Biopsies are often
taken but are usually nonspecific. For acute ulcers,
test for Herpes simplex, sexually transmitted diseases
including HIV, EpsteinBarr virus, and Mycoplasma.
For chronic recurrent ulcers investigate for inflammatory bowel disease and the less common causes above.
The differential diagnosis includes herpes simplex,
other sexually transmitted infections (syphilis, chancroid), and pyoderma gangrenosum.
A short course of prednisone is best for acute disease. For recurrent aphthae, colchicine, dapsone, colchicine combined with dapsone, cyclosporine, and
thalidomide have been used.53
Figure 78-10 Diffuse firm vulvar edema is a common presentation of Crohn disease.
symptoms. The primary disease to be differentiated
from anogenital Crohn disease is hidradenitis suppurativa (see Section Hidradenitis Suppurativa), which
is said to coexist in 17% of cases of Crohn disease.
Other diseases to rule out are sarcoidosis, tuberculosis,
lymphogranuloma venereum, and atypical pyogenic
infections. Treatment is with systemic therapy for the
underlying intestinal Crohn disease.56,57
Topical and intralesional glucocorticoids and local
care can help to induce healing of ulcerations.
SYPHILIS
(See Chapter 200)
CHANCROID
CROHN DISEASE
888
(See Chapter 150)

Crohn disease is a noninfectious granulomatous
inflammatory disorder that primarily involves the
bowel, but vulvar and perianal skin are sometimes
affected. Vulvar involvement is underrecognized and
misdiagnosed.54 Only 55 cases are reported in the literature, but most vulvar specialists have managed vulvar Crohn cases.
The average age is 34 years. Metastatic spread is the
most common presentation (91%). Symptoms include
swelling (62%) and pain (20%). Examination usually
shows swelling and induration in the labia majora
with or without ulcers that extend to the groin. The
ulcers occur in 41% and can be the classic knife-cut
type in the skin folds, aphthous ulcers, or both55 (Fig.
78-10 and eFigs. 78-10.178-10.3 in online edition).
The diagnosis is made on the basis of biopsy results
and identification of the bowel disease, but 25% of vulvar Crohn disease patients have no gastrointestinal
(See Chapter 202)
OTHER ULCERATIONS IN SEXUALLY

TRANSMITTED DISEASES
ABSCESSES
Abscesses occur in Crohn disease (see Section Crohn
Disease), gonorrhea (see Chapter 205), hidradenitis
suppurativa (see Section Hidradenitis Suppurativa),
and Bartholin gland (see below).
BARTHOLINS CYST AND ABSCESSES

The Bartholins glands are the largest of the vulvar
vestibular glands. They secrete mucus-like material for
1. Typical lesionsi.e., deep-seated painful nodules:
Bartholins gland abcess
Clitoris
Labium
minor
Labium
major
Vagina
Bartholins
gland
lubrication during sexual activity. Cysts form due to

occlusion of the opening ducts. They are located on the
lower labia minora at 5 and 7 oclock just lateral to the
hymenal ring. Cysts can range from 13 cm in size and
are often asymptomatic.58
Diagnosis is clinical with the typical nodule of varying size lying in the posterior vestibule with the labium
minus classically transecting the cyst (Fig. 78-11). No
treatment is necessary for asymptomatic Bartholins
cysts unless the patient is over 40 and there is concern
about carcinoma.
Bartholins duct abscesses develop as an infected
obstruction of the Bartholins duct. Infection is typically from Escherichia coli, Staphylococcus, or Streptococcus.59,60 Occasionally, it is a sexually transmitted
infection. Patients present with severe pain and swelling and sometimes an inability to sit or walk. The cyst
is warm, swollen, and tender with a varying degree of
surrounding edema and erythema. Treatment is with
incision and drainage and for complicated infections
appropriate antibiotics. Recurrent lesions require specific surgery.
Most commonly the axillary, inguinal, inframammary, and anogenital regions. This disease is more
common in women than men, with a ratio of 3.3 to
1 and affects 1% of the general population. It is frequently misdiagnosed as boils, delaying diagnosis,
and leading to fragmented care and progression to a
chronic, disabling condition that has a profoundly
negative impact on quality of life.62 Onset is usually in
a womans twenties with remission after menopause.
The course varies from intermittent and benign to continuous and severe.
In women these boils present classically in the
groin and around the hair-bearing areas of the vulva,
less often on the modified mucous membranes, but
commonly in the axillae and under the breasts (Fig.
78-12).
The nodules can be extremely painful nodules and
very debilitating. Rupture and drainage of malodorous purulent material can be very distressing. Lesions
vary from a few acneform nodules that last 715 days
to persistent chronic hypertrophic scars, with dense
fibrosis forming linear rope-like bands with varying
degrees of drainage from interconnecting sinuses. In
more severe cases, hidradenitis suppurativa results in
chronic erosions from draining ulcerations and lymphedema from lymphatic obstruction. It can be difficult to differentiate from Crohn disease and they can
coexist.65
The Second International Hidradenitis Suppurativa
Research Symposium (San Francisco; March, 2009)
adopted the following diagnostic criteria that must be
met to establish the diagnosis:
::
Figure 78-11 Bartholins gland abscess. This schematic

drawing shows the exact location of Bartholins gland and
abscess. (Used with permission from Petra Kohlberger,
MD.)
blind boils in early lesions; abscesses, draining

sinuses, scars, and tombstone open comedones in
secondary lesions.
2. Typical topographyi.e., axillary, groin, perineal and
perianal lesion, buttocks, infra and intermammary
folds.
3. Chronicity and recurrence.
Chapter 78
Inflamed
Bartholins
gland
(abcess)
Urethra
12
HIDRADENITIS SUPPURATIVA
(See Chapter 85)
Hidradenitis suppurativa is a chronic, inflammatory,
recurrent, debilitating, follicular disorder predisposed
to involve intertriginous areas.6164 It presents with
painful, deep seated, inflamed lesions, note that the
newest classification makes no mention of apocrine
gland involvement.
The Second International Hidradenitis Suppurativa
Research Symposium (San Francisco; March, 2009)
adopted the following diagnostic criteria that must be
met to establish the diagnosis:
Figure 78-12 Hidradenitis suppurativa (Hurleys Stage III)

of the vulva with chronic interconnecting draining sinuses,
painful swelling and discharge for years.
889
12
1. Typical lesionsi.e., deep-seated painful
nodules: blind boils in early lesions; abscesses,

draining sinuses, scars, and tombstone open
comedones in secondary lesions.
2. Typical topographyi.e., axillary, groin,
perineal and perianal lesion, buttocks, infra and
intermammary folds.
3. Chronicity and recurrence.
Section 12
Treatment depends on severity, using the Hurley

classification.66
At all stages, if appropriate, androgen blockade with
nonandrogenic birth control pills, spironolactone, and/
or finasteride are used.67 Smoking must cease. All friction
or trauma to the areas of involvement must be avoided.
Oral zinc has been used as an anti-inflammatory.68
STAGE I (ABSCESS FORMATION WITHOUT

SINUS TRACTS). Treatment is aimed at reducing
::
flares using topical clindamycin lotion, courses of

antibiotics for 710 days (tetracycline, doxycycline,
clindamycin), oral zinc gluconate, and intralesional
triamcinolone or a short oral course of predniso(lo)
ne. Low-dose isotretinoin is useful in a minority of
cases.69
STAGE II (RECURRENT ABSCESSES WITH

SINUS TRACTS AND SCARRING, SINGLE OR
MULTIPLE WIDELY SEPARATED LESIONS).
(eFig. 78-12.1 in online edition). Management requires

the above medical therapy as baseline plus surgical
treatment to reduce activity to Stage I and also to prepare for wide unroofing of sinuses and persistent cysts.
Antibiotics such as the tetracyclines or clindamycin and
rifampicin are used in combination for 3 months.70,71 At
times dapsone may be helpful. Intralesional triamcinolone and short courses of predniso(lo)ne are used to
quickly control swelling and inflammation.
STAGE III (DIFFUSE OR EXTENSIVE INVOLVEMENT, OR MULTIPLE INTERCONNECTING

TRACTS AND ABSCESSES ACROSS THE
ENTIRE AREA). This is a surgical disease. Medi-
cal treatment is essential in preparation for surgery.72

Anti-inflammatories may be necessary. The biologics
can provide dramatic preoperative improvement but
are not a cure.73,74
Surgical management need not be heroic and widely
ablative in Stage II and early Stage III. The preferred
technique is to unroof the sinuses as early as possible,
to include a thorough exploration and exposure of any
secondary sinuses and cysts, and then eradicate to the
extent possible inflammatory masses responsible for
perpetuating the lateral extension of lesions.75,76
VULVODYNIA
890
Vulvodynia is chronic vulvar pain with no identifiable

cause. Vulvar pain is a challenging problem for caregivers and, too often, a very difficult problem for women.
Pain can seriously impact their lives, affecting not only
their sexuality but also their daily activities, even what
Box 78-5 Classification of

Vulvar Pain
SECONDARY VULVAR PAIN (RELATED TO
A SPECIFIC DISORDER)
1. Infectious, e.g., candidiasis
2. Inflammatory, e.g., erosive lichen planus
3. Neoplastic, e.g., squamous cell carcinoma
4. Neurologic, e.g., postherpetic neuralgia
PRIMARY VULVAR PAIN (WITHOUT
VISIBLE LESIONS)
1. Localized vulvodynia (formerly vulvar vestibulitis)
2. Generalized (formerly dysesthetic or essential
vulvodynia)
they can wear. Vulvar pain and vulvodynia have been

defined and classified by the International Society for
the Study of Vulvovaginal Disease.77 (Box 78-5). Vulvodynia is defined as vulvar pain in the absence of relevant, visible physical findings or a specific clinically
identifiable neurological disorder. All vulvar pain conditions due to specific disorders, infections, inflammatory disorders, neoplastic conditions, or neurological
conditions must be excluded.7880
Vulvodynia is divided into localized (formerly vulvar vestibulitis) (eFig. 78-12.2 in online edition) and
generalized (formerly dysesthetic vulvodynia). Both
of these groups can be further divided into those who
experience provoked (brought on by touch), unprovoked (spontaneous), or mixed (both provoked and
unprovoked) pain. Localized vulvodynia can be primary as in pain present with first tampon use or vaginal entry, or secondary, as in acquired after some years
of no pain on touching/vaginal entry.
EPIDEMIOLOGY
Unexplained vulvar pain is highly prevalent among
women of reproductive age with lifetime prevalence
estimates ranging from 16%28%. The prevalence of
true vulvodynia is unknown because careful clinical
evaluation is required for a definitive diagnosis.3,81,82
Localized provoked vulvodynia usually affects
younger women and is more common than generalized vulvodynia.83

The etiology of vulvodynia is unclear. It is likely multifactorial with both organic and functional components.
Etiological factors being studied range from neuropathic mechanisms, neural hyperplasia, neurogenic
inflammation, abnormal nociception, and neurotransmitter and neuropeptides anomalies, to pelvic floor
muscle dysfunction. There are localized processes in
the vulva that can trigger pain and changes centrally
The diagnosis of vulvodynia is one of exclusion. The
diagnosis of localized vulvodynia is made on history and the demonstration of pain on Q-tip touching
around the hymenal ring. Patients with vulvodynia
should be examined carefully for any underlying skin
disease, infection, neoplasm, or well-defined neurologic disorder. Irritant contact dermatitis, vulvar
fissures, and lichen planus are the most common
skin diseases to be mistaken for vulvodynia. Painful vaginitis from nonalbicans Candida infection or a
noninfectious inflammatory vaginitis (desquamative
Vulvodynia is complex, and with multiple possible

contributing factors many medical/surgical, psychological, and alternate approaches have been used. The
different aspects of vulvodynia therapy are ideally
addressed simultaneously using a multidisciplinary
approach.
Education and support are vital. There are excellent
resources through the National Vulvodynia Association (http://www.nva.org).
All irritating hygiene practices must stop. Good
education here is needed to avoid laundry detergents,
cleansers, pads, ill-fitting clothing, etc., that could
cause local harm. Activities that hurt, like bike riding,
must stop. Sexual intercourse should be avoided when
there is pain.
For topical pain control lidocaine 5% ointment has
decreased pain up to 50%. Topical 6% compounded
gabapentin cream has been helpful for over 50% of
generalized vulvodynia patients. Topical estradiol
cream has been used for cases of localized vulvodynia.
Other local treatments with a few reports include topical capsaicin, and local injections (as pain blocks) using
lidocaine with methylprednisolone.
Systemic medications are often used as pain modulators. Tricyclic antidepressants such as amitriptyline
or desipramine, beginning at very low dosages and
increasing up to 150 mg or until the patient is comfortable, are first-line.90 For women who do not tolerate tricyclic antidepressants or who experience suboptimal
improvement, gabapentin has been used.91 The newer
antidepressants venlafaxine and duloxetine have
been used effectively as well. Pregabalin provides yet
another possible option. Combinations of these medications can be used.
Pelvic floor dysfunction needs to be addressed with
the help of a pelvic floor physiotherapist who can
also assess the back and hips to make sure no other
confounding biomechanical problems are present.
Treatments to normalize pelvic floor function include
myofascial release, trigger-point pressure, biofeedback, vaginal dilation, and exercises.
Attention to depression and sexual dysfunction
is mandatory. Most patients benefit from referral for
counseling to help them cope with their debilitating
symptoms. Behavior and cognitive-behavior therapy
Patients with localized vulvodynia are usually

between the ages of 2050. Typically there is pain on
touch or attempted vaginal entry (referred to as provoked pain). This may be with the first use of a tampon or sexual intercourse (primary vulvodynia) or
after years of no discomfort (secondary vulvodynia).
The patient complains of burning, stinging, irritation,
or a raw sensation at the vaginal entrance (hymenal
ring area).8789 The pain can be moderate-to-severe.
Sexual intercourse is difficult to impossible. They may
complain of constant vaginal infections despite negative tests or that their partner is too big. They are often
distressed, anxious, and/or depressed. Patients with
generalized vulvodynia, usually over 40 years old,
have constant or episodic vulvar pain. They complain
of burning, soreness, rawness, stabbing pain, irritation,
aching, or stinging, but they usually can have sexual
intercourse. They are hyperaware of their genital
area. They often complain of constant yeast. These
patients have often seen many caregivers, had multiple incorrect diagnoses, and tried many treatments.
On examination there is no visible abnormality. The
pelvic floor muscles may be tight and sensitive. Q-tip
sensitivity (see below) may be prominent in localized
vulvodynia.
TREATMENT
12
::
CLINICAL FINDINGS
inflammatory vaginitis) can be confused with vulvodynia. Desquamative inflammatory vaginitis is manifested by grossly and microscopically purulent vaginal
secretions and immature epithelial cells similar to
those seen in lichen planus. Nonalbicans Candida infections, such as C. glabrata, C. krusei, and Saccharomyces
cerevisiae infection also can cause chronic vulvovaginal
pain. These infections are easily missed unless a culture is performed, and they can be resistant to therapy.
Finally, neurologic disorders such as postherpetic neuralgia, pudendal nerve entrapment, pudendal neuralgia, and spinal compression need to be addressed
through history and imaging studies when appropriate.
Chapter 78
in the dorsal root ganglia and in the brain, changes that

keep the pain active. The result is abnormal pain perception so that light touch causes pain (allodynia).
More work has been done on localized vulvodynia.
Patients are overly sensitive to pain and cannot downregulate it. They have increased nerve fibers, inflammatory cells, and mediators in the vulvar vestibule
along with a poor ability to modify pain. The pelvic
floor muscles are dysfunctional, tight, and weak, and
play an important role in causation or perpetuation
(and are not just a consequence) of vulvodynia. Underlying psychosexual issues or personality traits, such as
somatization disorder, can be important.84 Depression
and anxiety have been reported. These patients may
have other comorbid hypersensitivity syndromes with
centralized pain such as migraines, irritable bowel
syndrome, and fibromyalgia.85,86 Very few studies have
looked at generalized vulvodynia, and it may represent pudendal neuralgia or a regional pain syndrome.
891
12
Section 12
::
892
can reduce the fear of pain and improve sexual functioning with good results.
For localized vulvodynia, surgical vestibulectomy
has been successful in over 60% of cases. It is best for
secondary vulvodynia, especially when combined
with pelvic floor therapy. It is usually chosen only
when conservative treatment fails.
For generalized vulvodynia with neuralgia, management in a pain clinic using nerve blocks and interventional devices (sacral nerve root stimulators) may
be needed.
However, improvement is usually slow and trialand-error therapy with support by the physician is
required.85,86,83,92,93
always important to eliminate all irritants and control

infection. Sedation to stop scratching is often imperative. Topical or at times systemic corticosteroids can be
very effective for inflammation. The calcineurin inhibitors can be used as steroid sparers.
There is a group of women in whom it is very difficult to pinpoint a cause for the itching. The majority of
these have some degree of neuropathy with or without
anxiety or depression. Treatment is with neurotropic
agents as used for vulvodynia; anxiety andor depression must be addressed.9496
PRURITUS VULVAE
Pruritus vulvae is common, affecting perhaps 10% of

women. It can be acute or chronic, minor, or debilitating. The most common cause is candidiasis. Irritant
contact dermatitis is next, due to overwashing and
topical irritants, particularly urine, feces, and sweat, as
well as various topical medications.
The commonest chronic vulvar conditions are lichen
simplex chronicus and lichen sclerosus and, less frequently, lichen planus and psoriasis. Often there is a
combination of infection, contact dermatitis, and one
or more dermatoses. Rarely the problem is due to a
neuropathy or underlying malignancy. Investigation
and treatment is directed at the individual causes. It is
6. Lynch PJ: Lichen simplex chronicus (atopic/neurodermatitis) of the anogenital region. Dermatol Ther 17(1):8-19,
2004
8. Margesson LJ: Contact dermatitis of the vulva. Dermatol
Ther 17(1):20-27, 2004
16. Smith YR, Haefner HK: Vulvar lichen sclerosus:
Pathophysiology and treatment. Am J Clin Dermatol
2004;5(2):105-125.
33. Moyal-Barracco M, Edwards L: Diagnosis and therapy of
anogenital lichen planus. Dermatol Ther 17(1):38-46, 2004
74. Revuz J: Hidradenitis suppurativa. J Eur Acad Dermatol
Venereol 23(9):985-998, 2009
85. Damsted-Petersen C, Boyer SC, Pukall CF: Current perspectives in vulvodynia. Womens Health (Lond Engl)
5(4):423-436, 2009
KEY REFERENCEs
Disorders of the
Skin Appendages
PA RT
Disorders of the Sebaceous Glands
Chapter 79 :: Biology of Sebaceous Glands

:: Amanda M. Nelson & Diane M. Thiboutot
SEBACEOUS GLANDS AT A GLANCE
Sebaceous glands are unilobular or
multilobular structures that consist of acini
connected to a common excretory duct and
are usually associated with a hair follicle.
Sebaceous glands vary considerably in size,
even in the same individual and in the same
anatomic area.
The sebaceous glands exude lipids by
disintegration of entire cells, a process
known as holocrine secretion.
Human sebum, as it leaves the sebaceous
gland, contains squalene, cholesterol,
cholesterol esters, wax esters, and
triglycerides.
Sebaceous glands are regulated by
androgens and retinoids.
Other factors, such as melanocortins, and
peroxisome proliferator-activated receptors
(PPARs), may regulate sebaceous gland
activity as well.
ANATOMY OF THE
SEBACEOUS GLAND
HISTOLOGY
Sebaceous glands are unilobular or multilobular structures that consist of acini connected to a common excretory duct, which is composed of stratified squamous
epithelium. Sebaceous glands are composed of lipidproducing sebocytes and of keratinocytes that line
the sebaceous ducts and are usually associated with a
hair follicle. The periphery of the sebaceous gland is
a basal cell layer composed of small, cuboidal, nucleated, highly mitotic sebocytes. Cells progress toward
the middle of the gland and accumulate lipid droplets
as they terminally differentiate. These fully differentiated sebocytes are full of lipid and lack all other cellular organelles (Fig. 79-1). Surrounding the glands are
connective tissue capsules composed of collagen fibers
that provide physical support.1
LOCATION
Sebaceous glands are associated with hair follicles all
over the body. A sebaceous gland associated with a hair
follicle is termed a pilosebaceous unit. The glands may
also be found in certain nonhairy sites, including the
13
Signaling pathways and transcription factors in

cell lineage determinations
Stem cell
Tcf3
Shh
Wnt
Myc
Lef1
Wnt
Section 13
Figure 79-1 Hematoxylin and eosin-stained section of

the human sebaceous gland showing its multilobular
structure.
::
eyelids (Meibomian glands), the nipples (Montgomery

glands), and around the genitals (Tyson glands). Only
the palms and soles, which have no hair follicles, are
totally devoid of sebaceous glands. Sebaceous glands
vary considerably in size, even within the same individual and within the same anatomic area. On the
external body surface, most glands are only a fraction
of a millimeter in size. The largest glands and greatest density of glands (up to 400900 glands/cm2) are
located on the face and scalp.13 The hairs associated
with these large glands are often tiny, and it has been
suggested that the total structures be more properly
termed sebaceous follicles rather than hair follicles.
In the oral epithelium, sebaceous glands known as
Fordyce spots are sometimes present. Fordyce spots are
visible to the unaided eye because of their large size
(up to 23 mm) and the transparency of the oral epithelium. In this location, the sebaceous ducts open
directly to the surface.
EMBRYOGENESIS AND
MORPHOGENESIS
894
In the human fetus, sebaceous glands develop in the

13th to 16th week of gestation from bulges (epithelial
placodes) on the developing hair follicles. The bulge
region of the follicle contains the epidermal stem cells
that generate multiple cell lineages, including epidermal and follicular keratinocytes, as well as sebaceous
glands. As daughter cells migrate from the bulge
region, changes in the expression patterns of numerous
transcription factors determine their final cell lineage.
Wnt/wingless (Wnt) and Sonic Hedgehog (Shh) signaling pathways are intricately involved in embryonic
patterning and cell fate decisions. Cells destined to
become sebocytes have increased Shh and Myc signaling and decreased Wnt signaling (Fig. 79-2). In transgenic mouse models, intact Wnt signaling promotes
hair follicle differentiation, whereas inhibition of Wnt
signaling by preventing the Lef1/B-catenin interaction
leads to sebocyte differentiation.4 Loss-of-function and
gain-of-function transgenic mouse models demon-
Sebocyte
Hair cell
Figure 79-2 Signaling pathways and transcription factors

that are involved in cell lineage determinations. As daughter cells migrate from the bulge region, changes in the
expression patterns of numerous transcription factors determine their final cell lineage. Data is far from complete in
this area; it is very likely that other pathways and transcription factors will play a significant role in determining each
cell lineage. Lef1 = lymphoid enhancer binding factor 1;
Myc = myelocytomatosis oncogene; Shh = Sonic Hedgehog; Tcf3 = transcription factor 3; Wnt = wingless (wg)/int.
strated that blocking Shh signaling inhibited normal
sebocyte differentiation and constitutively activating
Shh signaling increased the number and size of sebaceous glands in skin.5 When fully formed, the glands
remain attached to the hair follicles by a duct through
which sebum flows into the follicular canal and eventually to the skin surface.
PHYSIOLOGY OF THE
SEBACEOUS GLAND
HOLOCRINE SECRETION
The sebaceous glands exude lipids by disintegration of
entire cells, a process known as holocrine secretion. The
life span of a sebocyte from cell division to holocrine
secretion is approximately 2125 days.6 Because of the
constant state of renewal and secretion of the sebaceous gland, individual cells within the same gland
are engaged in different metabolic activities dependent upon their differentiation state.7 The stages of this
process are evident in the histology of the gland.8 The
outermost cells, basal cell layer membrane, are small,
nucleated, and devoid of lipid droplets. This layer contains the dividing cells that replenish the gland as cells
are lost in the process of lipid excretion. As cells are displaced into the center of the gland, they begin to produce lipid, which accumulates in droplets. Eventually
the cells become greatly distended with lipid droplets
and the nuclei and other subcellular structures disappear. As the cells approach the sebaceous duct, they
disintegrate and release their contents. Only neutral lipids reach the skin surface. Proteins, nucleic acids, and
the membrane phospholipids are digested and apparently recycled during the disintegration of the cells.
LIPID COMPOSITION OF SEBUM
Biology of Sebaceous Glands
The precise function of sebum in humans is unknown.

It has been proposed that its solitary role is to cause
acne.10 It has been suggested that sebum reduces water
loss from the skins surface and functions to keep skin
soft and smooth, although evidence for these claims in
humans is minimal; however, as demonstrated in the
sebaceous gland-deficient (Asebia) mouse model, glycerol derived from triglyceride hydrolysis in sebum is
critical for maintaining stratum corneum hydration.11
Sebum has been shown to have mild antibacterial
action, protecting the skin from infection by bacteria
and fungi, because it contains immunoglobulin A,
which is secreted from most exocrine glands.12 Vitamin
E delivery to the upper layers of the skin protects the
skin and its surface lipids from oxidation. Thus, sebum
flow to the surface of the skin may provide the transit
mechanism necessary for vitamin E to function.13
::
Human sebaceous gland lipids
FUNCTION OF SEBUM
13
Chapter 79
Human sebum, as it leaves the sebaceous gland, contains squalene, cholesterol, cholesterol esters, wax
esters, and triglycerides (Fig. 79-3). During passage
of sebum through the hair canal, bacterial enzymes
hydrolyze some of the triglycerides, so that the lipid
mixture reaching the skin surface contains free fatty
acids and small proportions of mono- and diglycerides, in addition to the original components. The wax
esters and squalene distinguish sebum from the lipids of human internal organs, which contain no wax
esters and little squalene. However, human sebaceous
glands appear to be unable to cyclize squalene to sterols
such as cholesterol. The patterns of unsaturation of
the fatty acids in the triglycerides, wax esters, and
cholesterol esters also distinguish human sebum from
the lipids of other organs. The normal mammalian
pathway of desaturation involves inserting a double
bond between the ninth and tenth carbon of stearic
acid (18:0) to form oleic acid (18:19). However, in
human sebaceous glands, the predominant pattern is
the insertion of a 6 double bond into palmitic acid

(16:0). The resulting sapienic acid (16:16) (Fig. 79-3) is
the major fatty acid of adult human sebum. Elongation
of the chain by two carbons and insertion of another
double bond gives sebaleic acid (18:25,8), a fatty acid
thought to be unique to human sebum.9
Sebaceous fatty acids and alcohols are also distinguished by chain branching. Methyl branches can
occur on the penultimate carbon of a fatty acid chain
(iso branching), on the third from the last (antepenultimate) carbon (anteiso branching), or on any evennumbered carbon (internal branching). Examples of
these unusual unsaturated and branched-chain moieties are included in the lipid structures in Fig. 79-3.
HO
Squalene
Cholesterol
O
O
Cholesterol ester
O
O
Wax ester
O
O
O
O
Triglyceride
Figure 79-3 Human sebaceous gland lipids. The structures of the cholesterol ester, wax ester, and triglyceride
are representative of the many species that are present.
Two sebaceous-type unsaturated fatty acid moieties are
shown: sapienic acid (16:16) (in the wax ester structure)
and sebaleic acid (18:25,8) (in the triglyceride structure).
Anteiso branching is shown in the alcohol moiety of the
wax ester, and iso branching is shown in the triglyceride.
INNATE IMMUNITY
Antimicrobial peptides, including cathelicidin, psoriasin, -defensin 1, and -defensin 2 are expressed within
the sebaceous gland. Functional cathelicidin peptides
have direct antimicrobrial activity against Propionibacterium acnes, but also initiate cytokine production and
inflammation in the host organism.14,15 In addition,
free fatty acids in human sebum is bactericidal against
Gram-positive organisms as a result of its ability to
increase -defensin 2 expression.16 Innate immune Tolllike receptors 2 and 4 (TLR2, TLR4), CD1d and CD14
molecules are also expressed in sebaceous glands and
immortalized human sebocytes. With the expression of
innate immune receptors and antibacterial peptides, the
sebaceous gland may play an important role in pathogen recognition and protection of the skin surface.
FACTORS REGULATING
SEBACEOUS GLAND SIZE AND
SEBUM PRODUCTION
Serum production is continuous and is not controlled by neural mechanisms. The exact mechanisms
895
13
underlying the regulation of human sebum production are not fully defined.
A variety of experimental models are used to study
the factors involved in sebaceous gland regulation,
including cell culture of isolated human sebaceous
glands, primary sebocytes, and immortalized sebocyte
cell lines; as well as mouse and hamster animal models.
Results from these investigations clearly indicate that
sebaceous glands are regulated by androgens and retinoids. Recent evidence suggests that melanocortins,
peroxisome proliferator-activated receptors (PPARs),
and fibroblast growth factor receptors (FGFRs) play a
role as well.
Section 13
ANDROGENS
::
Sebaceous glands require androgenic stimulation to

produce significant quantities of sebum. Individuals with a genetic deficiency of androgen receptors
(complete androgen insensitivity) have no detectable
sebum secretion and do not develop acne.17 A question
still exists about which androgen is physiologically
important. Although the most powerful androgens
are testosterone and its end-organ reduction product,
dihydrotestosterone (DHT), levels of testosterone do
not parallel the patterns of sebaceous gland activity.
For example, testosterone levels are many fold higher
in males than in females, with no overlap between the
sexes. However, the average rates of sebum secretion
are only slightly higher in males than in females, with
considerable overlap between the sexes. Also, sebum
secretion starts to increase in children during adrenarche, a developmental event that precedes puberty
by about 2 years.
The weak adrenal androgen, dehydroepiandrosterone sulfate (DHEAS), may be a significant regulator of sebaceous gland activity through its conversion
to testosterone and DHT in the sebaceous gland.
Levels of DHEAS are high in newborns, very low in
2- to 4-year-old children, and start to rise when sebum
secretion starts to increase. In adulthood, DHEAS levels show considerable individual variation, but are
only slightly higher in men than in women on the average. There is a decline in DHEAS levels in both sexes
starting in early adulthood and continuing throughout
life; this decline parallels the decline of sebum secretion. DHEAS is present in the blood in high concentration. The enzymes required to convert DHEAS to more
potent androgens are present in sebaceous glands.18
These include 3-hydroxysteroid dehydrogenase, 17hydroxysteroid dehydrogenase, and 5-reductase.
Each of these enzymes exists in two or more isoforms
that exhibit tissue-specific differences in their expression. The predominant isozymes in the sebaceous
gland include the type 1 3-hydroxysteroid dehydrogenase, the type 2 17-hydroxysteroid dehydrogenase,
and the type 1 5-reductase.
RETINOIDS
896
Isotretinoin (13-cis-retinoic acid, 13-cis-RA) is the most

potent pharmacologic inhibitor of sebum secretion.
Significant reductions in sebum production can be

observed as early as 2 weeks after use.19 Histologically,
sebaceous glands are markedly reduced in size and individual sebocytes appear undifferentiated lacking the characteristic cytoplasmic accumulation of sebaceous lipids.
Isotretinoin does not interact with any of the known
retinoid receptors. It may serve as a prodrug for the
synthesis of all-trans-retinoic acid or 9-cis-retinoic acid,
which do interact with retinoid receptors. However, it
has greater sebosuppressive action than do all-trans- or
9-cis-retinoic acid.20 The mechanism by which 13-cisRA lowers sebum secretion is currently under investigation. Experimental evidence shows that 13-cis-RA
inhibits the 3-hydroxysteriod activity of retinol dehydrogenase leading to decreased androgen synthesis.21
In addition, isotretinoin triggers cell cycle arrest in
human sebocytes and immortalized cell culture models of human sebocytes (SZ95 and SEB-1), as well as
induces apoptosis in SEB-1 sebocytes.22,23,24 Inhibition
of androgen synthesis, cell cycle arrest, and apoptosis
by 13-cis-RA may explain the reduction of sebaceous
gland size after treatment.
MELANOCORTINS
Melanocortins include melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH).
In rodents, melanocortins increase sebum production.
Transgenic mice deficient in the melanocortin-5 receptor have hypoplastic sebaceous glands and reduced
sebum production.25 The melanocortin-5 receptor has
been identified in human sebaceous glands, where it
may play a role in the modulation of sebum production.26 Further experimentation is required to test this
hypothesis.
PEROXISOME PROLIFERATORACTIVATED RECEPTORS

PPARs are orphan nuclear receptors that are similar to
retinoid receptors in many ways. Each of these receptors
forms heterodimers with retinoid X receptors in order
to regulate the transcription of genes involved in a variety of processes, including lipid metabolism and cellular proliferation and differentiation. PPAR-, -, and -
receptor subtypes have been detected in basal sebocytes.
PPAR- is also detected within differentiated sebocytes.
In patients receiving fibrates (PPAR- ligands) for
hyperlipidemia or thiazolidinediones (PPAR- ligands)
for diabetes, sebum secretion rates are increased.27 Rat
preputial cells serve as a model for human sebocytes
in the laboratory.28 In rat preputial cells, agonists of the
PPAR- receptor, such as drugs of the thiazolidinedione
class, increase lipid accumulation.29
FIBROBLAST GROWTH
FACTOR RECEPTORS
FGFR1 and FGFR2 are expressed in the epidermis and
skin appendages. Expression of FGFR3 and FGFR4 are
localized to dermal vessels and microvessels and are

notably absent in epidermis and appendages.30 FGFR2
plays an important role during embryogenesis in skin
formation.31 Germ line mutations in FGFR2 lead to
Apert syndrome, which is commonly associated with
acne. In addition, somatic mutations in the same location can lead to acne, but how this receptor is involved
in sebaceous gland development and how its mutation
leads to acne is unknown.32,33
CONCLUSION

Four key elements of pathogenesis: (1)

follicular epidermal hyperproliferation, (2)
excess sebum production, (3) inflammation,
and (4) the presence and activity of
Propionibacterium acnes.
Comedones, papules, pustules, nodules on
face, chest, and back.
Treatment often includes combinations
of oral and topical agents such as
antimicrobials, retinoids, and hormonal
agents. Laser and light sources are additional
treatment options.
Acne variants and acneiform eruptions also
exist, many of which have an identifiable
and reversible etiology.
ACNE VULGARIS
Acne vulgaris is a self-limited disorder of the pilosebaceous unit that is seen primarily in adolescents.
Most cases of acne present with a pleomorphic array
Acne Vulgaris and Acneiform Eruptions
Common disorder of the pilosebaceous unit.
of lesions, consisting of comedones, papules, pustules,

and nodules with varying extent and severity. While
the course of acne may be self-limiting, the sequelae
can be lifelong, with pitted or hypertrophic scar
formation.
::
1. Downie MMT, Guy R, Kealey T: Advances in sebaceous

gland research: Potential new approaches to acne management. Int J Cosmet Sci. 26:291-311, 2004
4. Merrill B et al: Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin. Genes Dev 15:16881705, 2001
9. Nicolaides N: Skin lipids: Their biochemical uniqueness.
Science 186:19-26, 1974
15. Lai Y, Gallo RL: AMPed up immunity: How antimicrobial
peptides have multiple roles in immune defense. Trends in
Immunology 30(3):131-141, 2009
18. Chen W, Thiboutot D, Zouboulis C: Cutaneous androgen
metabolism: Basic research and clinical perspectives. J
Invest Dermatol 119:992-1007, 2002
27. Trivedi NR et al: Peroxisome proliferator-activated receptors increase human sebum production. J Invest Dermatol
126(9):2002-2009, 2006
Chapter 80 :: Acne Vulgaris and Acneiform Eruptions

:: Andrea L. Zaenglein, Emmy M. Graber, &
Diane M. Thiboutot
ACNE AT A GLANCE
13
Chapter 80
The regulation of sebaceous glands and human

sebum production are complex. Advances are being
made in this area, which may lead to alternative therapies for the reduction of sebum and improvement
in acne.
KEY REFERENCES
EPIDEMIOLOGY
Acne is sufficiently common that it often has been
termed physiologic. Mild degrees of acne are frequently
seen at birth, probably resulting from follicular stimulation by adrenal androgens, and may continue into the
neonatal period. However, in the vast majority of cases
it is not until puberty that acne becomes a more significant problem. Acne often heralds the onset of puberty.
In girls, the occurrence of acne may precede menarche
by more than a year. In these very young patients, the
predominant lesions are comedones. Acne prevalence
hits its peak during the middle-to-late teenage period,
with more than 85% of adolescents affected, and then
steadily decreases. However, acne may persist through
the third decade or even later, particularly in women.
One study demonstrated a prevalence of facial acne in
women between ages 26 and 44 to be 14%.1 Acne severity seems to be familial. The prevalence of high school
students with moderate-to-severe acne was 19.9% in
those students with a family history of acne and 9.8%
in those students without a family history of acne.2
In twin studies, 81% of the population variance in acne
was found due to genetic factors (vs. 19% environmental
897
13
factors).3 Nodulocystic acne has been reported to be

more common in white males than in black males, and
one group of investigators has found that acne is more
severe in patients with the XYY genotype.4,5
Section 13
::
Understanding the underlying basis for acne, and the

mechanisms of action of the multitude of therapeutic
options in treating acne will assure better therapeutic results. The pathogenesis of acne is multifaceted,
but four basic steps have been identified. These key
elements (Fig. 80-1) are: (1) follicular epidermal
hyperproliferation, (2) excess sebum production, (3)
inflammation, and (4) the presence and activity of Propionibacterium acnes. Each of these processes are interrelated and under hormonal and immune influence.
Follicular epidermal hyperproliferation results in
the formation of a microcomedo. The epithelium of the
upper hair follicle, the infundibulum, becomes hyperkeratotic with increased cohesion of the keratinocytes.
The excess cells and their tackiness result in a plug
in the follicular ostium. This plug then causes downstream concretions of keratin, sebum, and bacteria to
accumulate in the follicle. These packed concretions
cause dilation of the upper hair follicle producing a
microcomedo.
The stimulus for keratinocyte hyperproliferation
and increased adhesion is unknown. However, several
proposed factors in keratinocyte hyperproliferation
include: androgen stimulation, decreased linoleic acid,
increased interleukin-1 (IL-1) activity, and effects of
P. acnes. Dihydrotestosterone (DHT) is a potent androgen that may play a role in acne. Fig. 80-2 demonstrates
the physiologic pathway for dehydroepiandrosterone
s ulfate (DHEA-S) conversion to the androgen DHT.

17- hydroxysteroid dehydrogenase (HSD) and 5-
reductase are enzymes responsible for converting
DHEA-S to DHT. When compared to epidermal keratinocytes, follicular keratinocytes have increased 17-
HSD and 5- reductase, thus enhancing DHT production.6,7 DHT may stimulate follicular keratinocyte
proliferation. Also supporting the role of androgens
in acne pathogenesis is the evidence that individuals
with complete androgen insensitivity do not develop
acne.8 Follicular keratinocyte proliferation may also be
regulated by linoleic acid. Linoleic acid is an essential
fatty acid in the skin that is decreased in subjects with
acne. The quantity of linoleic acid normalizes after
successful treatment with isotretinoin. Subnormal levels of linoleic acid may induce follicular keratinocyte
hyperproliferation and produce proinflammatory cytokines. It has also been suggested that regular quantities
of linoleic acid are actually produced but are simply
diluted by increased sebum production.9 In addition
to androgens and linoleic acid, IL-1 may also contribute to keratinocyte hyperproliferation. Human follicular keratinocytes demonstrate hyperproliferation
and microcomedone formation when IL-1 is added.
IL-1 receptor antagonists inhibit microcomedone formation providing additional support for the cytokines
role in acne pathogenesis.10,11 Fibroblast growth factor
receptor (FGFR)-2 signaling may also be involved in
hyperkeratinization. There is a long established relationship between acne and Apert syndrome, a complex
bony malformation syndrome, due to a gain in function
mutation in the gene encoding FGFR-2. Mutations in
FGFR-2 in a mosaic distribution underlie a nevus comedonicus-like lesion.12 The FGFR-2 pathway is androgen
dependent and proposed mechanisms in acne include
an increased production of IL-1 and 5- reductase.13,14
Acne pathogenesis
898
Microcomedone
Comedone
Hyperkeratotic
infundibulum
Cohesive
corneocytes
Sebum secretion
Accumulation of
shed corneocytes
and sebum
Dilation of fillicular
ostium
Figure 80-1 AD. Acne pathogenesis.
Inflammatory
papule/pustule
Nodule
Further expansion
of fillicular unit
Proliferation of
Proprionibacterium
acnes
Perifollicular
inflammation
Rupture of follicular
wall
Marked perifollicular
inflammation
Scarring
13
Pathways of steroid metabolism
Pituitary
DHEAS
FSH
LH
ACTH
3-HSD
Androstenedione
17-HSD
Adrenal
Ovary
17 Preg
17 Prog
Cortisol
Skin
Figure 80-2 Pathways of steroid metabolism. Dehydroepiandrosterone (DHEA) is a weak androgen that is
converted to the more potent testosterone by 3-hydroxysteroid dehydrogenase (HSD) and 17-HSD. 5-
reductase then converts testosterone to dihydrotestosterone (DHT), the predominant hormonal effector on the sebaceous gland. The sebaceous gland expresses each of these enzymes. A = androstenedione;
ACTH = adrenocorticotropin-stimulating hormone; DHEAS = dehydroepiandrosterone sulfate; E = estrogen;
FSH = follicle-stimulating hormone; LH = luteinizing hormone; T = testosterone; DOC = deoxycortisol.
The second key feature in the pathogenesis of acne
is excess sebum production from the sebaceous gland.
Patients with acne produce more sebum than those
without acne, although the quality of sebum is the same
between the two groups.15 Components of sebum
triglycerides and lipoperoxidesmay play a role in
acne pathogenesis. Triglycerides are broken down into
free fatty acids by P. acnes, normal flora of the pilosebaceous unit. These free fatty acids promote further
bacterial clumping and colonization of P. acnes, incite
inflammation, and may be comedogenic.16 Lipoperoxides also produce proinflammatory cytokines and activate the peroxisome proliferator-activated receptors
(PPAR) pathway, resulting in increased sebum.17,18
Androgenic hormones also influence sebum production through actions on sebocyte proliferation and
differentiation. Similar to their action on the follicular
infundibular keratinocytes, androgen hormones bind
to and influence sebocyte activity.19 Those with acne
have higher average serum androgen levels (although
still within normal range) than unaffected controls.20,21
5- reductase, the enzyme responsible for converting
testosterone to the potent DHT, has greatest activity in
areas of skin prone to acne, the face chest and back.14
The role of estrogen on sebum production is not well
defined. The dose of estrogen required to decrease
sebum production is greater than the dose required to
inhibit ovulation.22 The mechanisms by which estrogens may work include: (1) directly opposing the
effects of androgens within the sebaceous gland; (2)
inhibiting the production of androgens by gonadal tis-
sue via a negative feedback loop on pituitary gonadotropin release; and (3) regulating genes that suppress
sebaceous gland growth or lipid production.23
Corticotropin-releasing hormone may also play a
role. It is released by the hypothalamus and increased
in response to stress. Corticotropin-releasing hormone
receptors are present on a vast number of cells, including keratinocytes and sebocytes, and are upregulated
in the sebocytes of patients with acne.24
The microcomedo will continue to expand with
densely packed keratin, sebum, and bacteria. Eventually this distension will cause follicular wall rupture.
The extrusion of the keratin, sebum, and bacteria into
the dermis results in a brisk inflammatory response.
The predominant cell type within 24 hours of comedo rupture is the lymphocyte. CD4+ lymphocytes are
found around the pilosebaceous unit, while CD8+ cells
are found perivascularly. One to two days after comedo rupture, the neutrophil becomes the predominant
cell type surrounding the burst microcomedo.25
It was originally thought that inflammation follows
comedo formation, but there is evidence that dermal
inflammation may actually precede comedo formation. Biopsies taken from comedo-free acne-prone
skin, demonstrate increased dermal inflammation
compared to normal skin. Biopsies of newly formed
comedos demonstrate even greater inflammation.26
This may suggest that inflammation actually precedes
comedo formation, again emphasizing the interplay
between all of the pathogenic factors. As mentioned
above, P. acnes also plays an active role in the process
DOC
DHEA
::
5-reductase
DHT
Chapter 80
Testosterone
899
13
Section 13
::
of inflammation. P. acnes is a Gram-positive, anaerobic,

and microaerobic bacterium found in the sebaceous
follicle. Adolescents with acne have higher concentrations of P. acnes compared to nonacne controls. However, there is no correlation between the raw number
of P. acnes organisms present in a sebaceous follicle and
the severity of the acne.27 Sebocyte differentiation and
proinflammatory cytokine/chemokine responses are
varied depending on the strain of P. acnes predominating within the follicle.28
The cell wall of P. acnes contains a carbohydrate
antigen that stimulates antibody development. Those
patients with the most severe acne have the highest
titers of antibodies.29 The antipropionobacterium antibody enhances the inflammatory response by activating
complement initiating a cascade of proinflammatory
events.30 P. acnes also facilitates inflammation by eliciting a delayed type hypersensitivity response and by
producing lipases, proteases, hyaluronidases, and chemotactic factors.31,32 Reactive oxygen species and lysosomal enzymes are released by neutrophils and levels
may correlate with severity.33 Additionally, P. acnes has
been shown to stimulate expression of cytokines by
binding to toll-like receptor 2 (TLR-2) on monocytes
and polymorphonuclear cells surrounding the sebaceous follicle.34 After binding TLR-2, proinflammatory
cytokines such as IL-1, IL-8, IL-12, and TNF- are
released.35,36 The antimicrobial peptides, histone H4
and cathelicidin, are also secreted locally in response
to P. acnes. Histone H4 exerts direct microbial killing,
while cathelicidin interacts with components of the
innate immune system, such as defensins and psoriasin, in response to P. acnes.37,38 Another indicator of
the role of innate immunity in the pathogenesis of acne
is the differentiation of peripheral blood monocytes
to CD209+ macrophages and CD1b+ dendritic cells in
response to P. acnes.39
The impact of diet on acne is an emerging area of
interest, particularly relating to glycemic index and
dairy consumption. Both are thought to increase insulin-like growth factor (IGF)-1 with possible proacne
effects and an increase in androgen activity.40,41
CLINICAL FINDINGS
900
HISTORY. Most patients with acne vulgaris report

gradual onset of lesions around puberty. In other cases,
acne can be seen in the neonatal or infantile age. Neonatal acne appears at about 2 weeks of age and infantile
acne develops at 36 months of age (see Chapter 107).
Since classic acne vulgaris is usually gradual in onset,
patients describing an abrupt onset of acne should be
questioned to possibly discover an underlying etiology, such as an androgen-secreting tumor.
Hyperandrogenism should be considered in the
female patient whose acne is severe, sudden in its
onset, or associated with hirsutism or irregular menstrual periods. The patient should be asked about the
frequency and character of her menstrual periods and
whether her acne flares with changes in her menstrual
cycle. Hyperandrogenism can also result in deepening of the voice, an increase in libido and hirsutism.
A complete medication history is important, as some

medications can cause an abrupt onset of a monomorphous acneiform eruption. Drug-induced acne may
be caused by: anabolic steroids, corticosteroids, corticotropin, phenytoin, lithium, isoniazid, vitamin B
complexes, halogenated compounds, and certain chemotherapy medications, particularly with epidermal
growth factor receptor (EGFR) inhibitors.
CUTANEOUS LESIONS. The primary site of acne

is the face and to a lesser degree the back, chest, and
shoulders. On the trunk, lesions tend to be concentrated near the midline. The disease is characterized
by several clinical lesion types (Fig. 80-3). Although
one type of lesion may predominate, close inspection
usually reveals the presence of several types of lesions.
The lesions may be either noninflammatory or inflammatory. The noninflammatory lesions are comedos,
which may be either closed (whiteheads; Fig. 80-3A)
or open (blackheads; Fig. 80-3B). The open comedo
appears as a flat or slightly raised lesion with a central
dark-colored follicular impaction of keratin and lipid
(Fig. 80-4). Closed comedones, in contrast to the open
comedones, may be difficult to visualize. They appear
as pale, slightly elevated, small papules, and do not
have a clinically visible orifice (Fig. 80-3A). Stretching
of the skin is an aid in detecting the lesions.
The inflammatory lesions vary from small papules with a red border to pustules and large, tender,
fluctuant nodules (see Figs. 80-3C and 80-3D and
Figs. 80-480-6). Some of the large nodules were previously called cysts and the term nodulocystic has been
used to describe severe cases of inflammatory acne.
True cysts are rarely found in acne; this term should
be abandoned and substituted with severe nodular acne
(see Figs. 80-3D and 80-6). Whether the lesion appears
as a papule, pustule, or nodule depends on the extent
and location of the inflammatory infiltrate in the dermis.
Scarring can be a complication of both noninflammatory and inflammatory acne. There are four general
types of acne scars: (1) ice pick, (2) rolling, (3) boxcar, and (4) hypertrophic42 (Fig. 80-7). Ice pick scars
are narrow, deep scars that are widest at the surface
of the skin and taper to a point in the dermis. Rolling
scars are shallow, wide scars that have an undulating
appearance. Boxcar scars are wide sharply demarcated
scars. Unlike ice pick scars, the width of boxcar scars is
similar at the surface and base. In rare instances, especially on the trunk, the scars may be hypertrophic.
Acne vulgaris is usually an isolated cutaneous finding, other than in the presence of hyperandrogenism.
Such cases may have associated hirsutism, precocious
puberty, and other signs of hyperandrogenism.
LABORATORY TESTS
In general, laboratory workup is not indicated for
patients with acne unless hyperandrogenism is suspected. There are numerous clinical studies relating
acne to elevated serum levels of androgens in both adolescents and adults. Among 623 prepubertal girls, girls
with acne had increased levels of DHEAS as compared
13
Chapter 80
::
Figure 80-3 Clinicopathologic correlation of acne lesions. A. Closed comedone. The follicular infundibulum is distended,
filled with keratin and sebum, and the follicular epithelium is attenuated. The follicular ostium is narrow. B. Open comedone. Resembles the closed comedone with the exception of a patulous follicular ostium. C. Inflammatory papule. Acute
and chronic inflammatory cells surround and infiltrate the follicle, which shows infundibular hyperkeratosis. D. Nodule.
The follicle is filled with acute inflammatory cells. With the rupture of the distended follicle, there is a foreign body granulomatous response.
Figure 80-4 Acne vulgaris mild. A. A 13-year-old girl with mild acne vulgaris. Scattered comedones and/or inflammatory
lesions are seen, usually limited to less than half of the face. The T-zone of the face is commonly involved. No nodules are
present. B. An adult female with primarily inflammatory acne. Note the typical involvement of the jawline.
901
13
Section 13
::
Figure 80-5 Acne vulgaris moderate. A. A 15-year-old male with moderate acne is seen. Typically more than half of the face
is involved with increasing numbers of lesions, usually a mix of lesions is seen: papules, pustules, and comedones. Infrequent and limited nodules may be present. Chest and back involvement may also be moderately affected. B. A 16-year-old
female with open and deep closed comedones is pictured. Scarring and postinflammatory changes are possible sequelae.
902
C
Figure 80-6 Acne vulgaris severe. A. A

17-year-old female with extensive acne is
seen. Numerous pustules and nodular lesions
admixed with comedones and smaller papules
cover the entire face. B. Deep, friable nodules
that coalesce into pseudocysts are seen in
acne conglobata. C. Chest and back involvement can be extensive and severe. Scarring is a
common complication in severe acne.
13
Chapter 80
::
Figure 80-7 Acne vulgaris, scarring. A. Honeycomb scarring is seen in this young girl with mild-to-moderate inflammatory acne. B. Extensive keloidal scarring occurring as sequelae of acne fulminans. C. Rolling scars.
to age-matched controls without acne.43 DHEAS can
serve as a precursor for testosterone and DHT. Elevated serum levels of androgens have been found in
cases of severe cystic acne and in acne associated with
a variety of endocrine conditions, including congenital adrenal hyperplasia (11- and 21-hydroxylase
deficiencies), ovarian or adrenal tumors, and polycystic ovarian disease. However, in the majority of
acne patients serum androgens are within the normal
range.44,45
Excess androgens may be produced by either
the adrenal gland or ovary. The laboratory workup
should include measurement of serum DHEAS, total
testosterone, and free testosterone. Additional tests
to consider include the luteinizing hormone (LH) to
follicle-stimulating hormone (FSH) ratio or serum
17-hydroxyprogesterone to identify an adrenal source
of androgens in cases where testing does not clearly
indicate an adrenal or ovarian source of androgens.
Testing should be obtained just prior to or during the
menstrual period, not midcycle at the time of ovulation. Patients on contraceptives that prevent ovulation will need to discontinue their medication for at
least 1 month prior to testing. Values of DHEAS in the
range of 4,0008,000 ng/mL (units may vary at different laboratories) may be associated with congenital
adrenal hyperplasia. Patients with a serum level of
DHEAS >8,000 ng/mL could have an adrenal tumor
and should be referred to an endocrinologist for fur-
ther evaluation. An ovarian source of excess androgens can be suspected in cases where the serum total
testosterone is >150 ng/dL. Serum total testosterone
in the range of 150200 ng/dL or an increased LH/
FSH ratio (>2.0) can be found in cases of polycystic
ovary disease. Greater elevations in serum testosterone may indicate an ovarian tumor, and appropriate
referral should be made. There is a significant amount
of variability in individual serum androgen levels. In
cases in which abnormal results are obtained, it may
be wise to repeat the test before proceeding with therapy or additional testing.
Many patients report that their acne flares during
periods of stress. Although objective data are limited,
stress is known to increase the output of adrenal steroids, which may affect the sebaceous gland.46 It has
been shown that patients with acne have a greater
increase in urinary glucocorticoid levels after corticotropin administration.47
Although one type of lesion may predominate, acne
vulgaris is diagnosed by a variety of acne lesions
(comedones, pustules, papules, and nodules) on the
face, back, or chest (see Box 80-1). Diagnosis is usually
easy, but inflammatory acne may be confused with folliculitis, rosacea, or perioral dermatitis. Patients with
903
13

of Acne
Section 13
Most Likely
Closed comedonal acne
Milia
Sebaceous hyperplasia
Open comedonal acne
Dilated pore of Winer
FavreRacouchot syndrome
Inflammatory acne
Rosacea
Perioral dermatitis
Neonatal acne
Miliaria rubra
::
Consider
Osteoma cutis
Trichoepitheliomas
Trichodiscomas
Fibrofolliculomas
Eruptive vellus hair cysts, steatocystoma multiplex
Colloid milia
Flat warts
Open comedonal acne
Trichostasis spinulosa
Nevus comedonicus
Inflammatory acne
Pseudofolliculitis barbae, acne keloidalis nuchae
Keratosis pilaris
Neurotic excoriations/factitial
Lupus miliaris disseminatus faciei
Neonatal acne
Sebaceous hyperplasia
Milia
Always Rule Out
Acne due to systemic agents (e.g., corticosteroids)
Contact acne (e.g., occupational acne)
Chloracne
Open comedonal acne
Acne due to systemic agents
Contact acne
Chloracne
Inflammatory acne
Acne due to systemic agents
Staphylococcal folliculitis
Gram-negative folliculitis
Eosinophilic folliculitis
Furuncle/carbuncle
Angiofibromas of tuberous sclerosis
Neonatal acne
Candidal infections
Benign neonatal cephalic pustulosis
904
tuberous sclerosis and facial angiofibromas have been

misdiagnosed as having recalcitrant midfacial acne.
Facial flat warts or milia are occasionally confused
with closed comedones.
Acne can be seen in association with endocrinologic
abnormalities. Patients with hyperandrogenism may
have acne plus other stigmata of increased androgen levels (i.e., hirsutism, deepened voice, irregular
menses). Endocrinologic disorders such as polycystic
ovarian syndrome (including HAIR-AN syndrome),
congenital adrenal hyperplasia, and adrenal and ovarian neoplasms often have accompanying acne.
Variants of acne must also be differentiated from
typical acne vulgaris in order to guide treatment.
These types of acne include: neonatal acne, infantile
acne, acne fulminans, acne conglobata, acne with solid
facial edema, and acne excorie des jeunes filles. These
variants are discussed in detail later in the chapter.
There are several less common acneiform eruptions that can be confused with acne vulgaris. These
mimickers include: medication-induced acne, halogen
acne, chloracne, acne mechanica, tropical acne, radiation acne, and other various miscellaneous acneiform
disorders that are discussed subsequently.
COMPLICATIONS
All types of acne lesions have the potential to resolve
with sequelae. Almost all acne lesions leave a transient macular erythema after resolution. In darker skin
types, postinflammatory hyperpigmentation may persist months after resolution of acne lesions. In some
individuals, acne lesions may result in permanent
scarring.
Acne vulgaris may also take a psychological toll on
many patients. It is estimated that 30%50% of adolescents experience psychiatric disturbances due to
acne.48 Studies have shown that patients with acne
have similar levels of social, psychological, and emotional impairment as those with asthma and epilepsy.49
Additional studies have also shown that unemployment rates are higher among adults with acne than
those without.50 When appropriate, patients should be
referred for psychiatric counseling.

The age of onset of acne varies considerably. It may
start as early as 68 years of age or it may not appear
until the age of 20 or later. The course is one of several years duration followed by spontaneous remission in the majority of cases. While most patients will
clear by their early twenties, some have acne extending well into the third or fourth decades. The extent
of involvement varies, and spontaneous fluctuations
in the degree of involvement are the rule rather than
the exception. In women there is often a fluctuation
in association with menses, with a flare just before the
onset of menstruation. This flare is not due to a change
in sebaceous gland activity as there is no increase in
sebum production in the luteal phase of the menstrual
cycle. It has been shown that prepubescent females

with comedonal acne and those females with high
DHEAS levels are predictors of severe or long-standing
nodulocystic acne.51
for acne can be categorized in the following categories

as they relate to the pathophysiology:
13
1. Correct the altered pattern of follicular
keratinization.
2. Decrease sebaceous gland activity.

3. Decrease the follicular bacterial population,
TREATMENT
particularly P. acnes.
4. Exert an anti-inflammatory effect.
LOCAL THERAPY
Cleansing. The importance
of cleansing in the
treatment of acne is generally intuitive. Twice daily
washing with a gentle cleanser followed by the
application of acne treatments may encourage a routine
and therefore better compliance. Overcleansing or
using harsh alkaline soaps are likely to increase the
Chapter 80
Tailoring a patients acne regimen with the knowledge of the pathogenesis of acne and the mechanism
of action of the available acne treatments will ensure
maximum therapeutic response. Treatment regimens
should be initiated early and be sufficiently aggressive
to prevent permanent sequelae. Often multiple treatments are used in combination so as to combat many
factors in the pathogenesis of acne (Table 80-1). The
mechanism of action of the most common treatments
::
Treatment Algorithm for Acne Vulgaris

Mild
Moderate
Severe
Comedonal
Papular/
Pustular
Papular/Pustular
Nodular
Conglobata/
Fulminans
First
Topical
retinoid or
combinationa
Topical retinoid +
topical antimicrobial
or combinationa
Oral antibiotic +
topical retinoid BPO
or combinationa
Oral antibiotic +
Oral isotretinoin oral

corticosteroids
Second
Topical
dapsone or
azelaic acid or
salicylic acid
Topical dapsone
or azelaic acid or
salicylic acid
Oral antibiotic +
or combinationa
Oral isotretinoin
or oral antibiotic +
topical retinoid
BPO/azelaic acid or
combinationa
High-dose oral
antibiotic + topical
retinoid + BPO or
combinationa
Female
+ Oral contraceptive/
antiandrogen
antiandrogen
antiandrogen
Additional
options
Comedone
extraction
Laser/light therapy,
photodynamic
therapy
Comedone extraction,
laser/light therapy,
photodynamic
therapy
Comedone extraction;
intralesional
corticosteroid,
photodynamic
therapy
Intralesional
corticosteroid,
photodynamic therapy
Refractory to
treatment
Check
compliance
Check compliance
Exclude Gramnegative folliculitis
Females: Exclude
polycystic ovary
syndrome, adrenal
or ovarian tumors,
congenital adrenal
hyperplasia
Males: Exclude
congenital adrenal
hyperplasia
Maintenance
Topical
retinoid
BPO, or
combinationa
Topical retinoid
BPO, or combinationa
Topical retinoid BPO,

or combinationa
Topical retinoid
BPO, or combinationa
BPO = benzoyl peroxide.

a
Manufactured combination products include BPO/erythromycin, BPO/clindamycin, adapalene/BPO, tretinoin/clindamycin.
Adapted from Gollnick H et al: Management of acne: A report from a Global Alliance to improve outcomes in acne. J Am Acad Dermatol 49:1, 2003.
TABLE 80-1
905
13
skins pH, disrupt the cutaneous lipid barrier, and

compound the irritancy potential of many topical
acne treatments. Use of a syndet (synthetic detergent)
will allow cleansing without disruption of the skins
normal pH. Antibacterial soaps, containing agents
such as triclosan, inhibit Gram-positive cocci but
may increase Gram-negative rods; their overall affect
on acne is unclear. Medicated cleansers, containing
benzoyl peroxide or salicylic acid, offer convenience as
a wash and are excellent for hard to reach areas like
the back.
Topical Agents. (See Table 80-2)

Section 13
::
Sulfur/Sodium Sulfacetamide/Resorcinol. Products

containing sulfur, sodium sulfacetamide, and resorcinol,
once favored treatments for acne, are still found in several
over-the-counter and prescription niche formulations.
Sulfonamides are thought to have antibacterial properties
through their inhibition of para-aminobenzoic acid
(PABA), an essential substance for P. acnes growth.52 Sulfur
also inhibits the formation of free fatty acids and has
presumptive keratolytic properties. It is often combined
with sodium sulfacetamide to enhance its cosmetic
tolerability due to sulfurs distinctive odor. Resorcinol
is also indicated for use in acne for its antimicrobial
properties. It is generally found in 2% concentration in
combination with 5% sulfur.
Salicylic Acid. Salicylic acid is a ubiquitous ingredient
found in over-the-counter acne preparations in concentrations ranging from 0.5% to 2%. This lipid soluble
-hydroxy acid has comedolytic properties, though
somewhat weaker than those of a retinoid. Salicylic
acid also causes exfoliation of the stratum corneum
though decreased cohesion of the keratinocytes. Mild
irritant reactions may result.
Azelaic Acid. Azelaic acid is available by prescription
in a 20% cream or 15% gel. This dicarboxcylic acid has
both antimicrobial and comedolytic properties.53 It is
also a competitive inhibitor of tyrosinase and thus may
decrease postinflammatory hyperpigmentation.54 It is
generally well tolerated, though transient burning can
occur, and is safe in pregnancy.
Benzoyl Peroxide. Benzoyl peroxide preparations are
among the most common topical medications prescribed by dermatologists and are also readily available over-the-counter. Benzoyl peroxide is a powerful
antimicrobial agent through decreasing both the bacterial population and the hydrolysis of triglycerides.
Benzoyl peroxide preparations are available in creams,
lotion, gels, washes, and pledgets. Products that are
left on the skin, such as a gel, are generally considered
more effective. Benzoyl peroxide can produce significant dryness and irritation. Allergic contact dermatitis has been uncommonly reported. Of significance,
bacteria are unable to develop resistance to benzoyl
peroxide, making it the ideal agent for combination
therapy.55
906
Topical Antibiotics. (See Chapter 218). Erythromycin

and clindamycin are the most commonly used topical
antibiotics for the treatment of acne. These two agents

have also been used in combination preparations with
benzoyl peroxide. Increased levels of P. acnes resistance
have been reported in patients who are being treated
with antibiotics. However, the development of resistance is less likely in patients who are treated with a
combination of benzoyl peroxide/erythromycin or
clindamycin.56 Therefore, the combination of these two
products is preferable over monotherapy with topical antibiotics. Topical dapsone is the most recently
approved topical antibiotic for acne. With twice daily
application topical dapsone has shown better efficacy
in controlling inflammatory lesions (58%) versus noninflammatory lesions (19%).57,58 Unlike oral dapsone,
topical dapsone is safe for use even in patients with
a G6PD deficiency.59 It is generally well tolerated but
should not be applied concomitantly with benzoyl peroxide or it may impart an orange color on the skin.60
Retinoids. (See Chapter 217). Retinoids are defined
by their ability to bind to and activate retinoic acid
receptors (RAR) and in turn activate specific gene transcription resulting in a biologic response. Some have
chemical structures similar to tretinoin (all-trans-retinoic acid), but they may be entirely dissimilar, such
as adapalene or tazarotene, and still potentiate a retinoid effect. In general, the binding of these agents to
nuclear RAR affects the expression of genes involved
in cell proliferation, differentiation, melanogenesis,
and inflammation.61,62 The result is modification of
corneocyte accumulation and cohesion, and inflammation. Thus, retinoids have both comedolytic and antiinflammatory properties.62
Tretinoin is commercially available in several
strengths and formulations. Having both potent comedolytic and anti-inflammatory properties, it is widely
used. In general, all retinoids can be contact irritants,
with alcohol-based gels and solutions having the greatest irritancy potential. Some newer formulations utilize a microsphere delayed-delivery technology (Retin
A Micro 0.04% or 0.1% gel) or are incorporated within
a polyolprepolymer (PP-2) (Avita cream) to decrease
the irritancy potential of tretinoin while allowing
greater concentration of medication. Advising patients
to apply tretinoin on alternate nights during the first
few weeks of treatment can help ensure greater tolerability. Patients must also be cautioned about sun
exposure due to thinning of the stratum corneum,
especially those with any irritant reaction. Regular use
of a sunscreen should be advised. The comedolytic and
anti-inflammatory properties of topical retinoids make
them ideal for maintenance therapy of acne. Generic
tretinoin is inactivated by concomitant use of benzoyl
peroxide and is photolabile. Therefore, patients should
be counseled to apply tretinoin at bedtime.
Adapalene is a synthetic retinoid widely marketed
for its greater tolerability. It specifically targets the
RAR receptor. It is both photostable and can be used
in conjunction with benzoyl peroxide without degradation. Adapalene 0.1% gel has been shown in clinical trials to have greater or equal efficacy to tretinoin
0.025% gel with greater tolerability.63,64 It is available
at a 0.1% concentration in both a nonalcohol gel and
13
TABLE 80-2
Commonly Available Prescription Acne PreparationsTopical

Generic
Trade
Vehicle
Concentration
Size
Retin-A
Cream
Gel
Liquid
Gel with microsponge
0.025%, 0.05%, 0.1%

0.01%, 0.025%
0.05%
0.04%, 0.1%
Cream
Gel
Cream
Cream
Gel
Cream
Gel
Cream
Gel
Lotion
Gel
Cream
Gel
0.025%
0.025%
0.05%
0.025%, 0.05%, 0.1%
0.025%, 0.1%
0.025%, 0.05%, 0.1%
0.025%, 0.1%
0.1%
0.1%, 0.3%
0.1%
0.1%
0.1%
0.1%
20 g, 45 g
15 g, 45 g (0.025% only)
28 mL
20 g, 45 g
50-g pump
20 g, 45 g
20 g, 45 g
40 g
35 g (kit with cleanser)
20 g, 45 g
15 g, 45 g
15 g, 45 g
15 g, 45 g
2 oz
45 g
30 g, 60 g
30 g, 60 g
Ziana
Epiduo
Gel
Gel
0.025%/1.2%
2.5%/0.1%
30 g, 60 g
45 g
Benzac AC
Gel
Wash
Gel
Wash
Cream
Gel
Wash
Gel
Creamy wash
Gel
Gel
Gel
Cleanser
Pads
Foaming cloths
Cleanser
Pads
Hydrating wash
Gel
Wash
Gel
Ointment
Solution
Pledget
Gel
Lotion
Solution
Pledget
Foam
Gel
Gel
Lotion
Pledget
Gel
Lotion
Solution
Gel
Gel
2.5%, 5%, 10%

2.5%, 5%, 10%
2.5%, 5%, 10%
5%, 10%
5%, 10%
5.25%
5.25%
4%, 8%
4%, 8%
7%
2.5%, 5%, 10%
3%, 6%, 9%
3%, 6%, 9%
3%, 6%, 9%
3%, 6%, 9%
4.5%. 6.5%, 8.5%
4.5%. 6.5%, 8.5%
5.75%
5%, 10%
2.5%, 5%, 10%
2%
2%
2%
2%
1%
1%
1%
1%
1%
1%
1%
1%
1%
1%
1%
1%
5%
5%/3%
60 g
240 mL (2.5%), 226 mL
60 g
226 mL
113.4 g
50 g
175 g
42.5 g
45 g
42.5 g
42.5 g
6 oz, 12 oz
1 g (30 or 60/box)
3.2 g (30 or 60/box)
400 mL
6 mL (30/box)
400 mL
45 g, 60 g, 90 g
142 g, 227 g
30 g, 60 g
25 g
60 mL
(60/box)
30 g, 60 g
60 mL
30 mL, 60 mL
(60/box)
50 g, 100 g
40 mL, 75 mL
30 g, 60 g
60 mL
60 s
30 g, 60 g
30 g, 60 g
30 g
30 g
46.6 g, 60/box
Gel
Gel
5%/3%
5%/1%
Duac
Acanya
Generic
Vanoxide HC
Gel
Gel
Gel
Lotion
5%/1%
2.5%/1.2%
5%/1%
5%0.5%
23.2 g, 46.6 g
25 g, 50 g
50-g pump
45 g
50 g
50 g
25 mL
Sodium sulfacetamide
Sodium sulfacetamide/sulfur
Klaron
Sulfacet-R
Rosula
Azeleic acid
Azelex
Lotion
Lotion
Gel
Cleanser
10%
105%
10%5% in 10% urea
10%5% in 10% urea
4 oz
25 g
45 mL
355 mL
RetinoidsTopical
Tretinoin
Retin-A micro
Avita
Refissa
Tretin-X
Differin
Tazarotene
Generic
Tazorac
::
Retinoid CombinationsTopical
AntimicrobialsTopical
Benzoyl peroxide
Benzac W
Benzashave
Benziq LS
Brevoxyl
Clinac
Desquam E
Triaz
Zoderm
Generic
Erythromycin
Generic
Clindamycin
Cleocin T
Evoclin
Clindagel
ClindaMax
Clindets
Generic
Dapsone
Benzoyl peroxide/
erythromycin
Benzoyl peroxide/clindamycin
Benzoyl peroxide/
hydrocortisone
Aczone
Benzamycin
Benzamycin Gel Pak
Generic
Benzaclin
Tretinoin/clindamycin
Adapalene/benzoyl peroxide
Chapter 80
Generic
Adapalene
Miscellaneous
Cream
20%
30 g, 50 g
907
13
Section 13
::
908
cream and as a 0.3% gel. The 0.3% adapalene gel has

been shown to have similar efficacy to tazarotene 0.1%
gel with increased tolerability.65 A combination topical
agent containing 0.1% adapalene and 2.5% benzoyl
peroxide is also available.66,67
Tazarotene, also a synthetic retinoid, exerts is action
through its metabolite, tazarotenic acid, which in turn
inhibits the RAR receptor. It is a potent comedolytic
agent and has been show to be more effective than
tretinoin 0.025% gel and tretinoin 0.1% microsphere
gel.68,69 Both the 0.1% cream and gel formulations are
approved for the treatment of acne. The irritant properties of tazarotene can be minimized by the use of
short-term contact therapy. In this regimen, the medication is applied for 5 minutes then washed off with a
gentle cleanser. Tazarotene has been given a pregnancy
category X rating and female patients of childbearing
age should be adequately counseled.
An overview of topical agents for acne treatment is
outlined in Table 80-2.
SYSTEMIC THERAPY
Antibiotics and Antibacterial Agents.
Chapter 230).
(See
Tetracyclines. Broad-spectrum antibiotics are widely

used in the treatment of inflammatory acne. The tetracyclines are the most commonly used antibiotics in the
treatment of acne. Although the oral administration of
tetracyclines does not alter sebum production, it does
decrease the concentration of free fatty acids while
the esterified fatty acid content increases. Decreases
in free fatty acid formation also have been reported
with erythromycin, demethylchlortetracycline, clindamycin, and minocycline. The free fatty acids are probably not the major irritants in sebum, but their level is
an indication of the metabolic activity of the P. acnes
bacteria and its secretion of other proinflammatory
products. The decrease in free fatty acids may take
several weeks to become evident. This, in turn, is
reflected in the clinical course of the disease during
antibiotic therapy, as several weeks are often required
for maximal clinical benefit. The effect, then, is one of
prevention; the individual lesions require their usual
time to undergo resolution. However, the fact that a
decrease in free fatty acids does occur strengthens the
rationale for the use of tetracycline. Tetracycline may
also act through direct suppression of the number of
P. acnes, but part of its action may be due to its antiinflammatory activity. In clinical practice, tetracycline
is usually given initially in dosages of 5001,000 mg/
day. Higher doses of up to 3,500 mg/day have been
used in severe cases, but prudent monitoring of liver
functions is warranted. Tetracycline should be taken
on an empty stomach, 1 hour before or 2 hours after
meals, to promote absorption; thus, compliance by
adolescents with its administration can be challenging. Gastrointestinal (GI) upset is the most common
side effect, with esophagitis and pancreatitis possible.
Uncommon side effects include hepatotoxicity, hypersensitivity reactions, leukocytosis, thrombocytopenic purpura, and pseudotumor cerebri. Tetracyclines
should be used with caution in patients with renal
isease as they may increase uremia. Tetracyclines

d
have an affinity for rapidly mineralizing tissues and
are deposited in developing teeth, where they may
cause irreversible yellowbrown staining; also, tetracyclines have been reported to inhibit skeletal growth in
the fetus. Therefore, they should not be administered
to pregnant women, especially after the fourth month
of gestation and are not recommend for use in children
younger than 9 years of age in the treatment of acne.
The tetracycline derivatives, doxycycline and
minocycline, are also commonly used in the treatment of acne. They have the distinct advantage of
being able to be taken with food without impaired
absorption. Doxycycline is administered in dosages
of 50100 mg twice daily. Its major disadvantage
is the potential risk of photosensitivity reactions,
including photo-onycholysis, and patients may need
to be switched to another antibiotic during summer
months. Minocycline is given in divided dosages at
a level of 100200 mg/day. Patients on minocycline
should be monitored carefully, as the drug can cause
blueblack pigmentation, especially in the acne scars,
as well as the hard palate, alveolar ridge, and anterior shins. Vertigo has occasionally been described.
Minocycline-induced autoimmune hepatitis and a
systemic lupus erythematosus-like syndrome have
been reported during minocycline therapy, but these
side effects are very rare.70,71 Of note, patients who
develop lupus-like reactions can be safely switched to
an alternative tetracycline. Serum sickness-like reactions and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have also been
reported with minocycline use.
Macrolides. Due to the prevalence of erythromycinresistant strains of P. acnes, the use of oral erythromycin is generally limited to pregnant women or children.
Azithromycin has been used more often for acne,
typically at dosages of 250500 mg orally three times
weekly.72 Azithromycin undergoes hepatic metabolism
with GI upset and diarrhea as the most common side
effects.
TrimethoprimSulfamethoxazole. Trimethoprimsulfamethoxazole combinations are also effective in acne.
In general, because the potential for side effects is
greater with their use, they should be used only in
patients with severe acne who do not respond to
other antibiotics. GI upset and cutaneous hypersensitivity reactions are common. Serious adverse reactions, including the StevensJohnson syndrome-toxic
epidermal necrolysis spectrum (see Chapter 40) and
aplastic anemia, have been described. If trimethoprim
sulfamethoxazole is used, the patient must be monitored
for potential hematologic suppression approximately
monthly.
Cephalexin. Cephalexin, a first generation cephalosporin, has been shown in vitro to kill P. acnes. However,
because it is hydrophilic and not lipophilic it penetrates
poorly into the pilosebaceous unit. Success with oral
cephalexin73 is most likely due to its anti-inflammatory
rather than antimicrobial properties. Due to the risk
of promoting the development of bacterial resistance,
particularly to Staphylococcus, the authors discourage

the use of cephalexin for acne.
Oral Contraceptives. Oral contraceptives can

improve acne by four main mechanisms. Firstly, they
decrease the amount of gonadal androgen production by suppressing LH production. Secondly, they
decrease the amount of free testosterone by increasing the production of sex hormone binding globulin.
Thirdly, they inhibit the activity of 5- reductase activity, so as to prevent the conversion of testosterone to
the more potent DHT. Lastly, progestins that have an
antiandrogenic effect can block the androgen receptors on keratinocytes and sebocytes. The third-generation progestinsgestodene (not available in the
United States), desogestrel, and norgestimate, have
the lowest intrinsic androgenic activity.76 Two progestins have demonstrated antiandrogenic properties:
(1) cyproterone acetate (not available in the United
States) and (2) drospirenone. There are three oral con-
HORMONAL THERAPY OF ACNE. The goal of

hormonal therapy is to counteract the effects of androgens
on the sebaceous gland. This can be accomplished with
the antiandrogens, or agents designed to decrease
the endogenous production of androgens by the
ovary or adrenal gland, including oral contraceptives,
glucocorticoids, or gonadotropin-releasing hormone
(GnRH) agonists.
Glucocorticoids. Because of their anti-inflammatory activity, high-dose systemic glucocorticoids

may be of benefit in the treatment of acne. In practice,
their use is usually restricted to the severely involved
patient, often overlapping with isotretinoin to limit any
potential flaring from at the start of treatment. Furthermore, because of the potential side effects, these drugs
are ordinarily used for limited periods of time, and
recurrences after treatment are common. Prolonged use
may result in the appearance of steroid acne. Glucocorticoids in low dosages are also indicated in those female
patients who have an elevation in serum DHEAS associated with an 11- or 21-hydroxylase deficiency or in
other individuals with demonstrated androgen excess.
Low-dose prednisone (2.5 mg or 5 mg) or dexamethasone can be given orally at bedtime to suppress adrenal
androgen production.44 The combined use of glucocorticoids and estrogens has been used in recalcitrant acne
in women, based upon the inhibition of sebum production by this combination.80 The mechanism of action
is probably related to a greater reduction of plasma
androgen levels by combined therapy than is produced
by either drug alone.
::
Antibiotics and Bacterial Resistance. Antibiotic resistance is a growing concern worldwide

and should be suspected in patients unresponsive to
appropriate antibiotic therapy after 6 weeks of treatment. Increasing propionobacterium resistance has
been documented to all macrolides and tetracyclines
commonly used in the treatment of acne. A prevalence
rate of 65% was documented in one study performed
in the United Kingdom.74 Overall, resistance is highest with erythromycin and lowest with the lipophilic
tetracyclines, doxycycline, and minocycline.75 The
least resistance is noted with minocycline. To prevent
resistance, prescribers should avoid antibiotic monotherapy, limit long-term use of antibiotics and combine
usage with benzoyl peroxide whenever possible.55
13
Chapter 80
Clindamycin and Dapsone. Less commonly used

antibiotics include clindamycin and dapsone. Oral
clindamycin had been used more readily in the past,
but because of the risk of pseudomembranous colitis, it
is now rarely used systemically for acne. It is still commonly used topically, however, often in combination
with benzozyl peroxide. Dapsone (see Chapter 225),
a sulfone often used for cutaneous neutrophilic disorders, may be beneficial in severe markedly inflammatory acne and select cases of resistant acne. It is used
at doses of 50100 mg daily for 3 months. G6PD levels
should be examined prior to initiation of therapy and
regular monitoring for hemolysis and liver function
abnormalities is warranted. While not as reliably effective as isotretinoin, it is relatively low cost and should
be considered in severe cases where isotretinoin is not
an option.
traceptives currently Food and Drug Administration

(FDA) approved for the treatment of acne: (1) Ortho
Tri-Cyclen, (2) Estrostep, and (3) Yaz. Ortho Tri-Cyclen
is a triphasic oral contraceptive comprised of a norgestimate (180, 215, 250 mg)ethinyl estradiol (35 g)
combination.77 In an effort to reduce the estrogenic
side effects of oral contraceptives, preparations with
lower doses of estrogen (20 g) have been developed
for the treatment of acne. Estrostep contains a graduated dose of ethinyl estradiol (2035 g) in combination with norethindrone acetate (1 mg).78 Yaz contains
ethinyl estradiol (20 ug) and the antiandrogen drospirenone (3 mg). Drospirenone is a 17 -spironolactone
derivative that has both antimineralocorticoid and
antiandrogenic properties, which may improve
estrogen-related weight gain and bloating.78 An oral
contraceptive containing a low dose of estrogen
(20 g) in combination with levonorgestrel (Alesse)
has also demonstrated efficacy in acne.79 Side effects
from oral contraceptives include nausea, vomiting,
abnormal menses, weight gain, and breast tenderness.
Rare but more serious complications include thrombophlebitis, pulmonary embolism, and hypertension.
With the use of estrogenprogestin-containing oral
contraceptives rather than estrogen alone, side effects
such as delayed menses, menorrhagia, and premenstrual cramps are uncommon. However, other side
effects such as nausea, weight gain, spotting, breast
tenderness, amenorrhea, and melasma can occur.
Gonadotropin-Releasing Hormone Agonists. GnRH agonists, such as leuprolide (Lupron),
act on the pituitary gland to disrupt its cyclic release of

gonadotropins. The net effect is suppression of ovarian steroidogenesis in women. These agents are used
in the treatment of ovarian hyperandrogenism. GnRH
agonists have demonstrated efficacy in the treatment
of acne and hirsutism in females both with and without
endocrine disturbance.81 However, their use is limited
909
13
by their side effect profile, which includes menopausal

symptoms and bone loss.
Section 13
::
Antiandrogens. Spironolactone is an aldosterone

antagonist and functions in acne as both an androgenreceptor blocker and inhibitor of 5- reductase. In
doses of 50100 mg twice a day, it has been shown to
reduce sebum production and to improve acne.82 Side
effects include: diuresis, potential hyperkalemia, irregular menstrual periods, breast tenderness, headache,
and fatigue. Combining spironolactone treatment with
an oral contraceptive can alleviate the symptoms of
irregular menstrual bleeding. Although hyperkalemia
is a risk of spironolactone, this risk has shown to be
minimal, even when spironolactone is administered
with other aldosterone antagonists (such as drospirenone containing oral contraceptives).83 As an antiandrogen, there is a risk of feminization of a male fetus
if a pregnant female takes this medication. Long-term
studies in rats receiving high doses of spironolactone
demonstrated an increased incidence of adenomas on
endocrine organs and the liver. These findings recently
led to a black box warning by the FDA.84
Cyproterone acetate is a progestational antiandrogen that blocks the androgen receptor. It is combined
with ethinyl estradiol in an oral contraceptive formulation that is widely used in Europe for the treatment
of acne. Cyproterone acetate is not available in the
United States.
Flutamide, an androgen receptor blocker, has been
used at doses of 250 mg twice a day in combination
with oral contraceptives for treatment of acne or
hirsutism in females.85 Liver function tests should
be monitored, as cases of fatal hepatitis have been
reported.86 Pregnancy should be avoided. Use of flutamide in the treatment of acne may be limited by its
side effect profile.
Isotretinoin. (See Chapter 228). The use of the oral
910
retinoid, isotretinoin, has revolutionized the management of treatment-resistant acne.87 It is approved for
use in patients with severe recalcitrant nodular acne.
However, it is commonly used in many other acne scenarios, including any significant acne that is unresponsive to treatment with oral antibiotics and acne that
results in significant physical or emotional scarring.
Isotretinoin is also effective in the treatment of Gramnegative folliculitis, pyoderma faciale, and acne fulminans.88 The remarkable aspects of isotretinoin therapy
are the complete remission in almost all cases and the
longevity of the remission, which lasts for months to
years in the great majority of patients. However, due to
its teratogenicity its use has become highly regulated
in the United States with the initiation of the iPledge
program in March 2006 to insure that pregnancy-prevention procedures are followed.
The mechanism of action of isotretinoin is not completely known. The drug produces profound inhibition of sebaceous gland activity, and this undoubtedly
is of great importance in the initial clearing.89,90 In some
patients, sebaceous gland inhibition continues for
at least a year, but in the majority of patients, sebum
production returns to normal after 24 months.89
Thus, this action of the drug cannot be used to explain

the long-term remissions. The P. acnes population is
also decreased during isotretinoin therapy, but this
decrease is generally transient.90,91 Isotretinoin has
no inhibitory effect on P. acnes in vitro. Therefore, the
effect on the bacterial population is probably indirect,
resulting from the decrease in intrafollicular lipids
necessary for organism growth. Isotretinoin also has
anti-inflammatory activity and probably has an effect
on the pattern of follicular keratinization. These effects
also are temporary, and the explanation for long-term
remissions remains obscure.
Given the ubiquitous distribution of RAR, isotretinoin almost always causes side effects, mimicking
those seen in the chronic hypervitaminosis A syndrome.92 In general, the severity of side effects tends
to be dose dependent. The most common side effects
are related to the skin and mucous membranes. Cheilitis of varying degrees is found in virtually all cases.
Other side effects that are likely to be seen in over 50%
of patients are dryness of the mucous membranes and
skin. An eczematous dermatitis is occasionally seen,
particularly in cold, dry weather. Thinning of hair and
granulomatous paronychial lesions are less common.
Ophthalmologic findings include xerophthalmia, night
blindness, conjunctivitis, keratitis, and optic neuritis.
Corneal opacities and hearing loss (both transient and
persistent) have also been reported with isotretinoin
use. Pseudotumor cerebri, also known as benign intracranial hypertension, is evidenced by severe headache,
nausea, and visual changes. The risk of pseudotumor
cerebri may be increased with concomitant use of tetracyclines and isotretinoin; therefore, these two medications should not be used together without careful
prior consideration. If symptoms suggest benign intracranial hypertension, prompt neurological evaluation
for evidence of papilledema is required. Vague complaints of headache, fatigue, and lethargy are also not
infrequent.
The relationship between isotretinoin use and psychiatric effects is currently being examined. Risk of
depression, suicide, psychosis, and aggressive and/or
violent behavior are all listed as possible side effects.
While no clear mechanism of action has been established, some evidence for biologic plausibility does
exist. Psychiatric adverse events are described with
high-dose vitamin A and etretinate. Also, retinoids
have the demonstrated ability to enter the central
nervous system (CNS) of rats and mice. And finally,
there are documented case reports and studies linking
isotretinoin use to depression in certain individuals.93
A meta-analysis of nine studies looking at the possible link between isotretinoin and depression found
that the incidence of depression in patients on isotretinoin ranged from 1%11%.94 The authors importantly
pointed out that this range is similar to control group
patients on oral antibiotics. Another author examining case-control studies on isotretinoin and depression
found the relative risk to range from 0.9 to 2.7 with
wide confidence intervals.95 Some studies demonstrate
that those on isotretinoin have an overall improvement
in mood.96 Retinoids have not been shown to activate
genes to induce behavioral/psychiatric changes. Nor
13
::
organogenesis. Therefore, the production of retinoic

embryopathy occurs very early in pregnancy, with a
peak near the third week of gestation.102,103 A significant number of fetal abnormalities have been reported
after the use of isotretinoin. For this reason, it should
be emphasized that isotretinoin should be given only
to patients who have not responded to other therapy.
Furthermore, women who are of childbearing age
must be fully informed of the risk of pregnancy. The
patient must employ two highly effective contraception techniques such as the use of an oral contraceptive
and condoms with a spermicidal jelly. Contraception
must be started at least 1 month before isotretinoin
therapy. Female patients must be thoroughly counseled and demonstrate an understanding of contraception techniques before starting isotretinoin. Two
forms of contraception should be used throughout the
course of isotretinoin and for 1 month after stopping
treatment. No more than 1 months supply of isotretinoin should be given to a female patient so that she
can be counseled on a monthly basis on the hazards
of pregnancy during isotretinoin therapy. A pregnancy
test must be repeated monthly. Abstinence as a form
of birth control should only be allowed in special
instances. Because the drug is not mutagenic, there
is no risk to a fetus conceived by a male who is taking isotretinoin. Although it may seem obvious, it is
important to remind men who are taking isotretinoin
not to give any of their medication to female companions under any circumstances.
The recommended daily dosage of isotretinoin
is in the range of 0.51 mg/kg/day. A cumulative
weight-based dosing formula may also be used with
a total dose of 120150 mg/kg of isotretinoin during a course of therapy.104 This dosing regimen is of
particular use in patients who have variable dosages
or interrupted periods of treatment as achieving the
total dose will ensure the greatest chance of longterm remission. Because back and chest lesions show
less of a response than facial lesions, dosages as high
as 2 mg/kg/day may be necessary in those patients
who have very severe truncal involvement. Patients
with severe acne, particularly those with granulomatous lesions, will often develop marked flares of
their disease when isotretinoin is started. Therefore,
the initial dosing should be low, even below 0.5 mg/
kg/day. These patients often need pretreatment for
12 weeks with prednisone (4060 mg/day), which
may have to be continued for the first 2 weeks of
therapy. A typical course of isotretinoin is 20 weeks,
but the length of the course of treatment is not absolute; in patients who have not shown an adequate
response, therapy can be extended. Additional
improvement may be seen for 12 months after discontinuation, so that complete clearance may not be
a necessary endpoint for determining when to discontinue therapy. Low-dose regimens, 0.10.4 mg/
kg/day, have shown efficacy. However, with such
dosages, the incidence of relapses after therapy is
greater. Approximately 10% of patients treated with
isotretinoin require a second course of the drug. The
likelihood for repeat therapy is increased in patients
younger than 1617 years of age. It is standard
Chapter 80
is there evidence demonstrating functionality of retinoid signaling pathways in the mature CNS. Large
population-based studies have not supported causality. As dermatologists are often on the front line seeing
adolescents at risk for depression, careful screening
of adolescents is particularly needed, since the risk of
depression in this population is 10%20%.97
GI symptoms are generally uncommon, but nausea, esophagitis, gastritis, and colitis can occur. Acute
hepatitis is rare but liver function studies should be
regularly monitored, as elevation in liver enzymes can
occur in 15% of patients, sometimes necessitating dose
adjustments. Elevated levels of serum triglycerides
occur in approximately 25% of patients on isotretinoin. This elevation, which is dose-related, typically
occurs within the first 4 weeks of treatment and is
often accompanied by an overall increase in cholesterol with a decrease in the high-density lipoprotein
levels. The effect of this transient alteration on overall
coronary artery health is unclear. Acute pancreatitis is
a rare complication that may or may not be related to
triglyceride levels. There are case reports documenting
a potential link between isotretinoin and new-onset or
flared inflammatory bowel disease. However, a study
that critically examined these case reports found no
grounds for a causal relationship between isotretinoin
use and inflammatory bowel disease.98 A recent population-based case-control study found that patients
with inflammatory bowel disease were no more likely
to have used isotretinoin than those without inflammatory bowel disease.99 Patients with a family history
of inflammatory bowel disease, or those with a preexisting inflammatory bowel disease, should be counseled regarding the possibility of isotretinoin-induced
inflammatory bowel disease.
Isotretinoin has effects on bone mineralization as
well. A single course of isotretinoin was not shown to
have a significant effect on bone density.100 However,
chronic or repeated courses may result in significant
osteopenia. Osteoporosis, bone fractures, and delayed
healing of bone fractures have also been reported. The
significance of reported hyperostosis is unclear, but the
development of bony hyperostoses after isotretinoin
therapy is more likely in patients who receive the drug
for longer periods of time and in higher dosages, such
as for disorders of keratinization.101 Serial bone densitometry should be done in any patient on long-term
isotretinoin. Myalgias are the most common musculoskeletal complain, seen in 15% of patients. In severe
cases, creatine phosphokinase levels should be evaluated for possible rhabdomyolysis.
Other laboratory abnormalities that have been
reported with isotretinoin use are an elevated erythrocyte sedimentation rate and platelet count. Alterations
in the red blood cell parameters with decreased white
cell counts can occur. White blood cells in the urine
have rarely been linked to isotretinoin use. Most laboratory changes are mild and spontaneously resolve
upon discontinuation of medication use.
The greatest concern during isotretinoin therapy is
the risk of the drug being administered during pregnancy and thereby inducing teratogenic effects in the
fetus.102,103 The drug is not mutagenic; its effect is on
911
13
Section 13
::
912
practice to allow at least 23 months between courses

of isotretinoin.
Furthermore, laboratory monitoring is indicated.
It is appropriate to obtain a baseline complete blood
count and liver function tests, but the greatest attention should be paid to following serum triglyceride
levels. Baseline values for serum triglycerides should
be obtained and repeated at 34 weeks and 68 weeks
of therapy. If the values are normal at 68 weeks, there
is no need to repeat the test during the remaining
course of therapy unless there are risk factors. If serum
triglycerides increase above 500 mg/dL, the levels
should be monitored frequently. Levels above 700 to
800 mg/dL are a reason for interrupting therapy or
treating the patient with a lipid-lowering drug. Eruptive exanthemas or pancreatitis can occur at higher
serum triglyceride levels.
DIET. Several articles suggesting a role for diet in acne

exist.105,106 A recent review of these studies concluded
that there may be some link between milk and acne
as well as between high-glycemic index foods and
acne.107 Yet, overall the implications of these studies is
not clear and the role of chocolate, sweets, milk, highglycemic index foods, and fatty foods in patients with
acne requires further study. There is no evidence to
support the value of elimination of these foods. However, restricting a food firmly thought by the patient
to be a trigger is not harmful, as long as the patients
nutritional well-being is not compromised.
ACNE SURGERY. Acne surgery, a mainstay of therapy in the past used for the removal of comedones and
superficial pustules, aids in bringing about involution
of individual acne lesions. However, with the advent
of comedolytic agents, such as topical retinoids, its use
is primarily restricted to those patients who do not
respond to comedolytic agents. Even in those patients,
the comedones are removed with greater ease and
less trauma if the patient is pretreated with a topical
retinoid for 34 weeks. Acne surgery should not be
performed at home, as inaccurate placement of the
comedo extractor may rupture the follicle and incite
an inflammatory reaction. The Unna type of comedo
extractor, which has a broad flat plate and no narrow
sharp edges, is preferable. The removal of open comedones is desirable for cosmetic purposes, but does
not significantly influence the course of the disease. In
contrast, closed comedones should be removed to prevent their rupture. Unfortunately, the orifice of closed
comedones is often very small, and usually the material contained within the comedo can be removed only
after the orifice is gently enlarged with a no. 25 needle
or other suitable sharply pointed instrument.
INTRALESIONAL GLUCOCORTICOIDS. Intralesional injection of glucocorticoids can dramatically
decrease the size of deep nodular lesions. The injection
of 0.050.25 mL per lesion of a triamcinolone acetate
suspension (2.510 mg/mL) is recommended as the
anti-inflammatory agent. This is a very useful form of
therapy in the patient with nodular acne, but it often
has to be repeated every few weeks. A major advan-
tage is that it can be done without incising or draining the lesions, thus avoiding the possibility of scar
formation. Hypopigmentation, particularly in darker
skinned patients, and atrophy are risks.
PHOTOTHERAPY AND LASERS. Various forms

of phototherapy are under investigation for their use
in treating acne vulgaris. Ultraviolet (UV) light has
long been thought to be beneficial in the treatment
of acne. Up to 70% of patients report that sun exposure improves their acne.108 This reported benefit
may be due to camouflage by UV radiation induced
erythema and pigmentation, although it is likely that
the sunlight has a biologic effect on the pilosebaceous
unit and P. acnes. Although ultraviolet B (UVB) can
also kill P. acnes in vitro, UVB penetrates poorly to the
dermal follicle and only high doses causing sunburn
have be shown to improve acne.109,110 UV radiation
may have anti-inflammatory effects by inhibiting cytokine action.111 Twice-weekly phototherapy sessions are
needed for any clinical improvement. The therapeutic
utility of UV radiation in acne is superseded by its carcinogenic potential.112116
Other types of phototherapy for acne treatment
utilize porphyrins. Treatment of acne with phototherapy works either by activating the endogenous
porphyrins of P. acnes or by applying exogenous porphyrins. Coproporphyrin III is the major endogenous
porphyrin of P. acnes. Coproporphyrin III can absorb
light at the near-UV and blue light spectrum of
415 nm.117 Irradiation of P. acnes with blue light leads
to photoexcitation of endogenous bacterial porphyrins, singlet oxygen production, and subsequent bacterial destruction.118 A visible light source, either blue
or red, or both may be used to excite the endogenous
porphyrins. The high intensity, enhanced, narrowband (407420 nm) blue light known as ClearLight
(Lumenis) is currently FDA approved for the treatment of moderate inflammatory acne.116 Red light
too may be beneficial, as it penetrates deeper into the
dermis and has greater anti-inflammatory properties, but causes less photoactivation of the porphyrins. Therefore, the combination of blue and red light
may prove the most beneficial. Treatments should
be given twice weekly for 15-minute sessions for the
face alone, and 45 minutes for the face, chest, and
back. A multicenter study has shown that 80% of
patients treated with the ClearLight for 4 weeks had
a 60% reduction in acne lesions. There was a gradual
return of lesions over 36 months.119
The most consistent improvement in acne after light
treatment has been demonstrated with photodynamic
therapy.120 Photodynamic therapy involves the topical
application of aminolevulinic acid (ALA) 1 hour prior
to exposure to a low-power light source. These sources
include the pulsed dye laser, intense pulsed light, or a
broadband red light source. The topical ALA is taken
up by the pilosebaceous unit and metabolized to protoporphyrin IX.121 The protoporphyrin IX is targeted by
the light and produces singlet oxygen species, which
then damage the sebaceous glands.122 Several studies
utilizing ALA-PDT maintained clinical improvement
for up to 20 weeks.123,124
Neonatal acne can occur in up to 20% of healthy newborns. Lesions usually appear around 2 weeks of age
and resolve spontaneously within 3 months. Typically,
small, inflamed papules affect the nasal bridge and the
cheeks. Because comedone formation is absent, many
consider neonatal acne a variant of neonatal cephalic
pustulosis. However, it has been shown that sebum
excretion rates in newborns are transiently elevated in
the perinatal period.134 Additionally, Malassezia sympodialis, a normal commensal on human skin, may also
play a role. Some reports have demonstrated positive
cultures of the pustules with Malassezia and improve-
INFANTILE ACNE
Infantile acne presents at 36 months of age and typically shows comedones. Papules, pustules, and nodules can also present on the face and scarring may
occur even with relatively mild disease. Infantile acne
is caused in part by the transient elevation of DHEA
produced by the immature adrenal gland. Additionally, during the first 612 months of life boys may also
have an increased level of LH that stimulates testosterone production. Around 1 year of age, these hormone
levels begin to stabilize until they surge again during
adrenarche. As a result, infantile acne usually resolves
around 12 years of age. Treatment generally consists
of topical retinoids and benzoyl peroxide. Oral therapy
with erythromycin, trimethoprim, or isotretinoin can
be used in severe or refractory cases.136
ACNE CONGLOBATA
This severe form of nodular acne is most common in
teenage males, but can occur in either sex and into
adulthood. Acne conglobata (conglobate means shaped
in a rounded mass or ball) is a mixture of comedones,
papules, pustules, nodules, abscesses, and scars. It can
be on the back, buttocks, chest, and, to a lesser extent,
on the abdomen, shoulders, neck, face, upper arms,
and thighs (Fig. 80-6). The comedones often have multiple openings. The inflammatory lesions are large, tender, and dusky-colored. The draining lesions discharge
a foul-smelling serous, purulent, or mucoid material.
Subcutaneous dissection with the formation of multichanneled sinus tracts is common. Healing results
in an admixture of depressed and keloidal scars. The
management of these patients is very difficult and the
effect of treatment is often temporary. Several medications have been used, including intensive high-dose
therapy with antibiotics, intralesional glucocorticoids,
systemic glucocorticoids, surgical debridement, surgical incision, and surgical excision. The use of isotretinoin has produced dramatic results in some of these
patients. In severe cases, dosages as high as 2 mg/kg/
day for a 20-week course may be necessary. However,
because severe flares may occur when isotretinoin is
started, the initial dose should be 0.5 mg/kg/day or
less, and systemic glucocorticoids are often required
either before initiating isotretinoin therapy or as concomitant therapy.
NEONATAL ACNE
13
::
ACNE VARIANTS
ment with ketoconazole cream.135 While there appears

to be a strong association between Malassezia and neonatal acne, definite causality has not yet been proven.136
Chapter 80
Although lasers are beginning to find a role in the

treatment of acne, the authors consider them inferior
to the traditional medical treatments. They work by
emitting minimally divergent, coherent light that can
be focused over a small area of tissue. The pulsed KTP
laser (532 nm) has demonstrated a 35.9% decrease in
acne lesions when used twice weekly for 2 weeks.
Although there was no significant decrease in P. acnes,
there was significantly lower sebum production even
at 1 month.125 The pulsed dye laser (585 nm) can also
be used at lower fluences to treat acne. Instead of
ablating blood vessels and causing purpura, a lower
fluence can stimulate procollagen production by heating dermal perivascular tissue.122 The beneficial effects
of a single treatment can last 12 weeks.126 Some of the
nonablative infrared lasers, such as the 1,450 nm and
1,320 nm laser, have shown to be helpful in improving acne.127,128 These lasers work by causing thermal
damage to the sebaceous glands. The concurrent
use of a cryogen spray device protects the epidermis while the laser causes necrosis of the sebaceous
gland.129 In a pilot study, 14 out of 15 patients treated
with the 1,450 nm laser had a significant reduction in
inflammatory lesions that persisted for 6 months. The
1,320 nm Nd:Yag and the 1,540 erbium glass lasers
have also been demonstrated to improve acne.130,131
Multiple treatments are needed with either of these
lasers to lessen acne lesions. These treatments tend to
be painful and show a gradual modest improvement,
limiting their utility.
One of the newer uses of light for treating acne is
with a photopneumatic device (Isolaz, Solta Medical). This photopneumatic device has a handpiece that
applies negative pressure (i.e., suction) to the skin and
then delivers a broadband-pulsed light (4001,200 nm).
The suction is employed to unplug the infundibulum
of the pilsebaceous unit and the light is delivered to
activate the P. acnes porphyrins, thus releasing singlet
oxygen species. Patients treated with this device may
experience some posttreatment erythema or purpura.
Results are modest and temporary and the device is
best for inflammatory lesions.132,133 Although the lightbased treatments are beneficial in that they avoid some
of the side effects of the oral medications, the cost of
these light and laser treatments tends to be prohibitive.
ACNE FULMINANS
Acne fulminans (also known as acute febrile ulcerative acne) is the most severe form of nodular acne and
is accompanied by systemic symptoms. The sudden
appearance of massive, inflammatory, tender, oozing,
friable plaques with hemorrhagic crusts characterize
acne fulminans. The lesions predominate on the chest
913
13
Section 13
Figure 80-8 Acne fulminans. An eruptive form of acne with extensive inflammatory papules and nodules on the chest
(A) and back (B). Systemic symptoms may accompany this extreme form of acne and scarring is usually quite extensive.
::
and back (Figs. 80-8A and 80-8B) and rapidly become

ulcerative and heal with scarring. The disease is
reported to occur primarily in teenage boys. The face is
often uninvolved. The patients are febrile, have a leukocytosis of 10,00030,000/mm3 white blood cells, and
usually have polyarthralgia, myalgia, hepatosplenomegaly, and anemia. Bone pain is common, especially
at the clavicle and sternum. Radiologic examination
may demonstrate lytic bone lesions. Occasionally there
is accompanying erythema nodosum. Although this
disease is often classified with acne conglobata, there
are basic differences. The onset of acne fulminans is
more explosive; nodules and polymorphous comedones are less common; the face is not involved as frequently and the neck is usually spared; ulcerative and
crusted lesions are unique; and systemic symptoms are
more common. Systemic glucocorticoid therapy, along
with oral antibiotics and intralesional glucocorticoids,
is the treatment regimen required for these patients.
Isotretinoin is also of benefit in these patients, but in
order to prevent explosive flares, systemic glucocorticoids must be started before isotretinoin and continued during the first few weeks of isotretinoin therapy.
The initial dosing of isotretinoin must also be lowered
accordingly in the initial weeks of therapy until the
inflammation is controlled. The daily dose of glucocorticoids should be slowly decreased as tolerated.
Dapsone in conjunction with isotretinoin has been
reportedly beneficial in the treatment of acne fulminans associated with erythema nodosum.
SAPHO SYNDROME
914
SAPHO syndrome is manifested by synovitis, acne,

pustulosis, hyperostosis, and osteitis. It is predominantly associated with hyperostosis of the anterior
chest, palmoplantar pustulosis, hidradenitis suppurativa, and acne fulminans. Its etiology is unknown.
Reported successful treatments for SAPHO syndrome
are NSAIDS, sulfasalazine, and infliximab.137 The
bisphosphonates are beneficial for treating the associated bone pain.138
PAPA SYNDROME
PAPA syndrome, another acne variant with systemic
symptoms, is marked by sterile pyogenic arthritis,
pyoderma gangrenosum, and acne. Patients with
PAPA syndrome may also give a history of sterile
cutaneous abscesses, inflammatory bowel disease,
and pancytopenia following administration of sulfacontaining medications.139 It is an autoinflammatoy
disorder inherited in an autosomal dominant manner.
Due to mutations in the CD2 binding protein-1 gene
(also known as the protein serinethreonine phosphatase interacting protein), there is an increase in IL-1
production.140 There have been reports of successful
treatment with infliximab and anakinra.139,140
ACNE EXCORIE DES JEUNES FILLES

Acne excorie des jeunes filles, as the name suggests,
occurs primarily in young women who are picking
at their skin. Mild acne may be present and is accompanied by extensive excoriations. Comedones and
papules are systematically and neurotically excoriated leaving crusted erosions that may scar. Often
the lesions that are excoriated are minute. This condition may suggest underlying depression, anxiety,
obsessivecompulsive disorder, or a personality disorder. Antidepressants and psychotherapy can be helpful in treating these patients.
ACNE MECHANICA
Acneiform eruptions have been observed after repetitive physical trauma to the skin such as rubbing. This
can occur from clothing (belts and straps) or sports
equipment (football helmets and shoulder pads).
Occluding the skin with adhesive tape can also produce acne mechanica. Obstruction of the pilosebaceous gland results in comedo formation. It presents
as a well-defined, lichenified, hyperpigmented plaque
interspersed with comedones. A classic example of
acne mechanica is fiddlers neck, produced where the

violin pad repetitively rubs against the players lateral
neck.
ACNE WITH SOLID FACIAL EDEMA
POLYCYSTIC OVARY SYNDROME. Polycystic

ovary syndrome (PCOS) occurs in roughly 3%6% of
the general population. Patients with PCOS, also called
SteinLeventhal syndrome, ovulate infrequently or
not at all, have multiple cysts on their ovaries, and
often have irregular menses, obesity, androgenic
alopecia, hirsutism, and acne. There is an increased
risk of diabetes mellitus and endometrial carcinoma
in patients with PCOS.143 Serum total testosterone in
the range of 150200 ng/dL or an increased LH/FSH
ratio (greater than 2.0) can be found in cases of PCOS.
Patients with signs of hyperandrogenism should also
be asked about insulin resistance, since acne can occur
with the HAIR-AN syndrome, a subset of PCOS.
Hyperandrogenism, acne, insulin resistance, and
acanthosis nigricans are markers of this syndrome. It
is important to identify these patients because they
are at increased risk for accelerated cardiovascular
disease and diabetes mellitus.
CONGENITAL
ADRENAL
HYPERPLASIA.
Congenital adrenal hyperplasia, usually caused by

defects in the adrenal enzyme 21-hydroxylase, occurs
as both a classic severe type and as a nonclassic mild
type. Neonates are screened at birth for the classic type
and typically present with ambiguous genitalia and
salt-wasting. The nonclassic type is not identified at
Following administration of systemic glucocorticoids or corticotropin, folliculitis may appear. This

is very uncommon in children but may occur in any
adult as early as 2 weeks after steroids are started.
Similar lesions may follow the prolonged application of topical glucocorticoids to the face. For this
reason, topical glucocorticoids have no place in the
treatment of acne, and their use on the face, in general, should be limited. The pathology of steroid
acne is that of a focal folliculitis with a neutrophilic
infiltrate in and around the follicle. This type of acne
clearly differs from acne vulgaris in its distribution
and in the type of lesions observed. The lesions,
which are usually all in the same stage of development, consist of small pustules and red papules. In
contrast to acne vulgaris, they appear mainly on
the trunk, shoulders, and upper arms, with lesser
involvement of the face. Postinflammatory hyperpigmentation may occur, but comedones, cysts, and
scarring are unusual. Treatment consists primarily of stopping any corticosteroid use. Typical acne
treatments such as topical retinoids and antibiotics
may also be helpful.
Although the majority of cases of acne vulgaris occur in

patients without endocrinologic disturbances, there is
a certain population whose acne is driven or worsened
by endocrine abnormalities. As mentioned previously,
it is important to screen patients for such abnormalities by taking a thorough history. In addition to the
presence of acne, endocrinologic disturbances may be
marked by irregular menstrual cycles, deepened voice,
increased libido, and hirsutism. Laboratory work can
help define an endocrinologic problem causing acne.
STEROID FOLLICULITIS
::
ACNE WITH ASSOCIATED

ENDOCRINOLOGY ABNORMALITIES
ACNEIFORM ERUPTIONS
13
Chapter 80
A rare and disfiguring variant of acne vulgaris is

acne with solid facial edema, also known as Morbihans disease. There is a woody edema of the midthird
face with accompanying erythema and acne. Similar
changes have been reported with rosacea, Melkerson
Rosenthal syndrome, and rosacea. There may be
fluctuations in the severity of the edema, but spontaneous resolution does not occur. Oral antibiotic
treatment is ineffective. Treatment with low dose
isotretinoin (0.20.5 mg/kg/day) alone or in combination with oral glucocorticoids, ketotifen (12 mg/
day), or clofazimine for 45 months has been reported
to be beneficial.141,142
birth and can present throughout childhood and adolescence. The prevalence of the nonclassic type in the
white population is 1 in 1,000. Patients with this type
of congenital adrenal hyperplasia have normal cortisol levels but increased androgens. Female patients
present with precocious puberty, irregular menses,
polycystic ovaries, hirsutism, and acne.144 Values of
DHEAS in the range of 4,0008,000 ng/mL are suggestive of congenital adrenal hyperplasia. Findings of
CAH in males are often subtle, as acne may be the only
sign, but CAH should be considered in patients who
do not respond to treatment.145 Treatment of congenital
adrenal hyperplasia consists of low dose replacement
of glucocorticoids, as well as oral contraceptives, spironolactone, or flutamide in females.
DRUG-INDUCED ACNE
In addition to glucocorticoids, other medicines can
also cause a monomorphic, diffuse popular eruption
that mimics steroid folliculitis. Such drugs include:
phenytoin, lithium, isoniazid, high doses of vitamin B
complexes, halogenated compounds, and certain chemotherapy medications (see Box 80-2). Halogenated
compounds containing either bromides or iodides
are often found in cold and asthma remedies, sedatives, radioopaque contrast material, kelp (in many
fad diet pills), and other vitaminmineral combinations. With iodides, in particular, inflammation may
be marked.146,147 The iodine content of iodized salt is
low and, therefore, it is extremely unlikely that enough
iodized salt could be ingested to cause this type of
acne.
915
13
Box 80-2 Drug-Induced Acneiform

Eruptions

Glucocorticoids
Phenytoin
Lithium
Isoniazid
High-dose vitamin B complex
Halogenated compounds
Epidermal growth factor receptor inhibitors
Section 13
EPIDERMAL GROWTH FACTOR

RECEPTOR INHIBITOR
ASSOCIATED ERUPTION
::
A newer class of chemotherapy medicine, known as

the EGFR inhibitors, may also cause a follicular-based
eruption. EGFR inhibitors are primarily used to treat
nonsmall-cell lung cancer, colorectal cancer, and breast
cancer. Some of the EGFR inhibitors include: gefitinib
(Iressa), cetuximab (Erbitux), erlotinib (Tarceva), and
trastuzumab (Herceptin). In treatment responsive
patients, the EGFR inhibitors are indefinitely administered for their long-term ability to inhibit tumor
growth, progression, cell proliferation, and angiogenesis. A frequent side effect of the EGFR inhibitors is a
perifollicular, papulopustular eruption distributed on
the face and upper torso. The eruption occurs in up
to 86% of patients treated with EGFR inhibitors. An
associated lateral paronychia may also occur. Histopathological sections of lesional skin show a noninfectious perifolliculitis.148 The etiology of the acneiform
eruption is not clear, but it may occur because EGFR
is highly expressed in the basal cell layer of the epidermis, follicular keratinocytes, and the sebaceous
epithelium. The presence and severity of the eruption
correlates with a positive treatment response. If the
eruption is absent, dosing may be inadequate or the
patients tumor may be unresponsive to EGFR inhibitor therapy.149
OCCUPATIONAL ACNE
AND CHLORACNE
916
Several different groups of industrial compounds

encountered in the workplace may cause acne. These
include coal tar derivatives, insoluble cutting oils,
and chlorinated hydrocarbons (chloronaphthalene,
chlorobiphenyls, and chlorodiphenyloxide). Chloracne
is the term that is used to describe occupational acne
caused from chlorinated hydrocarbons. Occupational
acne tends to be quite inflammatory and, in addition to
large comedones, is characterized by papules, pustules,
large nodules, and true cysts. Tar acne is often accompanied by hyperpigmentation. The lesions of occupational acne are not restricted to the face and, in fact, are
more common on covered areas with intimate contact
to clothing saturated with the offending compound.

Because the cutting oils are so widely used, they are
the most common cause of industrial acne. However,
the chlorinated hydrocarbons, which cause chloracne,
have posed a more difficult problem because of the
severity of the disease induced with these compounds.
Exposure can cause comedones, cysts, and pigmentary
changes of the skin but can also affect the ophthalmic, nervous and hepatic systems.150 Many cases have
occurred as the result of massive exposure in industrial accidents.151 Chlorinated hydrocarbons are found
in fungicides, insecticides, and wood preservatives.
Chloracne classically affects the malar, retroauricular,
and mandibular regions of the head and neck, as well
as the axillae and scrotum (see eFig. 80-7.1 in online
edition), Pathology demonstrates multiple tiny infundibular cysts.152 In 2,004, Ukrainian President Viktor
Yushchenko was poisoned with dioxin, causing severe
chloracne. Most chloracne lesions clear up within 2
years, providing exposure to the chemical has stopped.
Treatment with topical or oral retinoids and oral antibiotics may be beneficial.
GRAM-NEGATIVE FOLLICULITIS
Gram-negative folliculitis may occur in patients with
preexisting acne vulgaris treated with long-term
oral antibiotics, especially the tetracyclines. Patients
usually give a history of initial success with oral tetracyclines followed by a worsening of their acne.
Gram-negative folliculitis may appear as either papulopustules concentrated around the nose or as deepseated nodules. Culture of these lesions may reveal
Enterobacter, Klebsiella, or Escherichia in the papulopustules or Proteus in the nodules. An appropriate antimicrobial agent with adequate Gram-negative coverage
should be used. In recalcitrant cases, Gram-negative
folliculitis improves with oral isotretinoin for 45
months. Gram-negative bacteria require a moist environment for survival and the drying action of isotretinoin will kill the bacteria.
RADIATION ACNE
Different types of radiation such as ionizing radiation and UV radiation may induce acneiform eruptions. Previous sites of therapeutic ionizing radiation
(e.g., external beam) can develop comedo-like papules. These lesions begin to appear as the acute phase
of radiation dermatitis is resolving. The ionizing rays
induce epithelial metaplasia within the follicle, creating adherent hyperkeratotic plugs in the pilosebaceous unit. These keratotic plugs are resistant to
extraction. Excessive exposure to UV radiation may
produce a yellow, atrophic plaque studded with large
open comedones. This condition is known as Favre
Racouchot, but has also been called solar comedones,
senile comedones, nodular cutaneous elastosis with
cysts and comedones, and nodular elastoidosis with
cysts and comedones. It has been estimated to occur in
6% of persons above age 50.153 The lesions are usually
13
symmetrically distributed on the temporal and periorbital areas. The exact pathogenesis of FavreRacouchot
is unknown, but it is suggested that extensive UV
exposure as well as exposure to harsh climates and
smoking may be risk factors. It can be treated with oral
or topical retinoids as well as extraction.154
TROPICAL ACNE
PSEUDOACNE OF THE NASAL CREASE

The transverse nasal crease is an anatomic variant
that appears as a transverse linear groove across the
middle of the nose. Preadolescent patients have been
described to develop acneiform red papules within
the nasal crease along with milia (Fig. 80-9). Histologic
examination of the papules reveals keratin granulomas
that may be derived from ruptured, inflamed milia.
Due to its similarity in clinical appearance to acne, but
deviation from acne histologically, it has been termed
pseudoacne of the nasal crease.155
Apert syndrome, also known as acrocephalosyndactyly, is an autosomal dominant disorder marked by

synostoses of the cranium, vertebral bodies and hands
and feet. It is caused by a mutation in the gene encoding FGFR-2. These patients have a diffuse acneiform
eruption that often involves the arms, buttocks, and
thighs. It is typically very resistant to treatment but
excellent responses to isotretinoin have been reported.
Patients with Apert syndrome may also present with
severe seborrhea, nail dystrophy, and cutaneous and
ocular hypopigmentation.
KEY REFERENCES
This monomorphous eruption consists of multiple,

uniform, red, papular lesions seen after sun exposure.
It is referred to as Mallorca acne because it occurred in
many Scandinavians after they had been on a sunny
vacation in Mallorca in southern Europe after a long,
dark winter. Almost all cases have occurred in women,
mainly 2030 years old. The lesions are common on
the shoulders, arms, neck, and chest. Histologically,
the lesions resemble steroid acne in that they show a
focal follicular destruction with neutrophilic infiltrate.
Comedones are not part of the clinical or histologic
picture. The eruption is due to the effects of UV radiation, primarily ultraviolet A (UVA). Rarely, a similar
clinical picture can be observed after starting psoralen
and UVA (PUVA) treatment. The eruption will subside
if the patient is protected from UV light for several
months. Oral antibiotics are ineffective in speeding up
the resolution, but topical retinoids and benzoyl peroxide may be helpful. Like polymorphous light eruption,
patients with acne aestivalis will flare on reexposure to
UV light.147
APERT SYNDROME
::
ACNE AESTIVALIS
Figure 80-9 Pseudoacne of the nasal crease. Open and

closed comedones and small papules line up along the
transverse nasal crease.
Chapter 80
In extreme heat, a severe acneiform folliculitis may

develop. This can be seen in tropical climates or in
scorching occupational environments, as in furnace
workers. This acneiform eruption is a major cause of
dermatologic disability in military troops serving in
tropical climates. Tropical acne occurs mainly on the
trunk and buttocks. It has many deep, large, inflammatory nodules with multiple draining areas, resembling acne conglobata. The pathogenesis of this type
of acne is unknown, although secondary infection
with coagulase-positive Staphylococci almost always
ensues. Systemic antibiotics must be given, but often
more important is removing the patient to a cooler
environment.

3. Bataille V et al: The influence of genetics and environmental factors in the pathogenesis of acne: A twin study
of acne in women. J Invest Dermatol 119:1317-1322, 2002
12. Munro CS, Wilkie AO: Epidermal mosaicism producing localised acne: Somatic mutation in FGFR2. Lancet
352:704-705, 1998
26. Jeremy A et al: Inflammatory events are involved in acne
lesion initiation. J Invest Dermatol 121:20-27, 2003
35. Kim J et al: Activation of toll-like receptor 2 in acne
triggers inflammatory cytokine responses. J Immunol
169:1535-1541, 2002
49. Mallon E et al: The quality of life in acne: A comparison
with general medical conditions using generic questionnaires. Br J Dermatol 140(4):672-676, 1999
53. Gollnick H, Schramm M: Topical therapy in acne. J Eur
Acad Dermatol Venereol 11(1), 1998
75. Ross JI et al: Antibiotic-resistant acne: Lessons from
Europe [see comment]. Br J Dermatol 148(3):467-478, 2003
94. Marqueling AL et al: Depression and suicidal behavior
in acne patients treated with isotretinoin: A systematic
review. Semin Cutan Med Surg 26(4):210-220, 2007
99. Bernstein CN et al: Isotretinoin is not associated with
inflammatory bowel disease: A population-based casecontrol study. Am J Gastroenterol 104(11):2774-2778, 2009
100. DiGiovanna JJ et al: Effect of a single course of isotretinoin therapy on bone mineral density in adolescent
patients with severe, recalcitrant, nodular acne [see comment]. J Am Acad Dermatol 51(5):709-717, 2004
917
13
Chapter 81 :: Rosacea

:: Michelle T. Pelle
ROSACEA AT A GLANCE
Rosacea affects all races, but is most common
in fair-skinned individuals.
Section 13
Triggers of rosacea may include hot or cold

temperature, sunlight, wind, hot drinks,
exercise, spicy food, alcohol, emotions,
cosmetics, topical irritants, menopausal
flushing, and medications that promote
flushing.
::
There are four rosacea subtypes:

erythematotelangiectatic, papulopustular,
phymatous, and ocular.
The primary clinical features of rosacea
include flushing, inflammatory papules,
pustules, and telangiectases.
Secondary features of rosacea may include
facial burning and stinging, edema, plaques,
a dry appearance, phyma, peripheral
flushing, and ocular manifestations.
Sun protection and trigger avoidance are
important for prevention in all types of
rosacea.
Rosacea therapy may include barrier
protection practices, topical antimicrobials,
oral antibiotics, retinoids, intense pulsed
light, and vascular laser modalities for
adequate long-term control of symptoms.
ROSACEA
918
Despite universal recognition, rosacea is clinically varied and of uncertain pathophysiology. Practitioners
and the public can easily identify the prototypical red
face of rosacea; however, confusion arises when photodamage, perioral dermatitis, postadolescent acne,
and topical steroid overuse present in a similar guise.
Recent theory has shifted conceptually from staged
progression of rosacea signs and symptoms to a new
classification that defines four subtypes with variable
severity and potential overlap.
Rosacea is characterized by erythema of the central
face that has persisted for months or more. The convex
areas of the nose, cheeks, chin, and forehead are the
characteristic distribution. Primary features of rosacea, which may be observed but are not required for
the diagnosis, include flushing, papules, pustules, and
telangiectases. Secondary features include facial burning or stinging, edema, plaques, a dry appearance,
phyma, peripheral flushing, and ocular manifestations. Erythema in peripheral locations (the scalp,
ears, lateral face, neck, and chest) can be observed in
rosacea, but is also a common feature of physiologic
flushing and chronic sun damage, and therefore must
be interpreted carefully.1
SUBTYPE CLASSIFICATION
The subtypes of rosacea were defined provisionally by
the National Rosacea Society (NRS) Expert Committee
in 2002 and include erythematotelangiectatic, papulopustular, phymatous, and ocular subtypes.1 These
represent the most common groupings of rosacea
signs and symptoms. The subtypes coincide with the
first rosacea staging classification devised by Plewig
and Kligman.2 The erythematotelangiectatic subtype
is analogous to PlewigKligman stage I disease, the
papulopustular subtype to PlewigKligman stage II,
and the phymatous subtype to PlewigKligman stage
III. In contrast, the NRS classification maintains that
progression of rosacea in stages (from one subtype to
another) does not occur, but that subtypes may overlap in the same individual. A provisional grading
system was also incorporated by the NRS Expert Committee to standardize the clinical assessment of rosacea.3 Rosacea severity assessments must additionally
include consideration of the psychological, social, and
occupational impacts of this disorder and individual
responsiveness to treatment.
EPIDEMIOLOGY
Although the prevalence of rosacea is unknown, the
vast majority of cases occur in fair-skinned populations and it is common. However, persons of African
and Asian descent may also develop rosacea.2,4 The
NRS has estimated that rosacea affects 14 million
Americans. Rosacea occurs in both men and women,
with onset typically after age 30.1,5 However, children,
adolescents, and young adults may develop rosacea.68

Because of prominent clinical variation among the
rosacea subtypes, it has been hypothesized that etiologic and pathophysiologic differences may exist.
Such differences may involve facial vascular reactivity, dermal connective tissue structure or composition,
matrix composition, pilosebaceous structure, microbial
colonization, or a combination of factors that alter the
cutaneous response to rosacea trigger factors.9 Rosacea
is unmasked or induced by chronic, repeated trigger
exposure, in particular by triggers of flushing that may
13
::
Rosacea
not progress to a rosacea phenotype, and photoprovocation studies in rosacea patients have not demonstrated
increased cutaneous sensitivity to acute ultraviolet
exposure.9,17,20,21
It has long been debated whether oral and topical
antimicrobial agents for rosacea exert their effects by
anti-inflammatory or antimicrobial mechanisms. The
concept of microbe-induced, follicle-based inflammation in rosacea is controversial. It is unclear whether
commensal organisms such as Propionibacterium acnes
and Demodex folliculorum, which reside in hair follicles and sebaceous glands, trigger folliculocentric
inflammatory papules in rosacea patients.9 Alternatively, a hypersensitivity reaction may be triggered
by these microbes or by mite-associated bacteria such
as Bacillus oleronius.22 Compelling arguments in favor
of a microbe-induced mechanism for papulopustular
rosacea (PPR) include the observation that nonsteroidal anti-inflammatory drugs and corticosteroids do
not clear rosacea papules and pustules as effectively
as oral tetracyclines. Furthermore, benzoyl peroxide
is quite effective for papules and pustules in rosacea
patients who tolerate this drug.10 It remains unclear
whether clinical improvement of PPR requires a quantitative reduction of P. acnes.
Chapter 81
include hot or cold temperature, sunlight, wind, hot

drinks, exercise, spicy food, alcohol, emotions, cosmetics, topical irritants, menopausal flushing, and medications that promote flushing.10 Both neural and humoral
mechanisms produce flush reactions that are visibly
limited to the face. Facial prominence occurs because
baseline facial blood flow is increased compared with
other body sites,11,12 and the facial cutaneous vasculature
is more superficial and comprised of larger and more
numerous vessels when compared with other sites.13
New investigations have demonstrated that exacerbation of the innate immune response occurs in rosacea.14,15 Individuals with rosacea express high levels of
cathelicidin peptides, and those peptides are processed
atypically compared to normal skin. Cathelicidin peptides appear to enable stratum corneum tryptic enzyme
(SCTE)-mediated inflammation in the epidermis.14,15
Dermal factors also play a role in rosacea pathogenesis. Matrix degeneration and endothelial damage have been demonstrated histologically in rosacea
specimens.16,17 Factors that contribute to matrix degeneration include inherent problems with vessel permeability and/or delayed clearance of inflammatory
mediators and waste products. Alternatively, photodamaged connective tissue may alter vascular and
lymphatic structure and support within the dermis.18
In either case, chronic and persistent dermal inflammation may occur and ultimately manifest as erythema
of the facial convexities in predisposed individuals.19
Sun damage is considered a contributing etiologic
factor, and solar elastosis is a common background on
which rosacea histologic features are superimposed.
However, rosacea prevalence is not increased in outdoor workers, sun damage in nonfacial locations does
CLINICAL FEATURES
Erythematotelangiectatic rosacea (ETR) is characterized by persistent facial erythema and flushing along
with telangiectases, central face edema, burning and
stinging, roughness or scaling, or any combination of
these signs and symptoms (Fig. 81-1). Mild, moderate,
Figure 81-1 A. Erythematotelangiectatic subtype, mild. B. Erythematotelangiectatic subtype, severe.

C. Close-up detailing the common occurrence of erythematotelangiectatic and papulopustular subtype
overlap.
919
13
Section 13
::
Figure 81-2 A. Papulopustular subtype. There is persistent erythema with papules and tiny
pustules. Mild subtype. B. Severe form of the papulopustular subtype.
and severe subtypes are recognized. In contrast, PPR
manifests as persistent, central-face erythema with
papules and pustules that predominate in convex
areas (Fig. 81-2).9 Again, mild (see Fig. 81-2A), moderate, and severe forms (see Fig. 81-2B) are distinguished. Burning and stinging of the facial skin may
occur in PPR, but occurs less commonly compared
with ETR. Flushing is often less severe in PPR compared with ETR. In both subtypes, erythema spares the
920
periorbital areas. Edema can be mild or severe. Severe

edema may take on the plaque morphology of solid
facial edema.1,23 This occurs most often on the forehead
and glabella and it less commonly affects the eyelids
and upper cheeks.
Phymatous rosacea is characterized by patulous follicular orifices, thickened skin, nodularities, and irregular
surface contours in convex areas (Fig. 81-3). Here also,
mild, moderate, and severe subtypes are distinguished.
Figure 81-3 A. Phymatous subtype. Moderate subtype with patulous follicular orifices, thickened
skin, and nodularities on nose and cheeks. B. Severe rhinophyma.
13
Chapter 81
HISTOPATHOLOGY
Rosacea is a clinical diagnosis; histology may be helpful when the facial distribution is atypical or when
Figure 81-5 Granulomatous rosacea. There are multiple

monomorphic red and yellow brown papules that, on diascopy, show apple-jelly-like color.
Rosacea
Phyma most often occurs on the nose (rhinophyma), but

may also develop on the chin (gnathophyma), forehead
(metophyma), eyelids (blepharophyma), and ears (otophyma).24 Women with rosacea do not develop phyma,
perhaps for hormonal reasons, but they can manifest
sebaceous or glandular features characterized by thickened skin and large follicular orifices.9
Ocular rosacea may develop before cutaneous symptoms in up to 20% of affected individuals25 (Fig. 81-4).
In half of patients, ocular symptoms develop after
skin symptoms. In a minority, skin and eye symptoms
present simultaneously.26 Ophthalmic rosacea severity does not coincide with cutaneous rosacea severity. Ocular involvement may manifest as blepharitis,
conjunctivitis, iritis, scleritis, hypopyon, and keratitis;
mild, moderate, and severe subtypes are recognized
(see Fig. 81-4).26 Blepharitis is the most common feature, characterized by eyelid margin erythema, scale,
and crust, with the variable presence of chalazia and
staphylococcal infections due to underlying meibomian gland dysfunction.25 Photophobia, pain, burning, itching, and foreign body sensation may be part of
the ocular symptom complex. In severe cases, rosacea
keratitis may lead to vision loss.
Granulomatous rosacea is considered the only true
rosacea variant.1 Granuloma formation is a histologic
feature of the condition; the clinical features of granulomatous rosacea include yellowbrown or red papules or nodules that are monomorphic and located
on the cheeks and periorificial facial skin27 (Fig. 81-5).
Upon diascopy, these papules reveal apple-jelly-like
change in color similar to sarcoidosis or lupus vulgaris. The background facial skin is otherwise normal.
Other signs and symptoms of rosacea are not required
to make a diagnosis of granulomatous rosacea.
::
Figure 81-4 Ocular subtype, severe. This patient has

blepharitis, conjunctivitis, and keratitis.
granuloma formation is suspected. In ETR, a sparse,

perivascular lymphohistiocytic infiltrate is accompanied by dermal edema and ectatic venules and lymphatics.16 Severe elastosis may be present. Similar
features are found in the papulopustular subtype, but
the inflammatory infiltrate also surrounds hair follicles
and sebaceous glands. Phymatous rosacea is characterized by prominent elastosis, fibrosis, dermal inflammation, sebaceous hyperplasia, and hypertrophy of
sebaceous follicles.16,28 Epithelialized tunnels undermine the hyperplastic tissue and are filled with inflammatory debris. D. folliculorum mites may be found in
all types of rosacea within the follicular infundibula
and sebaceous ducts.28
(Fig. 81-6)
Systemic diseases that must be differentiated from
rosacea include polycythemia vera, connective tissue
disorders (lupus erythematosus, dermatomyositis),
carcinoid syndrome, mastocytosis, and neurologic
causes of flushing. Neurologic causes include brain
tumors, spinal cord lesions, orthostatic hypotension,
migraine headaches, and Parkinson disease.29 Unilateral auriculotemporal flushing may follow parotid
gland injury or surgery.30
Medication-induced flushing has been associated with all vasodilators, calcium channel blockers, nicotinic acid (niacin), morphine, amyl and butyl
nitrite, cholinergic drugs, bromocriptine, thyroid
releasing hormone, tamoxifen, cyproterone acetate,
systemic steroids, and cyclosporine.29,31 The flush
associated with nicotinic acid may be blocked with
aspirin or indomethacin.32 Disulfiram, chlorpropamide,
921
13
Diagnosis and therapy of the rosacea sub-types
Primary features
Flushing
Persistent erythema
Papules and pustules
Telangiectasia
Secondary features
Burning/stinging
Dry appearance
Edema/plaques
Peripheral erythema
Ocular signs
Phyma
Patient assessment
Physical
Psychological
Social
Occupational
Response to therapy
Triggers
Heat/cold
Wind
Hot drinks
Spicy food
Exercise
Alcohol
Emotions
Topical irritants
Medications
Menopausal flushing
Section 13
Physician global sub-type assessment
::
Erythematotelangiectatic
All patients:
Trigger avoidance
Stress photoprotection
Assess topical sensitivity
Gentle cleanser
Gentle emollient
Therapeutics:
Mild topical antimicrobials
Low-dose isotretinoin
Oral tetracyclines (or oral
erythromycins or oral
metronidazole)
Vascular laser
Intense pulsed light
Topical retinoid
maintenance
Tretinoin cream plus
emollient
Papulopustular
All patients:
Trigger avoidance
Photoprotection
Assess sensitivity
Therapeutics:
Topical antimicrobial
Oral antimicrobial
(see ETR)
Low to mild dose
isotretinoin
Vascular laser or intense
pulsed light in some
cases
Topical retinoid
maintenance
Phymatous (and
glandular features
in women)
Ocular
All patients:
Trigger avoidance
Photoprotection
All patients:
Ophthalmology
assessment
Therapeutics:
Mild to high dose
isotretinoin
Spironolactone
Surgical debulking and
contouring techniques
Topical and/or oral
antimicrobials as needed
for inflammatory lesions
Topical retinoid
maintenance
Therapeutics:
Gentle nonmedicated
cleanser
Gentle S/S cleanser
S/S 10% ophthalmic
ointment
Oral tetracyclines
Sub-type overlap
Therapeutic modalities are chosen based on the sub-types and clinical features identified
Figure 81-6 Approach to patient. Diagnosis and therapy of the rosacea subtypes. aRegimen recommendation based on
author experience. ETR = erythematotelangiectatic; S/S = sodium sulfacetamide/sulfur.
922
metronidazole, phentolamine, and cephalosporins

induce flushing when they are combined with alcohol.29 Amiodarone has induced rosacea and multiple
chalazia.33 Food additives, including sulfites, sodium
nitrite, nitrates, and monosodium glutamate, may also
cause flushing.29 Dumping syndrome following gastric
surgery is characterized by flushing, sweats, tachycardia, and abdominal pain.
Cutaneous conditions that may mimic rosacea
include topical steroid-induced acneiform eruption
(formerly steroid-induced rosacea), acne vulgaris,
perioral dermatitis, inflammatory keratosis pilaris,
and chronic photodamage. In particular, acne vulgaris
(see Chapter 80) and rosacea may coexist, although

rosacea most often begins and reaches its peak incidence in the decades after acne declines. The primary
differentiating feature between acne vulgaris and
rosacea is the presence of open and closed comedones
in acne alone.2
Rosacea fulminans, also known as pyoderma faciale
and rosacea conglobata, occurs mainly in women in
their 20s.2,34,35 It is characterized by the sudden onset
of confluent papules, pustules, nodules, and draining sinuses on the chin, cheeks, and forehead within a
background of diffuse facial erythema. Rosacea fulminans has proved controversial in its classification and
TOPICAL THERAPY
The topical agents approved by the US Food and Drug
Administration (FDA) for rosacea include 15% azelaic
Rosacea
Before implementing therapy, rosacea trigger factors

specific to each individual must be identified (see Fig.
81-6).10 Patient education should stress trigger avoidance. Other key aspects of prevention include the
daily application of gentle, broad-spectrum ultraviolet
A and ultraviolet B sunscreen, hat use, avoidance of
midday sun, and seeking shade. Physical sunscreens
(zinc or titanium based) are best tolerated. Chemical
sunscreens are better tolerated when barrier protective
silicones (dimethicone, cyclomethicone) are included.38
Cosmetic intolerance and facial skin sensitivity are
common features of the erythematotelangiectatic and
papulopustular subtypes, perhaps due to inherent barrier
dysfunction or facial vascular hyperreactivity.39 As many
as 75% of these individuals may experience burning,
stinging, pruritus, or dryness and scaling in affected areas.
Avoidance of harsh products and ingredients, including
astringents, toners, menthol, camphor, and sodium lauryl
sulfate, is important when sensitivity is present.40 A soapfree cleanser applied with the fingers is best tolerated. A
protective, gentle emollient should be applied once or
twice daily before application of other products. Light liquid foundation makeup is the best choice for patients with
sensitivity. Green-tinted makeup can be applied before
foundation to further mask red areas.40
13
::
THERAPY
acid gel, 0.75% and 1% metronidazole (available in

cream, gel, and lotion vehicles), and 10% sodium sulfacetamide with 5% sulfur (available in cleanser, cream,
suspension, and lotion vehicles). Each has proved
effective for clearance of inflammatory papules and
pustules and for erythema reduction when applied
once daily.41 Twice-daily application or combinations
of these agents may be necessary when topical monotherapy is inadequate. Metronidazole and azelaic
acid are pregnancy category B, whereas sodium sulfacetamide and sulfur is category C. Azelaic acid may
be associated with initial tingling or burning that can
disappear with continued use. Sodium sulfacetamide/
sulfur medicated cleansers are better tolerated in sensitive patients compared with leave-on topical formulations that may increase burning and stinging.42 Daily
use of a barrier repair emollient is important in these
patients.
Off-label topical formulations used for rosacea
include benzoyl peroxide, clindamycin, erythromycin,
calcineurin inhibitors, and topical retinoids.10 Benzoyl
peroxide is effective for clearance of papules and pustules, but should be avoided in sensitive patients.10
Twice-daily topical clindamycin was more effective
than oral tetracycline for the eradication of pustules
in one series.43 Tacrolimus ointment and pimecrolimus
cream are most beneficial for topical, steroid-induced
acneiform eruptions, but they may offer a useful therapeutic alternative in some patients with rosacea. Niacinamide-containing facial emollients may improve
stratum corneum barrier function and hydration, and
have shown benefit as adjunctive topical therapy in
rosacea.44
Manual therapy should also be considered adjunctively in rosacea patients. Facial massage is performed
in the direction of the lymphatic flow, according to
Soybes technique, beginning at a central location on
the face (the glabella and nose) and pressing the fingers in a sweeping motion toward the inferolateral
face (the mandibles and lateral neck).17 This can help
to mobilize edema and speeds clearance of dermal
inflammation.
Tretinoin cream promotes connective tissue remodeling and minimizes dermal inflammation with longterm use.4547 Topical retinoids have demonstrated
benefit for rosacea in small clinical series.48,49 The clinical response to retinoids is delayed in the rosacea setting; generally 4 to 6 months of use is required to see
significant effects. Because of their potential for irritation and concerns regarding promotion of angiogenesis, retinoids are often avoided for rosacea. However,
their long-term use does not appear to promote the
development of telangiectasia. Retinoids inhibit vascular endothelial growth factor production by cultured
human skin keratinocytes via their anti-AP1 transcription factor activity.50,51 The use of barrier emollients in
conjunction with gradual introduction of topical retinoids allows them to be tolerated early on in treatment
when retinoid dermatitis is a problem. Topical retinoids are especially useful for long-term maintenance
in rosacea.
-Adrenergic receptor agonist topical therapies
(brimonidine, oxymetazoline) require further study
Chapter 81
was not included as a rosacea subtype or variant by the

NRS Expert Committee.1,2
Perioral dermatitis (see Chapter 82) differs from
rosacea in its facial distribution, signs, symptoms, and
patient demographic. It is characterized by perioral, and
sometimes periorbital, microvesicles, micropustules,
scaling, and peeling. It affects younger women and also
occurs in children. Central face erythema and inflammatory papules are not features of perioral dermatitis.9
Therapy includes topical and oral antimicrobials. Perioral dermatitis is exacerbated by topical steroid use.
Steroid-induced acneiform eruption (see Chapter 80)
can mimic PPR. With prolonged use of topical steroids
on the face, monomorphic inflammatory papules may
develop.1 The treatment is discontinuation of the topical corticosteroid and initiation of an oral tetracycline, a
topical antimicrobial, a topical calcineurin inhibitor, or a
combination of these agents.36,37 This regimen is generally
continued for 1 to 3 months, and relapse does not tend
to occur as long as topical steroids are not reintroduced.
In chronic photodamage (see Chapter 90), telangiectases and erythema are prominent features. However,
unlike rosacea, actinic damage affects the periphery
of the face and neck, the upper chest, and the posterior auricular skin. Hyperpigmentation and hypopigmentation are additional feature of sun damage not
observed in rosacea. Chin involvement is both mental
and submental in rosacea, while in chronic photodamage there is submental sparing.9
923
13
to characterize their efficacy and safety for ETR; however, their vasoconstrictive properties represent a
novel approach for the treatment of telangiectasia and
erythema.52,53
ORAL THERAPY
Section 13
::
Topical management of rosacea is possible and generally preferable, especially when considering issues
of antimicrobial resistance and the risks associated
with long-term use of oral antibiotics. Furthermore,
because rosacea is photoaggravated in many affected
individuals, photosensitizing oral agents must be used
with caution in this population. Oral antimicrobials in
particular are useful short-term tools that can achieve
rapid control of symptoms, but long-term topical
maintenance should be the eventual therapeutic goal.
In 2006, Oracea (doxycycline, USP, 40 mg) became the
first oral therapy to be FDA-approved for rosacea.
For moderate to severe flushing or erythema, shortterm oral therapy (2 to 4 months) with a tetracycline or
isotretinoin may be useful for initial control. Tetracyclines achieve faster reduction of papules, pustules, and
erythema when compared with isotretinoin, and since
the 1950s, rosacea has been treated and maintained with
both antimicrobial and subantimicrobial dosages of the
tetracyclines.54,55 Relapses occur in approximately onefourth of patients after 1 month off tetracycline, and
in over one-half of patients at 6 months off therapy.55
Therefore, topical maintenance therapy is advised. Oral
tetracyclines should be avoided in pregnant women
and in those contemplating pregnancy.
In one small series, a significant reduction of facial
cutaneous blood flow, measured by laser-Doppler, was
achieved in isotretinoin-treated patients (30 mg daily
for 10 weeks), whereas no significant change in facial
blood flow was observed in those treated with 250 mg
of tetracycline twice daily for 10 weeks.56 Low-dose
isotretinoin (10 to 40 mg daily or less than 0.5 mg/kg/
day) can be effective and is better tolerated in rosacea
patients.5759 Isotretinoin is teratogenic, and its use is
strictly monitored in women of child-bearing potential.
Other oral agents used for rosacea include macrolides, metronidazole, antiandrogenic agents (oral contraceptives, spironolactone, and cyproterone acetate),
blockers, clonidine, naloxone, and selective serotonin
reuptake inhibitors.10,6066 In patients with a history of
acne vulgaris or overlap of acne vulgaris with rosacea,
spironolactone in low doses (25 to 50 mg daily) and/
or oral contraceptive pills may prove helpful. When
high levels of Demodex exacerbate rosacea, or in cases
refractory to tetracyclines, ivermectin may be a useful adjunctive therapy. It can be given as a single 0.2
mg/kg dose repeated once weekly or once monthly as
needed for symptom control.67
LASER AND LIGHT THERAPY

924
(See Chapter 239)

Vascular lasers and intense pulsed light (IPL) therapy are useful alternatives to oral rosacea therapies;
they may be used adjunctively with topical and oral

rosacea regimens for faster and more complete symptom resolution. These nonablative modalities can
eliminate telangiectasia, reduce or eliminate erythema,
reduce papule and pustule counts, and they appear to
extend the duration of remission. Their drawbacks are
cost and side effects, which may include transient erythema, edema, purpura, blistering, dyschromia, burns,
and, rarely, scarring.
Vascular lasers include short and long wavelength
devices with a variety of pulse durations. Short wavelength lasers emit light that is selectively absorbed
by oxyhemoglobin absorption peaks that occur at
541 nm and 577 nm. This allows for superficial vessel destruction without collateral tissue damage.
Short wavelength lasers include the pulsed dye laser
(585 nm or 595 nm), long pulsed dye laser (595 nm), the
potassium-titanyl-phosphate laser (532 nm), and the
diode-pumped frequency-doubled laser (532 nm).6870
Long wavelength vascular lasers can eradicate deeper
and larger vessels by targeting the oxyhemoglobin
spectral peaks at 800 nm and above 1,000 nm. These
lasers include the long pulsed Alexandrite (755 nm),
the diode laser (810 nm), and the neodynium:yttriumaluminum-garnet laser (1,064 nm).10
The success and tolerability of laser therapy for
rosacea have been improved by modified pulse duration parameters and by advances in epidermal cooling mechanisms. Longer pulse durations can deliver
equivalent energy at a slower rate to heat vessels
uniformly and gently, minimizing tissue trauma and
purpura. Epidermal cooling gels and sprays prevent
epidermal damage and can help to minimize pain,
erythema, and edema and help to ensure safe delivery
of laser energy. Generally, two to four laser treatments
are required to achieve best outcomes for rosacea; purpuric treatment settings may eradicate telangiectasia
more quickly. Multiple laser passes and pulse-stacking
on larger vessels may improve treatment outcomes
when subpurpuric settings are utilized.71
Unlike laser devices that emit a single wavelength,
IPL (broadband light) emits a broad wavelength spectrum, ranging from approximately 550-nm visible light
to 1,200-nm infrared light. Filters are used to establish
the short end of the spectrum, which varies depending
on the device. Fluence and pulse width also vary with
the system used. IPL may cause transient erythema,
transient hyperpigmentation, or hypopigmentation,
and, rarely, purpura, burns, and scarring.72 Epidermal
cooling mechanisms are necessary to protect the epidermis. IPL effectively reduces facial erythema and
telangiectases and is generally well tolerated.7274 Vascular lasers and IPL may also impact rosacea by inducing fibroblasts to increase dermal collagen production,
perhaps achieving some degree of dermal remodeling
and rejuvenation.7577
TREATMENT OF PHYMA
Oral isotretinoin monotherapy is beneficial for early
to moderate phymatous change.24 Advanced phyma
is treated with surgical therapy or the combination
of surgery followed by isotretinoin therapy. Surgical approaches to the reshaping of rhinophyma have
included cold scalpel tangential excision, heated
scalpel excision, electrocautery, dermabrasion, laser
ablation, tangential excision combined with scissor
sculpturing, radiofrequency electrosurgery, or a combination of these approaches.24,7883 Techniques that use
partial thickness tangential excision and contouring
with preservation of the underlying sebaceous glands
allow spontaneous reepithelialization within 2 to 3
weeks, result in minimal scarring, and give an excellent aesthetic result with a low risk of recurrence.83
To effectively treat rosacea, practitioners must recognize the clinical spectrum of rosacea phenotypes
and what lies outside that spectrum. Subtyping of
rosacea is a useful guide to establish a multimodality
approach to therapy. Therapeutic success is achieved

1. Wilkin J et al: Standard classification of rosacea: Report
of the National Rosacea Society Expert Committee on the
classification and staging of rosacea. J Am Acad Dermatol
46:584, 2002
2. Plewig G, Kligman A: Acne and Rosacea, 3rd edition, Berlin, Springer-Verlag, 2000, p. 455
3. Wilkin J et al: Standard grading system for rosacea: Report
of the National Rosacea Society Expert Committee on the
classification and staging of rosacea. J Am Acad Dermatol
50:907, 2004
10. Pelle M, Crawford G, James W: Rosacea: II. Therapy. J Am
16. Marks R, Harcourt-Webster J: Histopathology of rosacea.
83. Bogetti P et al: Surgical treatment of rhinophyma: A comparison of techniques. Aesth Plast Surg 26:57, 2002
Perioral Dermatitis
SUMMARY
KEY REFERENCES
::
Ophthalmologic referral should be made for patients

with ocular symptoms. For mild blepharitis, careful
use of a gentle nonmedicated or sodium sulfacetamide/
sulfur cleanser may be used once to twice daily as initial therapy. Sodium sulfacetamide 10% ophthalmic
ointment is also effective for control of blepharitis.
When topical management is inadequate, oral tetracyclines are generally effective.7,25,26
13
Chapter 82
TREATMENT OF OCULAR ROSACEA
by inducing remission of signs and symptoms, and

by minimizing and controlling relapses. Ultimately,
early recognition of this disorder, some key behavioral
modifications, and the combination of sunscreen and
topical agents can achieve safe, effective, and longterm control of rosacea, while avoiding the risks of
oral pharmaceuticals and the financial strain of laser
and light therapies.
Recommended Reading
Rosacea Symposium, ESDR 2009 and 2010. J. invest. Dermatol
Symp Proc 15(1):1-62, 2011
Chapter 82 :: Perioral Dermatitis

:: Leslie P. Lawley & Sareeta R.S. Parker
PERIORAL DERMATITIS AT A GLANCE
Inflammatory skin disorder of young women
and children.
Small papules, vesicles, and pustules in
perioral, periorbital, and/or perinasal
distribution.
Treatment: stop topical corticosteroid
use; initiate 2- to 3-month course of
systemic antibiotics (tetracycline family or
erythromycin) and/or topical metronidazole.
Perioral dermatitis is characterized by small, discrete

papules and pustules in a periorificial distribution, predominantly around the mouth. Because this condition
can involve areas other than the perioral region, the
term periorificial dermatitis has been proposed for this
disorder.1,2 The classic presentation is an eruption with

overlapping features of an eczematous dermatitis and
an acneiform eruption. Although initially described in
young women of 1525 years of age, perioral dermatitis is now recognized to occur in children as well.3 A
subset of perioral dermatitis shows granulomas when
lesional skin is examined histologically. Several names
have been used to describe this granulomatous form of
perioral dermatitis, including granulomatous perioral
dermatitis, facial Afro-Caribbean childhood eruption,
and granulomatous periorificial dermatitis.2,4,5
HISTORICAL ASPECTS
The first reports describing perioral dermatitis
appeared in the 1950s; various names were given to the
condition, however, there was a lack of defining clinical
criteria. In 1957, Frumess and Lewis described a light
sensitive seborrheid that is generally accepted as the
first account of what was later termed perioral dermatitis by Mihan and Ayres in 1964.6,7 Later descriptions
925
13
by Cochran and Thomson8 and Wilkinson, Kirton, and

Wilkinson9 further defined this disorder, and more
recently the term periorificial dermatitis has been proposed.2 The condition was first described in children
in the late 1960s.
EPIDEMIOLOGY
Section 13
::
926
Adult perioral dermatitis predominantly affects

women. Pediatric perioral dermatitis may have a slight
female preponderance and is seen equally among those
of different races.1,10 The granulomatous form of perioral dermatitis has been reported mostly in children
of prepubertal age.5 Perioral dermatitis can occur as
early as 6 months.1 An increased prevalence in AfricanAmerican children has been reported, but more recent
reviews do not support this finding.2,11

A relationship of perioral dermatitis to the misuse of
topical corticosteroids (fluorinated or nonfluorinated)
has been well established.12 Patients often reveal a history of an acute steroid-responsive eruption around the
mouth, nose, and/or eyes that worsens when the topical
corticosteroid is discontinued. Dependency on the use
of the topical corticosteroid may develop as the patient
repeatedly treats the recurrent eruption. In other cases,
the condition may worsen with the application of topical
corticosteroids, especially in the granulomatous variant
of perioral dermatitis, which usually occurs in prepubertal children.2 Perioral dermatitis has been reported in
patients using inhaled corticosteroids13 and with inadvertent facial exposure to topical corticosteroids.14 However, perioral dermatitis is not always linked to topical
corticosteroids.9 The exact cause of perioral dermatitis
in these other cases is unclear. Although isolated reports
of affected siblings exist,2,15 no clear genetic predisposition has been noted, nor have specific environmental
exposures been consistently implicated. Of note, the
disease is predominant in young women, yet no link to
hormonal causes has been found. The initial reports of
photosensitivity by Frumess and Lewis6 were not further substantiated, nor were theories of microbiologic
causes such as infection with Candida, fusiform bacteria,
or Demodex folliculorum.16 Cases of allergic contact with
fluorides or other components in toothpaste and dentifrices have also been reported, however, use of these
agents after clearing of the perioral dermatitis without
further eruption has also been described. Patch testing
in a small series of patients led to few positive results,
and these were not considered relevant.9
In the past, authors have considered the relationship
of perioral dermatitis to acne rosacea, however, the clinical features are distinct (see Section Differential Diagnosis). In perioral dermatitis, the histopathologic findings
are variable and are dependent on the form of perioral
dermatitis. In a histopathologic review of 26 patients with
the nongranulomatous form, follicular spongiosis and
eczematous changes were prominent features, suggesting that perioral dermatitis is distinct from rosacea.17 A
lymphohistiocytic infiltrate and occasional plasma cells
Figure 82-1 Typical perioral dermatitis. The eruption is

confined to the nasolabial folds and the skin of the chin.
were noted in a perifollicular and perivascular distribution in this series. In granulomatous perioral dermatitis,
histopathology demonstrates follicular hyperkeratosis,
edema and vasodilatation in the papillary dermis, perivascular and parafollicular infiltrates of lymphocytes,
histiocytes, and polymorphonuclear leukocytes with
occasional epithelioid granulomas and giant cells, similar
to the histopathologic changes in acne rosacea.5,18
CLINICAL FINDINGS
The primary lesions of perioral dermatitis are discrete
and grouped erythematous papules, vesicles, and pustules (Figs. 82-1 and 82-2). The lesions are often symmetric but may be unilateral and appear in the perioral,
perinasal, and/or periocular regions (Figs. 82-2 and
82-3 and eFigs. 82-3.1 and 82-3.2 in online edition).
In a retrospective review of 79 children with perioral
Figure 82-2 Perioral (granulomatous periorificial) dermatitis. This child shows the typical small papules studding
the area around the mouth and eyes.
vermilion edge is well described (Fig. 82-2). The granulomatous variant of perioral dermatitis presents with
small flesh-colored, erythematous, or yellowbrown
papules, some with confluence, and shares the distribution of perioral dermatitis in adults (Fig. 82-3). In
addition, lesions have been reported to appear on the
ears, neck, scalp, trunk, labia majora, and extremities.1,11
Occasionally, an associated burning sensation or itching is reported, and intolerance to moisturizers and
other topical products is described.1,9 In a few cases of
granulomatous perioral dermatitis, an associated blepharitis or conjunctivitis has been reported.11 Systemic
findings and regional lymphadenopathy are absent.
Box 82-1 Differential Diagnosis of Perioral Dermatitis

DISORDER
Perioral Dermatitis
ermatitis, isolated perioral involvement was present

d
in only 39%, and in rare cases nonperioral regions were
involved exclusively.1 Background erythema and/or
scale may be present. A distinct 5-mm clear zone at the
(Box 82-1)
The differential diagnosis of nongranulomatous and
granulomatous perioral dermatitis is outlined in Box
82-1.1924 Both forms of perioral dermatitis lack systemic symptoms and a thorough history and physical
examination are generally sufficient to establish the
diagnosis. However, in some cases histopathological
evaluation of lesional skin, chest radiography, and/or
::
Figure 82-3 Perioral dermatitis, granulomatous form:

child with densely aggregated periorificial erythematous
and edematous papules.
Chapter 82
13
DISTINGUISHING CLINICAL FEATURES
Nongranulomatous Perioral Dermatitis

Most Likely
Rosacea
Involves the nose, facial convexities; persistent erythema, and
telangiectasias
Accentuated at nasolabial folds; scale
Consider musical instruments, toothpaste/dentrifices, latex gloves, dental
appliances, and lipstick
Common in children (from saliva, foods)
Lip-licking cheilitis
Common in children; scale, well demarcated border
Consider
Acne vulgaris
May involve chest and back; comedones
Gram-negative folliculitis
Predominance of pustules
Demodex folliculorum infestation
Pustules, pruritus; often immunocompromised host19
Infants with acral and/or diaper dermatitis; zinc deficiency
Tinea facei
KOH positive for hyphal elements
Psoriasis
Involvement of other cutaneous sites common
Impetigo
Honey-colored crusts
Eosinophilic folliculitis-HIV related
Immunocompromised host
Granulomatous Perioral Dermatitis
Most Likely
Granulomatous rosacea
Consider
Familial juvenile systemic granulomatosis (Blau syndrome)
Fungal or mycobacterial infection
Lupus miliaris disseminatus faciei
Benign cephalic histiocytosis
Sarcoidosis
Zirconium dermatitis
Flushing, telangiectases, pustules, and edema; similar histopathologic

features
Synovial cysts, uveitis, granulomatous arthritis, camptodactyly,
papular rash
Diffuse distribution on the face
Rare in children; reported cases may represent Blau syndrome
May involve axillae
927
13
Box 82-2 Treatment for Perioral Dermatitis

First line
TOPICAL
Metronidazole
DOSE
Apply bid
SYSTEMIC
Tetracycline
Doxycycline
Minocycline
ADULT DOSE
250500 mg p.o. bid
50100 mg p.o. bid
50100 mg p.o. bid
Second line
Erythromycin or clindamycin
Apply bid
Erythromycin
400 mg p.o. tid
Or
Sulfur preparations
Azelaic acid
Apply bid
Apply bid
Pediatric dose
Section 13
::
ophthalmologic examination may be necessary, particularly with the granulomatous variant.11 Sarcoidosis in
young children is rare and often accompanied by systemic signs and symptoms such as weight loss, fatigue,
joint pains, lymphadenopathy, and uveitis.5,25 At least
some of the reported cases of sarcoidosis in young children represent Blau syndrome with underlying mutations in CARD15/NOD2 (see Chapter 134).11,26
COMPLICATIONS
The majority of cases of perioral dermatitis and granulomatous perioral dermatitis resolve without sequelae
or relapse. However, there are rare reports of scarring.5

COURSE
Perioral dermatitis is usually a self-limited disorder that evolves over a few weeks and resolves over
months or rarely years. The condition may take on a
waxing and waning course, often with a tendency to
progress (granulomatous form). If treated with topical corticosteroids alone, recurrent episodes on withdrawal of therapy or with continuing therapy are
typical. With appropriate intervention the condition
resolves with rare recurrences.
TREATMENT
928
3050 mg/kg/day p.o.

divided tida
(Box 82-2)
If topical corticosteroids are being used, they should
be discontinued. If fluorinated corticosteroids are being
applied, initial substitution with a low-potency hydrocortisone cream may minimize a flare of the dermatitis. Patients should be educated about the link between
application of topical corticosteroids and exacerbation
of the dermatitis.
In most cases, effective therapy is oral tetracycline, doxycycline, or minocycline, for a course of 8
to 10 weeks, with a taper over the last 2 to 4 weeks.
In children under 8 years of age, nursing mothers, or
tetracycline-allergic patients, oral erythromycin is recommended. Not uncommonly, patients require continued low-dose systemic antibiotic therapy for months
or sometimes years to maintain control. In recalcitrant
cases, isotretinoin may be considered.27
Topical antibiotic therapy, most commonly with topical metronidazole, should be initiated concurrently with
the systemic antibiotic. For milder cases, topical metronidazole alone may suffice.1,28,29 In a retrospective review of
79 children, best outcomes were associated with the use
of topical metronidazole, oral erythromycin, or both.1
Response is generally noted within 23 months. Other
options include topical clindamycin or erythromycin,
topical sulfur-based preparations, and topical azelaic
acid.30 Reports of successful use of topical calcineurin
inhibitors exist, particularly in adults; however, caution
is advised given the occasional reports of granulomatous eruptions after the use of these agents.3135 Ointment preparations should generally be avoided in the
treatment of perioral dermatitis. Photodynamic therapy
with topical 5-aminolevulinic acid has shown promise
for treating perioral dermatitis in one report.36
PREVENTION
The only widely accepted factor that may predispose
to the development of perioral dermatitis is the use of
topical corticosteroids. Avoiding facial skin exposure to
these products may prevent the eruption in some cases.
KEY REFERENCES
1. Nguyen V, Eichenfield LF: Periorificial dermatitis in children and adolescents. J Am Acad Dermatol 55:781, 2006
3. Manders SM, Lucky AW: Perioral dermatitis in childhood. J Am Acad Dermatol 27:688, 1992
5. Frieden IJ et al: Granulomatous perioral dermatitis in children. Arch Dermatol 125:369, 1989
9. Wilkinson DS, Kirton V, Wilkinson JD: Perioral dermatitis:
A 12-year review. Br J Dermatol 101:245, 1979
12. Weston WL, Morelli JG: Identical twins with perioral dermatitis. Pediatr Dermatol 15:144, 1998
14
Disorders of the Eccrine and
Apocrine Glands
SWEATING AT A GLANCE
Humans have 224 million sweat glands.
Hypothalamic temperature is the strongest

stimulus for sweating.
Acetylcholine is the major stimulus secreted
by sympathetic nerves.
Botulinum toxin inhibits sweating by
preventing acetylcholine release.
Oxidative metabolism of glucose is a
major source of eccrine gland adenosine
triphosphate.
ANATOMY AND FUNCTION OF

ECCRINE SWEAT GLANDS
Ductal reabsorption conserves NaCl.
Two distinct segments, the secretory coil and the

duct, form the eccrine sweat gland. The secretory coil
secretes an isotonic sweat, while the duct resorbs Na+
and Cl, thus producing sweat to cool the body while
preserving Na+ and Cl body stores.
In individuals with cystic fibrosis, mutated

chloride channels increase NaCl loss.
Bacteria are necessary for apocrine odor.
Odiferous precursors secretion is controlled
by the MRP8 encoded by ABCC11.
Adrenergic stimulation controls apocrine
gland secretion.
In humans, sweat glands generally are found as two

types, (1) eccrine and (2) apocrine. Eccrine-gland
sweat allows the body to control its internal temperature in response to thermal stress. Apocrine gland
function is more obscure but likely includes pheromone production.
Biology of Eccrine and Apocrine Glands
The three eccrine cell types are (1) clear

(secretory), (2) dark (mucoid), and (3)
myoepithelial (contractile).
Humans have approximately 24 million sweat

glands.1 Sweat glands are found over nearly the entire
body surface, and are especially dense on the palms,
soles, forehead, and upper limbs.2 Analgen of eccrine
sweat glands first appear in the 3.5-month-old fetus
on the palms and soles (see Chapter 7), then develop
in the axillary skin in the fifth fetal month, and finally
develop over the entire body by the sixth fetal month.3
The analog of the eccrine sweat gland, which developed from the epidermal ridge, is double layered,
and develops a lumen between the layers between
the fourth and eighth fetal months. By the eighth
fetal month eccrine secretory cells resemble those of
the adult; by the ninth fetal month myoepithelial cells
form.
::
Up to 10 L/day of sweat is produced by

acclimatized individuals.
DEVELOPMENT OF ECCRINE
SWEAT GLANDS
Chapter 83
Chapter 83 :: Biology of Eccrine and Apocrine Glands

:: Theodora M. Mauro
SECRETORY COIL
The secretory coil contains three distinct cell types: (1)
clear (secretory), (2) dark (mucoid), and (3) myoepithelial.4 The clear and dark cells occur in approximately
equal numbers but differ in their distribution (Fig.
83-1). While the dark cells border the apical (luminal)
surfaces, the clear cells rest either directly on the basement membrane or on the on the myoepithelial cells.
The clear cells directly access the lumen by forming
intercellular canaliculi (Fig. 83-2). Spindle shaped contractile myoepithelial cells lie on the basement membrane and abut the clear cells. The adult secretory coil
is approximately 25-mm long, and approximately
3050 m in diameter. Heat accumulation results in
larger sweat glands and ducts, and their dimensions,
929
14
Ultrastructure of the eccrine duct and secretory

coil and the localization of Na+, K+-ATPase
Basal cell
Luminal cell
(Lumen)
Duct
Disorders of the Eccrine and Apocrine Glands
in turn, correlate with enhanced sweat output.5 Clear

cells contain abundant mitochondria and an autofluorescent body, called the lipofuscin granule, in the cytoplasm. The clear cell plasma membrane forms many
villi. The clear cell secretes water and electrolytes. Dark
cells have a smooth cell surface and contain abundant dark cell granules.4 The function of dark cells are
unknown. Myoepithelial cells contain actin filaments6
and are contractile,7,8 producing pulsatile sweat.
Na+, K+-ATPase
Secretory
coil
M
(Lumen)
Section 14 ::
Figure 83-1 Light photomicrograph of the secretory

coil of an acetylcholine-stimulated monkey palm eccrine
sweat gland. A 1-m thick section was cut from an Eponembedded specimen and stained with methylene blue.
Inset: A higher-power view of the area marked by the
square. CC = clear cell; DC = dark cell; ICC = intercellular
canaliculi; Lu = lumen; MC = myoepithelial cell.
C
IC
Mc
C
DUCT
D
The eccrine sweat duct consists of an outer ring of

peripheral or basal cells and an inner ring of luminal
BM
Figure 83-3 Drawing of the ultrastructure of the eccrine

duct and secretory coil and the localization of Na+, K+-adenosine triphosphatase (ATPase). The thick lines indicate
the localization of Na+, K+-ATPase. BM = basement membrane; C = clear cell; D = dark cells; IC = intercellular canaliculi; M = myoepithelial cell; Mc = mitochondria.
930
Figure 83-2 Electron micrograph of the secretory coil of a

human eccrine sweat gland. B with arrow = basal lamina;
other symbols are the same as in Fig. 83-1.
or cuticular cells. It seems that the proximal (coiled)

duct is functionally more active than the distal straight
portion in pumping Na+ for ductal Na+ reabsorption,
because Na+, K+-adenosine triphosphatase (ATPase)
activity and the number of mitochondria are higher in
the proximal portion (Fig. 83-3).4,7,9,10 In contrast, the
luminal ductal cells have fewer mitochondria, much
less Na+, K+-ATPase activity, and a dense layer of tonofilaments near the luminal membrane, which is often
referred to as the cuticular border. The cuticular border provides structural resilience to the ductal lumen,
which may dilate whenever ductal flow of sweat is
blocked. The entire structural organization of the duct
is well designed for the most efficient Na+ absorptive
function. The luminal membrane serves as the absorptive surface by accommodating both Na+ and Cl channels, and the basal ductal cells serve in Na+ pumping
by providing maximally expanded Na+ pump sites
and efficient energy metabolism. The lumen and the
duct contain -defensin, an antimicrobial, cysteinerich, low-molecular-weight peptide.11,12 In the epidermis, the duct spirals tightly upon itself.
NEURAL CONTROL OF ECCRINE

SWEATING
14
::
Efferent nerve fibers originating

from the hypothalamic preoptic sweat center descend
through the ipsilateral brainstem and medulla and
synapse in the intermediolateral cell columns of the
spinal cord without crossing (although sympathetic
vasomotor fibers may partially cross).15 The myelinated axons rising from the intermediolateral horn of
the spinal cord (preganglionic fibers) pass out in the
anterior roots to reach (through white ramus communicans) the sympathetic chain and synapse. Unmyelinated postganglionic sympathetic class C fibers arising
from sympathetic ganglia join the major peripheral
nerves and end around the sweat gland. The supply to
the skin of the upper limb is commonly from T2 to T8.
The face and the eyelids are supplied by T1 to T4, so
that resection of T2 for the treatment of palmar hyperhidrosis is likely to cause Horner syndrome. The trunk
is supplied by T4 to T12 and the lower limbs by T10 to
L2. Unlike the sensory innervation, a significant overlap of innervation occurs in the sympathetic dermatome because a single preganglionic fiber can synapse
with several postganglionic fibers.
The major neurotransmitter released from the periglandular nerve endings is acetylcholine (Ach), an
exception to the general rule of sympathetic innervation, in which noradrenaline is the peripheral
neurotransmitter. In addition to ACh, adenosine triphosphate (ATP), catecholamine, vasoactive intestinal
peptide, atrial natriuretic peptide, calcitonin generelated peptide, and galanin have been localized in the
periglandular nerves. The significance of these peptides or neurotransmitters in relation to sweat gland
function is not fully understood.
Botulinum toxin interferes with ACh release. Its
heavy chain binds the neurotoxin selectively to the
cholinergic terminal and the light chain acts within
the cells to prevent ACh release. Type A toxin cleaves
sensory nerve action potential-25, a 25-kDa synaptosomal-associated protein; the type B light chain cleaves
vesicle-associated membrane protein (also called synaptobrevin). Botulinum toxins are used for symptomatic
relief of hyperhidrosis.16 A more detailed description
can be found in Chapters 84 and 255.
Chapter 83
The preoptic hypothalamic area plays an essential

role in regulating body temperature: local heating of
the preoptic hypothalamic tissue activates generalized
sweating, vasodilatation, and rapid breathing, whereas
local cooling of the preoptic area causes generalized
vasoconstriction and shivering. The elevation of hypothalamic temperature associated with an increase in
body temperature provides the strongest stimulus for
thermoregulatory sweating responses, while cutaneous temperature exerts a weaker influence on the rate
of sweating.13 On a degree-to-degree basis, an increase
in internal temperature is about nine times more efficient than an increase in mean skin temperature in
stimulating the sweat center. The local temperature
effect is speculated to be due to increased release of
periglandular neurotransmitters.
The sweating in menopausal hot flashes reinforces
the concept of a central hypothalamic mechanism for
thermal sweating, but also shows that the response of
individuals to the same changes in core temperature
can vary. Although hormonal factors influence sweating during menopause, excessive sweating does not
correlate simply with hormonal levels. Instead, menopausal hot flashes seem to be due to a hypersensitive
brain response (particularly the hypothalamus, but perhaps the insula, anterior cingulate, amygdala, and primary somatosensory cortex as well). In asymptomatic
menopausal women and premenopausal women, the
core temperature can change up to 0.4C (33F) without eliciting a response. In symptomatic postmenopausal women, changes as small as 0.1C (32F) trigger
peripheral vasodilation and sweating. Why the brain is
hypersensitive to small changes in core temperature is
poorly understood, but increased levels of brain norepinephrine appear to influence the response to small
changes in core temperature through their action on
2-adrenergic receptors in the brain; higher levels of
the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol have also been found in symptomatic
menopausal women than in asymptomatic women.
Decreased norepinephrine release is postulated as the
mechanism by which clonidine relieves hot flashes
in symptomatic women. Decreased core temperature
may be the reason that women with decreased body
mass index tend to have fewer symptoms, even though
their estrogen levels probably are lower than those
in women with increased body mass index. Levels of
estrogen, luteinizing hormone, and -endorphins also
were originally thought to influence hot flashes, but
later studies have suggested no association.14
INNERVATION.
DENERVATION. In humans, the sweating response

to intradermal injection of nicotine or ACh disappears
within a few weeks after denervation of the postganglionic fibers,17 while the sweating response to heat ceases
immediately after resection of the nerves. In contrast,
after denervation of preganglionic fibers (due to spinal
cord injuries or neuropathies), pharmacologic responsiveness of the sweat glands is maintained from several months to 2 years, even though their thermally
induced sweating is no longer present.18
EMOTIONAL SWEATING
Sweating induced by emotional stress (emotional
sweating) can occur over the whole skin surface in
some individuals, but it is usually confined to the
palms, soles, axillae, and the forehead. Emotional
sweating on the palms and soles ceases during sleep,
931
14
whereas thermal sweating occurs even during sleep

if the body temperature rises. Because both types
of sweating can be inhibited by atropine, emotional
sweating is cholinergically medicated.
PHARMACOLOGY OF THE ECCRINE

SWEAT GLAND AND SWEATING RATE
Section 14 ::
932
Sweat glands respond to cholinergic agents, - and

-adrenergic stimulants, and other periglandular neurotransmitters, such as vasoactive intestinal peptide
and ATP. Periglandular ACh is the major stimulant of
sweat secretion, and its periglandular concentration
determines the sweat rate in humans. When dissociated clear cells are stimulated in vitro by cholinergic
agents, they lose K+ & Cl, increase intracellular Ca2+,
and shrink, mimicking actions seen in vivo.19 Striking
individual differences exist in the degree of sweating
in response to a given thermal or physical stress. In
general, males perspire more profusely than females.20
The sweat rate in a given area of the skin is determined
by the number of active glands and the average sweat
rate per gland. The maximal sweat rate per gland varies from 2 to 20 nL/min2. Sweat rate increases during
acclimatization, but the morphologic and pharmacologic bases of the individual and regional differences
in sweating rate during acclimatization are still poorly
understood (Fig. 83-4). In thermally induced sweating, the sweat rate can be mathematically related to
the body and skin temperatures in a given subject only
in the low sweat rate range. Cholinergic stimulation
yields a five to ten times higher sweating rate than does
-adrenergic stimulation. -Adrenergic stimulation
(by phenylephrine) is no more potent than isoproterenol (ISO) (a -adrenergic agonist) in humans in vivo.21
Whereas cholinergic sweating begins immediately on
intradermal injection, -adrenergic sweating requires
a latent period of from 1 to 2 minutes, which suggests
that the intracellular mechanism of sweat induction
Figure 83-4 Individual variation in the size of the sweat

gland in four male adults, aged 2228 years. Sweat glands
were isolated from skin biopsy specimens obtained from
the upper back behind the axilla. Subject 1 is a sedentary
man who does not exercise regularly, whereas subject 4 is
a well-acclimatized athletic individual.
may be different for methacholine and for ISO. Because

the sweat rate in response to adrenergic agents is rather
low, it may be reasonable to surmise that adrenergic
stimulation in periglandular nerves may be involved
in the regulation of sweat gland function but not in the
induction of sweat secretion. One consequence of dual
cholinergic and adrenergic innervation is to maximize
tissue accumulation of cyclic adenosine monophosphate, which may be instrumental in stimulating the
synthesis of sweat and glandular hypertrophy of the
sweat gland. The possibility that periglandular catecholamine is directly involved in emotional sweating
or sweating associated with pheochromocytoma22 may
be ruled out, because these sweating responses can be
blocked by anticholinergic agents.
PHARMACOLOGY AND FUNCTION OF

ECCRINE MYOEPITHELIUM
The periodicity of sweat secretion in vivo is caused by
the periodicity of central nerve impulse discharges,
which occur synchronously with vasomotor tonus
waves. Myoepithelial contraction occurs with cholinergic stimulation, but neither - nor -adrenergic agents
induce tubular contraction.23 While the myoepithelium
may contribute to sweat production via pulsatile contractions, it also seems to provide structural support
for the secretory epithelium, especially under conditions in which stagnation of sweat flow (due to ductal
blockade) results in an increase in luminal hydrostatic
pressure.8
ENERGY METABOLISM
Sweat secretion is mediated by the energy (i.e., ATP)dependent active transport of ions, so a continuous
supply of metabolic energy is mandatory for sustained
sweat secretion. Endogenous glycogen stored in the
clear cells can sustain sweat secretion for less than 10
minutes; thus the sweat gland must depend almost
exclusively on exogenous substrates for its energy
metabolism. Mannose, lactate, and pyruvate are used
nearly as readily as glucose; other hexoses, fatty acids,
ketone bodies, intermediates of the tricarboxylic acid
cycle, and amino acids are either very poorly used or
not used as substrates. The physiologic significance
of lactate or pyruvate utilization by the sweat gland
is not yet clear. However, because the plasma level of
glucose (5.5 mM) is much higher than that of lactate
(12 mM) or pyruvate (less than 1 mM), glucose may
play a major role in sweat secretion. Oxidative metabolism of glucose is favored as the major route of ATP
formation for secretory activity.23
COMPOSITION OF HUMAN
ECCRINE SWEAT
INORGANIC IONS. Sweat is formed in two steps:
(1) secretion of a primary fluid containing nearly isotonic NaCl concentrations by the secretory coil, and
UREA. Urea in sweat is derived mostly from serum
Sweat ingredients vs. sweat rates
urea.26 Sweat urea content is usually expressed as a

sweatplasma ratio (S/P urea). S/P urea is high (24)
at a low sweat rate range but approaches a plateau at
1.21.5 as the sweat rate increases.
Hydration
100
Na+ and Clin CF
60
Na+
Cl-
40
Lactate
K+
AMMONIA AND AMINO ACIDS. Ammonia

concentration in sweat is 0.58 mM,27 which is 2050
times higher than the plasma ammonia level. The concentration of sweat ammonia is inversely related to the
sweat rate and sweat pH. Free amino acids are present
in human sweat,27 although it is not clear what proportion of measured amino acids derive from epidermal
contamination.
Urea
Ammonia
20
0
Pyruvate
1.0
0.1
0
0
Sweat rate (mL/min/cm2)
Figure 83-5 Relationship between the concentration of

sweat ingredients and the sweat rate in thermally induced
human sweat in normal individuals and in persons with
cystic fibrosis (CF).
(2) reabsorption of NaCl from the primary fluid by the

duct. Although a number of factors affect ductal NaCl
absorption, the sweat rate (and thus the transit time of
sweat) has the most important influence on final NaCl
concentration. Sweat NaCl concentration increases
with increasing sweat rate to plateau at around
100 mM (Fig. 83-5). Potassium (K+) concentration in
sweat is relatively constant. It ranges from 5 to 10 mM,
which is slightly higher than plasma K+ concentration.
HCO3 concentration in the primary sweat fluid is
approximately 10 mM, but that of final sweat is less than
1 mM, which indicates that HCO3 is reabsorbed by the
duct, presumably accompanied by ductal acidification.24
Sweat NaCl concentration is increased in individuals
with cystic fibrosis. Aquagenic wrinkling of the palms
(whitened, wrinkling, and papillation of the palms after
brief water exposure) is seen more frequently in carriers
and patients with cystic fibrosis (see Chapter 84).
LACTATE. The concentration of lactate in sweat usually depends on the sweat rate. At low sweat rates,
lactate concentration is as high as 3040 mM, but it
rapidly drops to a plateau at around 1015 mM as
the sweat rate increases. Acclimatization is known to
lower sweat lactate concentrations, whereas arterial
occlusion rapidly raises sweat NaCl and lactate concentrations and reduces the sweat rate.23 Sweat lactate
is probably produced by glycolysis of glucose by the
secretory cells.25
Glucose
0.2
::
Total Ca2+
Free Ca2+
0.3
PROTEINS INCLUDING PROTEASES. The concentration of sweat protein in the least contaminated,
thermally induced sweat is approximately 20 mg/dL,
with the major portion being low-molecular-weight
proteins (i.e., MW <10,000). Because sweat samples
collected by simple scraping, and even those collected
with a plastic bag, can be massively contaminated with
plasma or epidermal proteins, previous reports on the
presence of - and -globulins, transferrin, ceruloplasmin, orosomucoid, and albumin28,29 and immunoglobulin E must be carefully reexamined. The sweat samples
collected over an oil barrier placed on the skin (the leastcontaminated sweat) contain no or trace of -globulin
and a very small amount of albumin. Yokozeki et al30
also reported the presence of cysteine proteinases and
their endogenous inhibitors in sweat and the sweat
gland. Dermcidin is an antimicrobial peptide produced
and secreted in sweat.31 Other organic compounds
reported to be present in sweat include histamine,32
prostaglandin,33 and vitamin K-like substances.34 Sweat
also contains traces of pyruvate and glucose. Sweat glucose increases concurrently with a rise in plasma glucose
level. Some orally ingested drugs, including griseofulvin,35 ketoconazole,36 amphetamines,37 and various chemotherapeutic agents,38 are secreted in sweat.
Chapter 83
Concentration (mM)
80
14
MECHANISMS OF SWEAT SECRETION

Several distinct sequential processes lead to eccrine
gland sweat production39: (1) stimulation of the eccrine
sweat gland by ACh via increased intra cellular Ca2+;
(2) Ca2+-stimulated loss of cellular K+, Cl, and H2O,
which leads to eccrine gland cell shrinkage; and (3)
volume-activated transcellular plus paracellular fluxes
of Na+, Cl, and H2O, which leads to net flux of largely
isotonic NaCl solution into the glandular lumen. These
processes are illustrated in Fig. 83-6.
Sweating initially is stimulated when ACh is released
from periglandular cholinergic nerve endings in
response to thermal or emotional stimuli. ACh binds to
cholinergic receptors on the clear cell plasma membrane,
stimulating intracellular Ca2+ release and influx, and
increasing cytosolic Ca2+ concentrations. Increased intracellular Ca2+, in turn, opens Ca2+-sensitive Cl and K+
channels in the clear cell basolateral membrane, which
allows Cl and K+ to escape. Because H2O follows K+ and
Cl, to maintain cell iso-osmolarity, the cell shrinks.39,40
933
14
Modified Na/K/Cl co-transplant model

ACh
CICa2+
MECHANISM OF DUCTAL
REABSORPTION
K+
H2O
B
Section 14 ::
934
and H2O into the glandular lumen to form the isotonic

NaCl precursor of sweat.
ACh-induced sweating, which constitutes the bulk
of sweat production, appears to be mediated by intracellular Ca2+, as detailed earlier. In contrast, adrenergicinduced sweating appears to be mediated by increased
intracellular cyclic adenosine monophosphate.41
Cell shrinkage
Na+
K+
2CI-
CI-
Na+
K+
Na+
Figure 83-6 Modified Na/K/2Cl cotransport model for the

ionic mechanism of cholinergic eccrine sweat secretion.
Periglandular neurotransmitters, such as acetylcholine
(ACh), bind to receptors on the basolateral membrane,
which leads to increased intracellular Ca2+; this in turn activates K+ and Cl channels, mediating K+, Cl, and H2O efflux
from the cell. The resulting cell shrinkage activates the
basolateral Na+/K+/2Cl antiporter, which leads to Na+, K+,
and Cl influx. The Na+ and K+ fluxes are recycled across the
basolateral membrane by the Na+, K+-adenosine triphosphatase. In contrast, Cl fluxes flow unopposed into the
lumen, causing an electrical gradient that drives Na+ exit
from the tissue into the lumen via a paracellular pathway.
Net fluxes: H2O, Cl, and Na+ (isotonic) flow into the lumen.
pH of the secreted fluid is neutral. Paracellular Na+ fluxes
across the cell junction are indicated with an arrow at
the bottom of the figure. B = basolateral membrane; L =
luminal or apical membrane; arrows = conductive flux of
ions through ionic channels.
This decrease in cell volume sets off a second cascade of cell signaling events. First, decreased cell
volume stimulates the NKCC141 class of Na/K/2Cl
cotransporters, which carry Na+, K+, and 2Cl into the
cell in an electrically neutral fashion (i.e., two cations
and two anions cancel out net charges). The resulting
increase in cytosolic Na+ activates the Na+, K+-ATPase,
located in the basolateral membrane, which recycles
Na+ and K+ across the basolateral membrane. The net
movement of the negatively charged Cl ion across the
apical membrane into the lumen in turn drives the positively charged Na+ ion into the lumen as well, along
a paracellular pathway. Therefore, the final product of
glandular secretion is the net movement of Na+, Cl,
Because the production of large sweat volumes could

lead to dangerous losses of NaCl, the sweat duct has
evolved to reabsorb NaCl, which minimizes electrolyte
loss, even at high sweat volumes (Fig. 83-7).
Ductal Na+ reabsorption is accomplished through
the coordinated activities of intracellular enzymes and
plasma membrane ion channels, pumps, and exchangers. These mechanisms not only reabsorb electrolytes
but also acidify the sweat, which results in a final
sweat product that is hypotonic and acidic. Na+ reenters the duct cells through the apical membrane via
amiloride-sensitive42 epithelial Na+ channels (ENaC)42
and is transported across the basolateral membrane
by ouabain-sensitive10 Na+, K+-ATPase pumps. Cl
transport appears to be both transcellular and paracellular, with the cystic fibrosis transmembrane regulator
(CFTR) Cl channels playing an important role in
transcellular fluxes.43 In cystic fibrosis, CFTR Cl channels are mutated, and eccrine duct Cl reabsorption is
defective, although not completely abolished.24 Na+ is
increased in the duct and the sweat at the skin surface.44 Unlike in the lung, CFTR mutations do not lead
to increased ENaC-mediated Na+ influx, which suggests that the CFTRENaC interactions seen in other
tissues differ from that in the eccrine duct. Sweat
acidification appears to be mediated via the enzyme
carbonic anhydrase, the HCO3/Cl and Na+/H+
exchangers, and the V-type H+ ATPase. The intracellular enzyme carbonic anhydrase catalyzes HCO3 and
H+ production. Intracellular HCO3 is cleared via the
HCO3/Cl antiporter, whereas H+ is pumped into the
luminal sweat by the V-type H+ ATPase.45 The Na+/
H+ antiporter NHE1 (Na+/H+ exchanger isoform 1)44,46
found in the basolateral membrane, is important in
intracellular pH regulation.
Several drugs are known to modify ductal NaCl
reabsorption. When aldosterone is injected systemically or locally, the Na/K ratio in sweat begins to
decrease within 6 hours, reaching a nadir at 24 hours
and returning to the preinjection level in 4872 hours.44
Na+ deprivation stimulates both renin and aldosterone secretion, but high thermal stress per se [a single
1-hour exposure of humans to a temperature of 40C
(104F)] is a potent stimulator of renin and aldosterone
secretion in either the presence or absence of sodium
deprivation. In an in vitro sweat gland preparation,
neither acetazolamide (a carbonic anhydrase inhibitor)
nor antidiuretic hormone changed ductal or secretory
function. However, more potent carbonic anhydrase
inhibitors, such as topiramate,47 have been reported to
induce oligohidrosis.
14
Ion reabsorption in the sweat duct

L
B
CA
H2O + CO2
CIK+
H++HCO3-
H+
CI-
H+V-ATPase
HC30-
CI+
(CFTR)
Na+
(ENaC)
Na+
H+
(NHE1)
Na+
In addition to the eccrine sweat glands, described earlier, apocrine sweat glands are found in humans, largely
confined to the regions of the axillae and perineum.48
They do not become functional until just before puberty;
thus, it is assumed that their development is associated
with the hormonal changes at puberty, although the
exact hormones have not been identified.
ANATOMY
Apocrine glands are coiled and localized in the
subcutaneous fat near the dermis. The gland consists of a single layer of cuboidal or columnar cells.
These secretory cells rest on a layer of myoepithelial
cells.49 The duct is composed of a double layer of
cuboidal cells, and empties into hair follicle infundibulum.
Like the eccrine gland, the myoepithelium fulfills
dual functions in both providing structural support
and pumping out preformed sweat.
-adrenergic receptors and purinergic receptors
have been identified on apocrine glands. However,
nerve fibers and muscarinc receptors have not been
identified, suggesting that any cholinergic stimulation
acts humorally.50
FUNCTIONS
A number of functions have been attributed to the
apocrine glands, including roles as odoriferous sexual
attractants, territorial markers, and warning signals.

These glands play a role in increasing frictional resistance and tactile sensibility as well as in increasing
evaporative heat loss in some species. The production
of pheromones by the apocrine glands of many species
is well established.51
Because the apocrine glands of humans do not begin
to function until puberty and are odor producing, it
is attractive to speculate that they have some sexual
function, which may now be vestigial. There are high
levels of 15-lipoxygenase-2 in the secretory cells of
the apocrine gland. Its product, 15-hydroxyeicosatetraenoic, a ligand for the nuclear receptor peroxisome
proliferator-activated receptor-, may function as a
signaling molecule and in secretion or differentiation.51
For nonhuman furred primates, apocrine glands may
have a purpose in thermoregulation as well.
APOCRINE SWEAT GLAND
::
Figure 83-7 Illustration of ion reabsorption in the sweat duct. Na+ enters the apical (luminal) membrane through epithelial Na+ channels (ENaC) and is transported across the basolateral membrane by Na+, K+-adenosine triphosphatase (ATPase).
Cl enters the cell through the cystic fibrosis transmembrane regulator Cl channel (CFTR) and also is transported across
the lumen via a paracellular pathway. H+ generated by the enzyme carbonic anhydrase (CA) is pumped into the lumen
by a V-type H+ ATPase (H+ V-ATPase). Intracellular pH homeostasis is maintained by parallel HCO3/H+ and Na+/H+ (NHE1)
exchangers. The activity of these enzymes, transporters, and channels results in H+ secretion and Na+ and Cl reabsorption,
which produces a final sweat that is hypotonic and acidic. Paracellular Cl fluxes across the cell junction are indicated with
an arrow at the bottom of the figure. B = basolateral membrane; L = luminal or apical membrane; arrows = conductive flux
of ions through ionic channels.
Chapter 83
CI-
COMPOSITION OF SECRETION
When it is first secreted, the apocrine sweat of humans
is milky, viscid, and without odor. Apocrine sweat
contains three types of precursors: fatty acids, sulfanyl
alkanols and odiferous steroids, which are converted
by bacteria on axillary skin, particularly corynebacterium striatum, into odiferous substances. Secretion of
amino acid and steroid precursors is controlled by an
ATP-dependent efflux pump multidrug resistance protein 8 (MRP8), encoded by the gene ABCC11, which is
expressed in apocrine sweat glands. Axillary odor is
significantly reduced in Asian populations that carry
a single nucleotide polymorphism (SNP) in this gene,
which also affects earwax characteristics.52
935
14
MODE OF SECRETION
Apocrine (decapitation), holocrine and merocrine
types of secretion have been reported in apocrine
glands. Cannulation of the duct of the human apocrine
sweat gland has shown that secretion is pulsatile, and
it is assumed that contractions of the myoepithelial
cells surrounding the secretory cells are responsible for
these pulsations.53
CONTROL OF SECRETION
Section 14 ::
The apocrine sweat glands of humans respond to emotive stimuli only after puberty. They can be stimulated
by either epinephrine or norepinephrine given locally
or systemically. Studies have shown that the apocrine
glands are controlled mainly by adrenergic agonists52;
although some cholinergic control also has been
reported.49,54 This is in contrast to the eccrine glands,
which are under cholinergic control.
Although an intact nerve supply is a functional
requirement of apocrine sweating, the demonstration
of nerve endings or varicosities in close proximity to
the glands has been difficult.49,55 Local capillary circulation likely assists in conveying transmitter substance
to the sweat gland cells, a form of neurohumoral transmission.
As would be expected, drugs that affect adrenergic
systems also have an effect on apocrine sweat glands.
Adrenergic neuron-blocking agents inhibit sweating,
as do drugs that deplete the stores of transmitter substance in adrenergic neurons. Drugs that block specific adrenergic receptors also inhibit sweating, but
the types of receptors that must be blocked differ in
various species. The type of receptor that mediates the
response of the apocrine glands of humans has not
been elucidated.
KEY REFERENCES
12. Murakami M et al: Postsecretory processing generates
multiple cathelicidins for enhanced topical antimicrobial
defense. J Immunol 172(5):3070-3077, 2004
13. Nadel ER, Bullard RW, Stolwijk JA: Importance of skin
temperature in the regulation of sweating. J Appl Physiol
31(1):80-87, 1971
17. Coon J, Rothman S: The sweat response to drugs with
nicotine-like action. J Pharmacol Exp Ther 23:1, 1941
23. Sato K: The physiology, pharmacology, and biochemistry
of the eccrine sweat gland. Rev Physiol Biochem Pharmacol
79:51-131, 1977
38. Bolognia JL, Cooper DL, Glusac EJ: Toxic erythema of
chemotherapy: A useful clinical term. J Am Acad Dermatol
59(3):524-529, 2008
46. Nejsum LN, Praetorius J, Nielsen S: NKCC1 and NHE1
are abundantly expressed in the basolateral plasma membrane of secretory coil cells in rat, mouse, and human
sweat glands. Am J Physiol Cell Physiol 289(2):C333-C340,
2005
47. de Carolis P et al: Transient hypohidrosis induced by topiramate. Epilepsia 44(7):974-976, 2003
Chapter 84 :: D
isorders of the Eccrine Sweat Glands
and Sweating

:: Robert D. Fealey & Adelaide A. Hebert
HYPERHIDROSIS AND ANHIDROSIS AT A GLANCE
Primary focal (essential) hyperhidrosis:
Affects over 6 million young people
worldwide.
Excessive palmar sweating affects quality of
life.
Effective treatments (stratified to match
the severity) include topical agents,
iontophoresis, oral anticholinergics, and
botulinum toxin.
Endoscopic thoracic sympathetic surgery is
a last-line choice for severe hyperhidrosis.
Localized, large areas of hyperhidrosis may be
compensatory.
936
Clue to loss of sweating elsewhere.
Determine location of sudomotor lesion and

underlying cause by thermoregulatory sweat
testing combined with direct and axon reflex
sweat evaluation.
Patterns of anhidrosis provide objective
evidence of small nerve fiber and/or eccrine
gland involvement in many neurologic and
dermatologic disorders.
Analysis of sweat composition continues to be
diagnostic in cystic fibrosis.
Determination of sweat-derived antimicrobial
peptides may provide evidence of impaired
innate defense in skin disorders such as
atopic dermatitis and neutrophilic eccrine
hidradenitis.
14
The physical examination continues to be important

in the diagnosis of sweating disorders. For example,
the skin of an infant with cystic fibrosis is much saltier
than infants without cystic fibrosis and when collected
sweat is dried, it forms fern-like crystals. Infants with
widespread sweat loss may present with fever of
unknown origin. Taking note of the beads of sweat on
the palms and soles of a young adult goes a long way to
making a diagnosis of primary focal (essential) hyperhidrosis. In uremia, the evaporation of sweat with high
urea concentrations results in the deposition of urea on
Figure 84-3 Secretory tubules, nerve fibers, and blood

vessels in a normal human sweat gland fluorescently
stained by immunohistochemical and lectin methods and
visualized via laser scanning confocal microscope. Immunoreactive staining of nerves with protein gene product
9.5 antibody (green staining) shows axons wrapped
around secretory tubules. (Photo used with permission
from Dr. William Kennedy, MD, Minneapolis, MN.)
Disorders of the Eccrine Sweat Glands and Sweating
Disorders of eccrine sweating can occur for many different reasons, including dysfunction of the thermoregulatory centers in the brains central autonomic
network, changes in the spinal sympathetic preganglionic, ganglionic, or postganglionic neurons/axons or
in the muscarinic (M3) cholinergic synapse on sweat
glands. Abnormalities of eccrine sweat formation by
the secretory coil and sweat ductal cells may occur or
ductal disruption or occlusion may develop, preventing delivery of sweat to the skin surface.
A review of the normal anatomy and physiology of
eccrine sweat glands and sweating may be found in
Chapter 83. This chapter focuses on neurologic and
dermatologic disorders that cause focal or generalized abnormalities of sweating, highlighting an exciting interface where disorders are better understood,
diagnosed, and treated based on recognition of the
integrated function of nerves, skin, and the immune
system (Fig. 84-1). There are a variety of techniques
that can be used clinically and in research of sweating that are discussed online. Table 84-1 is a comprehensive table based on disorders with increased or
decreased sweatingsome diseases are discussed in
this textthe others are discussed online. Many are disorders related to nervous system structural, functional
and inherited disorders; therefore any patient with a
sweating disorder should be evaluated carefully for
internal medicine diseases and neurologically by consultants in some cases.
VISUAL EXAMINATION
OF THE SKIN
::
Figure 84-1 A patient with an acquired idiopathic

anhidrosis shows anhidrotic (yellow) and sweating (purple)
staining of sodium alizarin sulfonate (alizarin Red S) indicator powder. Punch skin biopsy from an anhidrotic skin
site (a) shows marked perieccrine lymphocytic infiltration
of sweat gland secretory coils, whereas sweating skin (b)
shows normal sweat gland morphology. The presence of
perieccrine inflammation prompted immunomodulatory
therapy with corticosteroids and pulsed methotrexate and
a trial of topical tacrolimus.
Chapter 84
Figure 84-2 A patient with segmental anhidrosis (yellow)

with compensatory left-sided hemihyperhidrosis (purple)
due to a right greater than left-sided upper thoracic spinal
cord injury (sodium alizarin sulfate indicator powder).
937
14
TABLE 84-1
Classification of Disorders of Eccrine Sweating
Section 14 ::
938
Primary Focal (Essential) Hyperhidrosis

Palmoplantar, axillary, craniofacial,
generalized hyperhidrosis
Secondary Causes of Focal Hyperhidrosis
Due to cerebral infarction
Frontal opercular infarct
Brainstem stroke
Associated with spinal cord injury
Autonomic dysreflexia
Posttraumatic syringomyelia
Orthostatic hypotension triggered
Associated with other central nervous system
disorders
Chiari type I and II malformation
Myelopathies due to infarction,
syringomyelia, tumor
Cold-induced sweating syndrome
Olfactory hyperhidrosis
Associated with peripheral nervous system
disorders
Peripheral motor neuropathy with
autonomic dysfunction
Dermatomal or focal hyperhidrosis
due to nerve trunk irritation
Compensatory segmental
hyperhidrosis (postsympathectomy,
Ross syndrome, pure autonomic
failure)
Gustatory sweating
Physiologic
Idiopathic
Postherpetic
Post nerve injury (postsurgical, diabetic
autonomic neuropathy, postinfectious,
tumor invasion)
Lacrimal sweating
Harlequin syndrome
Idiopathic, localized hyperhidrosis
Idiopathic unilateral circumscribed
hyperhidrosis
Postmenopausal localized
hyperhidrosis
Associated with local skin disorders
Blue rubber bleb nevi
Eccrine angiomatous hamartoma
Tufted angioma
Glomus tumor
Burning feet syndrome
Pachydermoperiostosis
Granulosis rubra nasi
Pretibial myxedema
POEMS (polyneuropathy,
organomegaly, endocrinopathy, M
protein, and skin changes) syndrome
Secondary Causes of Generalized

Hyperhidrosis
Associated with central nervous system
disorders
Episodic hypothermia with
hyperhidrosis (HinesBannick or
Shapiro syndrome)
Posttraumatic or posthemorrhagic
diencephalic epilepsy
Fatal familial insomnia and Parkinson
disease
Associated with fever and chronic infection
Tuberculosis, malaria, brucellosis,
endocarditis
Associated with metabolic and systemic
medical diseases
Hyperthyroidism, diabetes mellitus,
hypoglycemia, hypercortisolism,
acromegaly
Associated with malignancy
Leukemia, lymphoma,
pheochromocytoma, Castleman
disease, carcinoids, renal cell cancer
Medication-induced
See Table 84-3
Neuroleptic malignant syndrome
Serotonin syndrome, other
medications
Toxic syndromes
Alcohol, opioid withdrawal, delirium
tremens
Associated with central and peripheral
nervous system disorders
Familial dysautonomia (RileyDay),
Morvan fibrillary chorea
Primary Autonomic Disorders with
Acquired Anhidrosis
Isolated sudomotor disorders
Progressive isolated segmental
anhidrosis
Idiopathic pure sudomotor failure
Chronic idiopathic anhidrosis
Sudomotor plus other autonomic disorders
Ross syndrome
Pure autonomic failure
Autoimmune autonomic neuropathy
Secondary Autonomic Disorders
Associated with Anhidrosis
Central nervous system lesions (stroke, tumor,
infection, infiltration, trauma, etc.)
Hypothalamic lesions
Brainstem lesions
Spinal cord lesions
Degenerative disorders
Multiple system atrophy, dementia
with Lewy body disease, Parkinson
diseaseautonomic failure
Peripheral Nerve Lesions Causing

Anhidrosis
Hereditary sensory and autonomic
neuropathy types I, II, IV (congenital
insensitivity to pain with anhidrosis)
GuillainBarr syndrome (acute
inflammatory demyelinating
polyneuropathy)
Diabetic autonomic neuropathy
Amyloidosis
Lepromatous neuropathy
LambertEaton myasthenic
syndrome
Alcoholic neuropathy
Fabry disease
Idiopathic small-fiber neuropathy
Erythromelalgia
Sympathectomy and other surgical
lesions
Harlequin syndrome
Anhidrosis due to toxins, pharmacologic
agents and heat exposure
Botulism
Ganglionic blockers, anticholinergics,
carbonic anhydrase inhibitors
Opioids
Heat hyperpyrexia and heat stroke
Anhidrosis Associated with Diseases of
Skin and Sweat Glands
Anhidrosis due to physical agents damaging
skin
Trauma, burns, pressure, scar
formation, radiation therapy
Anhidrosis due to congenital and acquired
skin diseases
Fabry and other congenital
metabolic diseases
Congenital ectodermal dysplasia
Ichthyosis
Neutrophilic eccrine hidradenitis
Sjgren syndrome
Systemic sclerosis (scleroderma)
Segmental vitiligo
BazexDupreChristol syndrome
Disorders affecting the sweat duct
Miliaria
Palmoplantar pustulosis
Psoriasis
Lichen planus
Atopic dermatitis
Disorders with abnormal sweat composition
Atopic dermatitis (reduced dermcidin
levels)
Cystic fibrosis (increased chloride
concentration)
the skin, referred to as uremic frost. Patients with craniofacial hyperhidrosis may develop a darkened hue
to their skin known as chromhidrosis. Focal or segmental compensatory hyperhidrosis may be apparent on
examination. Dry, atrophic skin may be seen in areas
affected by small-fiber neuropathy. Disorders affecting
the sweat duct (miliaria or psoriasis, for example) are
often diagnosed via visual inspection of the skin.
DISORDERS OF SWEATING
Table 84-1 organizes disorders of sweating into the six
categories discussed in this chapter.
Primary focal (essential) hyperhidrosis is one of the

most common disorders of eccrine sweating.16 This
condition is defined as focal visible, excessive sweating of at least 6-months duration without apparent
cause with at least two of the following characteristics:
(1) bilateral and relatively symmetric sweating; (2) the
sweating impairs daily activities; (3) a frequency of at
least one episode per week; (4) an age of onset before
the age of 25 years; (5) a positive family history; (6)
cessation of sweating during sleep.17 A national survey estimated that hyperhidrosis affects 2.8% of the
US population, and that half of those affected experience excessive sweating of the axillae.18 Hyperhidrosis of the palms, soles, axillae, and, to a lesser extent,
craniofacial and groin regions may occur at any time
irrespective of temperature, stress, or pleasure. Primary focal hyperhidrosis does not manifest when the
patient undergoes general anesthesia and augmentation with thermal stimuli and physical exertion is not
uncommon. Sweating may be continuous or phasic;
when continuous, sweating is most troublesome in
summer. Phasic outbursts with minor emotional activity are similar year round.
Severe primary focal hyperhidrosis interferes with
many activities of daily living and patients report a
reduced quality of life19 Avoiding a handshake can
lead to professional embarrassment, and avoidance of
touch can lead to social or interpersonal seclusion and
other symptoms of social anxiety disorder. Symptoms
begin in childhood or around puberty and affect either
sex equally. A family history is present in approximately one-fourth of patients. The disorder persists for
years with occasional spontaneous improvement after
35 years of age.
The central autonomic network control of emotional sweating is distinct from the preoptic-anterior
hypothalamic controller of thermoregulatory sweating. The anterior cingulate cortex, which orchestrates the sweat response from the palms and soles,
may modulate hypothalamic output inappropriately.
Treatment involves determining the severity and distribution of the disorder, ruling out other causes of
hyperhidrosis, and selecting a modality of therapy
appropriate to age of the patient and severity of the
disorder. Some current treatment methods are shown
in Box 84-1. Treatment begins with discussing the
nature of the disorder and discerning patient wishes
and expectations. Mild cases of axillary and palmar
sweating are controlled via topical application of aluminum chloride hexahydrate or glycopyrrolate, an
anticholinergic agent. Care should be taken to have the
aluminum chloride applied to completely dry skin as
use of the agent on moist skin can result in the formation of a weak hydrochloric acid that can result in discomfort, and burning and peeling of the skin surface.
This irritation can be managed by cessation of therapy
for a few days and the use of a class VII topical steroid
cream. Oral glycopyrrolate, oral or transdermal clonidine, transdermal scopolamine, or oral topiramate21
can be administered if topical agents alone are not
helpful or are too irritating. Control of palmar-plantar
sweating is sometimes possible using tap water (or a
solution of glycopyrrolate) iontophoresis. Intradermal
injection of botulinum toxin (BTX), (onabotulinumtoxinA) is appropriate for treatment of focal areas, such as
axillae, palms of hands, soles of feet and groin, and is
effective for 28 months per treatment.22 Facial hyperhidrosis can be treated with oral or topical23 glycopyrrolate.
Immunohistochemical studies show sweat glands
appear structurally normal in hyperhidrotic patients
before BTX therapy, whereas after therapy the luminal area of the gland and protein gene product 9.5
(neural marker) staining is diminished. This suggests
that BTX therapy induces long-standing functional
denervation of the sweat glands. However, growthassociated protein 43, indicative of axonal sprouting,
is increased, suggesting reinnervation may eventually take place.24
Repeat BTX injections do not demonstrate a diminished duration of efficacy.25 Pain with palmar botulinum injections is common and several techniques are
in use to minimize this.26,27 Iontophoresis of BTX in
solution has been successfully tried with better control
::
CLINICAL MANIFESTATIONS AND

PATHOMECHANISM
TREATMENT
14
Chapter 84
PRIMARY FOCAL (ESSENTIAL)

HYPERHIDROSIS
These patients have less reflex bradycardia than control subjects in response to the Valsalva maneuver or
facial immersion, but a higher degree of cutaneous
vasoconstriction in response to finger immersion in
cold, suggesting that they have increased sympathetic outflow passing through the T2T3 ganglia.20
Ventilated capsule recordings of palmar sweating
provide further evidence of emotionally triggered,
centrally derived sweat output. Such sweating is augmented at rest, bilaterally synchronous, and pulsatile
(eFig. 84-3.1 in online edition).
The severity of primary focal hyperhidrosis ranges
from intermittent, slightly moist palms and soles to
daily sweat drippage from hands and feet, requiring
the frequent use of towels.
939
14
Box 84-1 Treatments for Hyperhidrosis

Type of
Hyperhidrosis
Treatment
Formulation
Craniofacial, gustatory
Glycopyrrolate
0.5%2% Vanicream base Topical, once to twice daily. Tablet started at 1 mg bid;
or roll-on lotion; 1- to
increase prn up to 2 mg three to four times daily.
2-mg tablet
Clonidine
0.1-mg tablet, 0.10.3 mg/ Oral incremental increases up to 0.61.2 mg/day in two
day, transdermal patch
or three divided doses; 0.1 mg/day patch first week
increased weekly up to two 0.3 mg/day patches.
Craniofacial, gustatory
Paroxysmal localized
Donnatal extend Phenobarbital, USP (3/4 gr.) One tablet orally every 12 hr.
tab
48.6 mg
Hyoscyamine Sulfate, USP
0.3111 mg
Atropine Sulfate, USP
0.0582 mg
Scopolamine Hydrobromide, USP 0.0195 mg
Topiramate
25-mg tablet
Begin 25 mg twice daily; increase each dose weekly by
25 mg up to 100200 mg daily in two divided doses.
Axillary, palmar-plantar,
craniofacial
Aluminum
chloride
Axillary
Over the counter Aluminum Zirconium

clinical strength Trichlorohydrex Gly 20%
antiperspirant
anhydrous
Apply to axillae twice a day
Palmarplantar
Iontophoresis
unit
Patient-controlled current, 1530 mA using tap

water; glycopyrrolate can
be added, making a 0.1%
solution
Immerse hands, feet for 30 min once or twice daily, or

20 min at each site every 23 days, or 10 min at each site
three to five times weekly; anode site is most effective so
switch sides after one-half of each treatment; direct current more effective, but AC current less painful and may
be used part of time; glycopyrrolate solution enhances
effect. Most modern iontophoresis unit do not require
switching of anodes.
Palmarplantar, axillary,
gustatory, recalcitrant
Botulinum toxin
A injection
25 units of botulinum
toxin
Glycopyrrolate
1- to 2-mg tablet
Given via high intradermal injections to 1 cm2 iced/

anesthetized skin areas; for botulinum toxin A, total of
1220 injections (50 units total) given per axilla, 5075
injections in the palm/each foot; benefit lasts 28
months; reinjection is effective.
Tablet started at 1 mg bid; increase 1 mg each week as
tolerated up to 2 mg three to four times daily.
Axillary
Local incision
Liposuction and curettage of sweat glands in

dermis
Define area of involvement with starch-iodide

Minor test or equivalent; small incisions with sharp
suction-curettage cannula; usually permanent,
40%70% reduction in sweating achieved.
Palmar, axillary; documented severely affected

cases resistant to other
treatment modalities
Sympathetic
surgery
Various procedures affecting the T2, T3, and/or T4

sympathetic ganglia and
connections
Invasive, video-assisted endoscopic thoracic procedure

preferred; intraoperative monitoring of hand/finger skin
blood flow/temperature suggested; sympathotomy (disconnection of sympathetic chain between T2 and stellate
ganglia done to minimize compensatory hyperhidrosis;
selective T3 sympathectomy may have less compensatory
hyperhidrosis; T2T4 sympathectomy done for axillary
hyperhidrosis has high incidence of compensatory hyperhidrosis on trunk and gustatory hyperhidrosis.
Section 14 ::
940
Route of Administration and Dosage
20% aluminum chloride

in anhydrous ethyl alcohol; 12% aluminum chloride in sodium carbonate
water
Topically, nightly, until desired sweat reduction

achieved. Then taper to once weekly; follow Physicians
Desk Reference directions carefully for each body region
to maximize effect and minimize skin irritation.
of sweating than with water alone.28,29 However, the

cost effectiveness of this has been questioned.
Only the most severe cases of palmar hyperhidrosis not responding to conservative treatment
may be considered for surgical management. Many
patients have been successfully treated with endoscopic, upper thoracic sympathectomy30 (eFig. 84-3.2
in online edition); however, the best procedure to use
is still being investigated.10,3036 These surgical procedures carry the risk of creating minor to severe compensatory hyperhidrosis in body segments below
the treated area (see eFig. 84-3.3 in online edition)
as well as much less common surgical complications
of wound infection, Horners syndrome, pneumoor hemothorax, and atelectasis. Long-term surveys
of patients having undergone thoracic sympathectomy for treatment of palmar hyperhidrosis have
illustrated that many patients wish they had not
undergone the procedure due to the compensatory
sweating that developed after the surgery.37,38
Another surgical option for axillary hyperhidrosis is
tumescent suction curettage, which is performed in an
outpatient setting. In one limited study of 63 subjects,
greater than 75% were still satisfied with their reduction in sweating 2 years after treatment.39
(Secondary causes of localized hyperhidrosis are
discussed online only.)
Treatment with topical scopolamine, clonidine,53 glycopyrrolate,59,60 aluminum chloride, or BTX injection61,62 can be effective; rarely, intracranial section of
the glossopharyngeal nerve or tympanic neurectomy
is needed.
SECONDARY CAUSES OF
LOCALIZED HYPERHIDROSIS
Increased sweating has been reported in diabetes mellitus, hypoglycemia, congestive heart failure, thyrotoxicosis, hyperpituitarism, dumping syndrome, carcinoid
syndrome, and alcohol and drug withdrawal. Sweating
is increased (especially in males) in acromegaly (in which
the size of sweat gland acini and the density of innervation to the sweat glands is greater than in controls) and is
decreased in growth hormone deficiency (GHD).
Some studies of GHD pre- and posttreatment, using
histochemistry for acetylcholinesterase and immunohistochemistry for the neuropeptide vasoactive
intestinal polypeptide and protein gene product 9.5,
a general neural marker, have shown increased sweat
gland acinar size and periacinar innervation and pilocarpine iontophoresis sweat rate after GH therapy.
However, other studies have shown that even treated
GHD subjects still sweat less than controls implying
permanent eccrine gland hypofunction and androgen
deficiency as a cofactor of reduced sweating.
METABOLIC AND SYSTEMIC

MEDICAL PROBLEMS
Malaria, tuberculosis, brucellosis, and subacute bacterial endocarditis may present with fever and generalized hyperhidrosis due to exogenous bacterial
pyrogens that stimulate phagocytic leukocytes to produce endogenous pyrogen [interleukin 1 (IL-1) and
IL-6, tumor necrosis factor (TNF), and -interferon].
These cytokines act not only as circulating hormones,
but also as intrinsic modulators in the brain. Signals
that stimulate IL-1 production in the brain include
humoral factors, such as circulating IL-6 and activation of peripheral C fibers and vagal afferents. These
effects can raise set-point temperature (producing fever), while simultaneously activating antipyretic mechanisms (eventually producing drenching
sweats).75
::
Localized sweating on lips, forehead, scalp, and nose

while eating hot and spicy foods occurs physiologically in many people via a trigeminovascular reflex.
Pathologic gustatory hyperhidrosis is asymmetric,
intense, and may produce patches of sweating on
the trunk and even extremities. The cause is aberrant
regeneration of damaged and undamaged facial parasympathetic fibers, destined for salivary glands, which
instead supply facial sweat glands that have been sympathetically denervated. Thus, gustatory stimuli that
previously caused parotid, salivary gland, or gastric
secretion now also cause sweating in the distribution
of the damaged sympathetic nerve. The most common occurrence is in Frey syndrome, in which sweating occurs in the distribution of the auriculotemporal
nerve after an injury, abscess, or surgery in the parotid
region.50 Frey syndrome can be seen in infants and children, often following birth trauma with forcep delivery, but two cases of familial, bilateral Frey syndrome
without birth trauma have also been reported.51 Gustatory sweating may follow upper thoracic and cervical
sympathectomy,50,5254 facial herpes zoster, or chorda
tympani injury and has been reported in cluster headache, diabetic neuropathy,5557 encephalitis, syringomyelia, and invasion of the cervical sympathetic trunk
by a tumor.58 The exact distribution can be delineated
with indicator powder on the face, neck, and upper
trunk while the subject chews and is photographed.
FEVER AND CHRONIC INFECTION
Chapter 84
GUSTATORY SWEATING
14
HYPERHIDROSIS AND MALIGNANCY

Hodgkin disease is characterized by the triad of fever,
sweating, and weight loss; night sweats may be the
only symptom and 31 of 100 patients present with
B-cell symptoms (fever, weight loss, sweating).76 The
excessive production of IL-1 by activated macrophages
is implicated as the cause of temperature instability.77
IL-1 is known to induce an abrupt increase in the
synthesis of prostaglandin E2 in the preoptic anterior
hypothalamic region, causing an elevation of the temperature set point. Excessive production of IL-6 by
Hodgkin lymphoma cells78 is also implicated as cause
941
14
Section 14 ::
942
of fever and subsequent night sweating. Advanced

solid tumors may also cause sweating via immunologic mechanisms relating to TNF- and effect of ILs
on central thermoregulation.
The symptomatic triad of excessive and inappropriate paroxysmal sweating, tachycardia, and pounding
headaches (associated with increased blood pressure)
almost assures the diagnosis of pheochromocytoma as
the cause of hyperhidrosis. Anti-- and -adrenergic
therapy is a mainstay of this disorder, with a rare
patient developing sweat gland necrosis during preoperative therapy.
GENERALIZED HYPERHIDROSIS DUE

TO MEDICATIONS/TOXINS
Hyperhidrosis is frequently associated with serotonin (5-hydroxytryptamine) reuptake inhibitors,
opioids, and sometimes with prostaglandin inhibitors
(naproxen). The serotonin syndrome and the neuroleptic malignant syndrome include hyperthermia, labile
blood pressure, hyperhidrosis, rigidity, agitation and
confusion. The mechanisms may relate to 5-hydroxy-
tryptamine (2A) and dopamine receptor antagonism.

The hyperhidrosis that commonly occurs during acute
and chronic administration of opioids is mainly due to
stimulation of mast cell degranulation, resulting in the
release of histamine.79 Excessive sweating can occur
in as much as 45% of patients taking methadone.80
Hyperhidrosis is also a recognized side effect of transdermal fentanyl.81 Sweating in combination with
hypertension, nausea, and mydriasis characterizes
acute opioid and alcohol withdrawal. Despite their
well-recognized anticholinergic effects, tricyclic antidepressants occasionally cause hyperhidrosis due to
their sympathomimetic effect. The presumed mechanism is inhibited reuptake of norepinephrine, leading
to stimulation of peripheral adrenergic receptors and
a generalized diaphoretic response. Cholinergic agonists such as pilocarpine and bethanechol and reversible cholinesterase inhibitors such as pyridostigmine
can increase sweating directly or indirectly via activation of M3 cholinergic receptors on sweat glands.
See Table 84-2 for an abbreviated listing by drug class,
example, and mechanism of hyperhidrosis and Table
84-3 for a complete listing of medications reported to
cause hyperhidrosis.
TABLE 84-2
Some Drugs that can Cause Hyperhidrosis

Class
Examples
Probable Mechanism
Anticholinesterases
Pyridostigmine
Cholinesterase inhibition
Antiglaucoma agents
Physostigmine Pilocarpine
Cholinesterase inhibition for physostigmine;

muscarinic cholinergic agonism for pilocarpine
Bladder stimulants
Bethanechol
Muscarinic cholinergic agonist
Opioids
Fentanyl
Hydrocodone
Methadone
Morphine
Oxycodone
Histamine release; alteration of central

thermoregulation
Serotonin-selective reuptake inhibitors
Citalopram
Duloxetine
Escitalopram
Fluoxetine
Fluvoxamine
Mirtazapine
Paroxetine
Trazodone
Venlafaxine
Serotonergic effect on hypothalamus or spinal cord
Sialogogues
Cevimeline
Pilocarpine
Muscarinic cholinergic agonist
Tricyclic antidepressants
Amitriptyline
Desipramine
Doxepin
Imipramine
Nortriptyline
Protriptyline
Norepinephrine reuptake inhibition with stimulation

of peripheral adrenoreceptors
14
TABLE 84-3
Some Drugs that can Cause Hypohidrosis
Anticholinergics
Glycopyrrolate Hyoscyamine
Scopolamine
Propantheline
Dicyclomine
Belladonna
Atropine
Antimuscarinic effect
Antiepileptics
Topiramate
Zonisamide
Carbamazepine
Carbonic anhydrase inhibition for

topiramate and zonisamide; central
anticholinergic effect for carbamazepine
Antihistamines
Cyproheptadine
Diphenhydramine
Promethazine
Antihypertensives
Clonidine
Central antiadrenergic effect
Antipsychotics and antiemetics
Chlorpromazine
Clozapine
Olanzapine
Thioridazine Quetiapine
Antivertigo
Meclizine Scopolamine
Bladder antispasmodics
Darifenacin
Oxybutynin
Solifenacin
Tolterodine
Gastric antisecretory
Propantheline
Muscle relaxants
Cyclobenzaprine
Tizanidine
Uncertain, possibly inhibition of spinal

excitatory interneurons; possible central
and peripheral antimuscarinic effect
Neuromuscular paralytics
Botulinum toxins
Cleavage of synaptosomal-associated
protein-25 (SNAP-25) inhibiting
presynaptic release of Ach
Opioids
Fentanyl
Hydrocodone
Methadone
Morphine
Oxycodone
Elevation of hypothalamic set point;

calcium channel antagonism
Tricyclic antidepressants
Amitriptyline
Desipramine
Doxepin
Imipramine
Nortriptyline
Protriptyline
Antimuscarinic effect (marked for

amitriptyline, doxepin; moderate for
imipramine and protriptyline; low for
nortriptyline)
ANHIDROSIS DUE TO TOXINS AND

PHARMACOLOGIC AGENTS
BOTULINUM TOXIN. BTX type A (onabotulinumtoxinA) and B both exhibit a dose-responsive
suppression of sweating when injected intra- and
subcutaneously (see Chapter 255). This chemodenervation of sweat glands is caused by the structural
architecture of BTX with its heavy chain binding to
the nerve cell, and its light chain catalyzing the prote-
olysis of one of the three SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor)
proteins preventing vesicle membrane fusion and
therefore the release of ACh and transmission of the
nerve impulse. This unique property has made BTX
(especially type A) very popular for the treatment
of localized hyperhidrosis of the axilla and palms
and skin areas affected by gustatory sweating. More
widespread anhidrosis can occur with BTX as well
as organophosphate ingestion as a consequence of
bioterrorism.114
Mechanism
::
Common Examples
Chapter 84
Class
943
14
adrenergic agonists can suppress sweating, probably

by reducing norepinephrines effect on hypothalamic
thermoregulatory neurons. The drug can be effective
in Shapiro syndrome, essential hyperhidrosis, and
postmenopausal sweating.
HEAT HYPERPYREXIA AND

HEAT STROKE
Section 14 ::
Figure 84-4 Thermoregulatory sweat test (left inset) in a

patient with lepromatous leprosy. Note the well-defined
anhidrotic areas of the extremities (yellow) with greater
involvement distally in cooler body regions. The patients
skin (right inset) showed ill-defined, scaling, and erythematous to hyperpigmented patches. Patchy loss of pinprick
sensation in the distal feet and toes was noted. Skin biopsy
from the right forearm (background photo) shows numerous acidfast bacilli (red staining) in a background of lymphohistiocytic inflammation. (Fite, 600.) (Fite stain and
skin photo used with permission from the Mayo Clinic
Department of Dermatology.)
PHARMACOLOGIC AGENTS. Many pharmacologic agents can cause anhidrosis, especially

those that are anticholinergic and interfere with
the binding of ACh at M3 muscarinic receptor on
sweat glands. Blockade at the sympathetic ganglionic level can inhibit sweating and cause orthostatic
hypotension. Recently, oligohidrosis in children has
been reported in those taking the carbonic anhydrase (CAII) inhibitors zonisamide and topiramate
and studies show reduction in axon reflex-mediated
sweating compatible with an effect on the sweat
gland. Such observations and the location of CAII
in the secretory coil clear cells and at the apex of the
ductal cells suggest that the formation of HCO3 and
H+ by CAII plays a significant role in sweat fluid
secretion.115,116
-OPIOID AGONISTS.
944
-Opioid agonists (e.g.,

morphine) tend to inhibit warm-sensitive neurons in
the hypothalamus. This action raises the bodys setpoint temperature, allowing core temperature to rise
substantially. This results in anhidrosis even in a hot
environment. After opioid drug levels drop, set-point
temperature drops below the elevated core temperature, producing profuse sweating.79 Clonidine and 2-
Heat hyperpyrexia and heat stroke are states of thermoregulatory failure of sudden onset that are characterized by general anhidrosis, hyperpyrexia [rectal
temperature greater than 40.5C (105F)], and disturbances of the central nervous system. The exact cause
of this disorder is unknown. The picture is generally
one of environmental stress, too severe for the thermoregulatory system, which suddenly collapses. In
the early stages, sweating may still be present and
the patient rational, but the rectal temperature may
be greater than 40.5C (105F). Within minutes, anhidrosis, mental confusion, coma, and/or seizures may
appear. The diagnosis should be suspected from the
clinical setting of activity in extreme heat and rectal
temperature greater than 40.5C (105F); it should
be accepted with the additional presence of anhidrosis, hot, dry skin, and any degree of central nervous
system manifestations. If untreated, the disorder
is uniformly fatal. In treated cases, the mortality is
approximately 35%.
ANHIDROSIS ASSOCIATED WITH

OTHER DISORDERS OF SKIN
AND SWEAT GLANDS
ANHIDROSIS DUE TO DAMAGE FROM
PHYSICAL AGENTS
Localized anhidrosis can occur whenever sweat glands
are damaged by surgery or trauma, scar formation,
cutaneous neoplasms, radiation therapy, infection,
inflammation of the skin, granulomatous lesions,
scleroderma, or vasculitis. Delivery of sweat to the skin
surface may be impaired in a variety of dermatoses
and papulosquamous diseases, presumably because
of poral occlusion. Blister formation with sweat gland
necrosis has been reported during intoxication with
barbiturates, methadone, diazepam, carbon monoxide,
amitriptyline, and clorazepate. Similar changes may
occur in coma induced by hypoglycemia and other neurologic events, suggesting the changes are due in part
to pressure over skin areas not usually subject to pressure. Radiation-induced dermatitis can abolish eccrine
function in a dose-dependent fashion. Mantle irradiation (usually in the 25- to 50-Gy range) often produces
a permanent loss of eccrine gland function, which tends
to be discovered incidentally when previously treated
patients undergo autonomic testing (see eFig. 84-4.2
in online edition). Keratotic changes blocking the
eccrine duct with or without syringoma-like ductal
proliferation have been described. Similar changes

have been noted with breast cancer radiation therapy.
Congenital ectodermal dysplasia (see Chapter 142),
acantholytic dermatosis (Grover disease; see Chapter
51), cholinergic urticaria (see Chapter 38), and various
forms of ichthyosis (see Chapter 49) may also be associated with altered sweating.
ANHIDROSIS DUE TO CONGENITAL

AND ACQUIRED SKIN DISEASES
INCONTINENTIA PIGMENTI. Hypohidrosis has

also been noted in the hypopigmented streaks and
patches on the legs, arms, and scalp of ten women
with incontinentia pigmenti.133 Skin biopsies reveal a
lack of eccrine sweat glands and hair follicles at these
sites. Hypohidrosis has also been described in segmental vitiligo, but not the generalized or acrofacial
types.134,135 Anhidrosis of the face and neck has also
been reported in members of a family with follicular
atrophoderma, basal cell carcinoma, and hypotrichosis, a rare X-linked, dominantly inherited syndrome
(BazexDupreChristol syndrome). Milia and sweat
duct occlusions may occur, but are inconstant features
of the disease.136
in Sjgren syndrome (see Chapter 161). Most often

patchy areas of anhidrosis occur on proximal and/or
distal limbs, compatible with a small-fiber neuropathy. Case reports of widespread anhidrosis and heat
intolerance associated with dry eyes and dry mouth,
positive extractable nuclear antigen panel, and lymphocytic infiltrates of minor salivary glands exist.123,124
Skin biopsies have shown perieccrine infiltrates in
some patients, but not in others. The failure of the
anhidrotic skin on TST to respond to ACh/pilocarpine iontophoresis in one report suggests that autoantibodies to the muscarinic (type 3, M3) cholinergic
receptor interfere with eccrine gland function.125128 M3
cholinergic receptors predominate on salivary glands
and sweat glands, which further supports an association. The stage of the immune-mediated response may
determine whether lymphocytic infiltration is present
or not.129
The aquaporin 5 (AQP5) water channel has been
identified in the apical plasma membrane of sweat
gland cells,130 and mobilization of these channels may
influence sweat production.131 The effects of drugs or
disease on these channels at this time are speculative
with regard to sweat gland disorders. Preliminary
evidence of autoantibody-mediated alterations in M3
cholinergic receptor activation and AQP5 expression
in salivary gland cells of Sjgrens syndrome patients
raises the possibility that some patients with disturbances of sweating may turn out to have AQP5 channelopathies.21
Atrophic sweat glands and focal anhidrosis have
been noted in patients with linear scleroderma. The
forehead is most commonly affected.132
::
NEUTROPHILIC ECCRINE HIDRADENITIS.
Lesions are most often painful, pruritic, erythematous

plaques or papules developing on the limbs, trunk,
neck, face, and ears. Most commonly reported is chemotherapy-associated neutrophilic eccrine hidradenitis (NEH), typically occurring within 2 weeks of
initiation of multiagent antineoplastic therapy. Fever
and neutropenia may occur and the disorder is usually self-limited (lasting several weeks). Necrosis
of eccrine secretory coils and associated epithelium
with surrounding dense neutrophilic neutrophilic
infiltrate that characterizes NEH is seen histologically (see eFig. 84-4.3 in online edition). A direct toxic
effect of the drug on eccrine glands is suspected and
recurrences with repeated chemotherapy may occur.
Treatment with colchicine and dapsone has been
beneficial. Another category of NEH appears due to
bacterial infection. Biopsied lesions have grown Serratia, Staphylococcus, Enterococcus, Pseudomonas, and
Nocardia.117 Community outbreaks due to swimming
pool water contamination with P. aeruginosa have
been described. Spontaneous resolution in weeks is
common, although some patients receive antibiotics.
It is not known whether susceptible individuals have
deficient innate dermcidin antimicrobial peptide
secretion in sweat (see Section Disorders Affecting
the Sweat Duct) or if changes in sweat duct structural proteins produce reduced barrier protection
against infection.
A recent case of NEH due to Streptococci showed the
presence of human -defensin 2, an epithelial antimicrobial peptide, in lesional epidermis and the eccrine
duct; however, levels of dermcidin, a recently discovered antimicrobial peptide constitutively expressed in
human eccrine sweat glands and secreted into sweat,
were not determined. Dermcidin levels have been
reported to be reduced in atopic dermatitis and have
recently been shown to activate normal human keratinocytes.118
Recurrent, palmoplantar NEH has been increasingly reported in otherwise healthy children
between 1 and 15 years of age. Vigorous exercise
SJGREN SYNDROME AND SCLERODERMA. Variable degrees of anhidrosis can occur
14
Chapter 84
STORAGE DISEASES. Sweat gland cellular inclusions

that can be identified on skin biopsy include membranebound vacuoles in secretory cells in the mucopolysaccharidoses, intracytoplasmic lipid in NiemannPick and
Sandhoff storage diseases, inclusions in adrenoleukodystrophy, maltase deficiency, and periodic acid-Schiff
(PAS)-positive granules in the outer duct cells in Lafora
myoclonic epilepsy.
with heavy sweating and damp, occlusive footwear

are possible risk factors.119 Spontaneous resolution
in 34 weeks is common, but repeated bouts with
subsequent exercise occur. Treatment with cool
compresses and topical steroids and rest has provided symptomatic relief. NEH has been described
in association with Behet disease120 and human
immunodeficiency virus infection. A possible treatment for NEH-Behet is an anti-TNF- agent, such
as infliximab, which has been effective for other
manifestations of Behet disease121,122 (see eTable
84-1.1 in online edition for summary of NEH).
945
14
DISORDERS AFFECTING THE

SWEAT DUCT
Section 14 ::
MILIARIA. Miliaria results from disruption of sweat

ductal integrity137 with consequent sweat secretion
into layers of the epidermis. Ultraviolet light exposure,
resident organisms on skin, and repeated sweating
episodes are facilitating factors. Focal anhidrosis can
occur and persist for several weeks, much longer than
the miliaria in affected skin regions. Based on clinical
and histopathology findings, miliaria is subdivided
into four groups: (1) miliaria crystallina; (2) miliaria
rubra; (3) miliaria pustulosa; and (4) miliaria profunda.
Miliaria crystallina (sudamina) consists of superficial, subcorneal, noninflammatory vesicles that easily
rupture when rubbed with a finger (Fig. 84-5). They are
common in infants in warmed environments, including
in intensive care units where medications employed
(cholinergic and adrenergic agents) may be stimulating sweating and aggravating the problem.138,139
Miliaria rubra (prickly heat) results when obstructed
sweat migrates into the epidermis as well as the upper
dermis, causing pruritic inflammatory papules around
the sweat pores (see eFig. 84-5.1 in online edition).
This disorder is common in infants, but also occurs in
children and adults after repeated episodes of sweating in a hot, humid environment. The eruption usually subsides within a day after the patient moves to
a cool environment. However, anhidrosis associated
with miliaria takes 2 weeks (the time needed to repair
the affected epidermal sweat duct unit by epidermal
turnover) to recover completely. Some of the eruptions of miliaria rubra become pustular, resulting in
miliaria pustulosa. Miliaria profunda results when the
sweat leaks into the deeper dermis. During exposure
to intense heat or after local injection of cholinergic
agents, the affected skin can be uniformly covered
with multiple discrete, flesh-colored papules that
resemble gooseflesh. Ductal blockade at various levels
is the immediate cause of miliaria. However, investigators do not agree on why the sweat escapes the
duct at different levels (causing different subgroups of
miliaria) nor on what causes the ductal blockade and/
or ductal leakage at different levels.
It is puzzling that the morphologic evidence of ductal blockade, such as keratin rings, PAS-positive proteins, or clusters of microorganisms, is rarely seen by
light microscopic observation of miliarial lesions. Thus,
Holzle and Kligman speculated that the keratin rings
and PAS-positive proteins are the consequence but not
the cause of ductal damage. The role of resident organisms especially Staphylococcus epidermidis has been proposed as a leading predisposing factor in miliaria.140,141
Indeed, there was a linear correlation between the severity of miliaria rubra and the number of cocci in experimental miliaria under a plastic film. The development
of experimental miliaria could be markedly suppressed
by pretreatment of the skin with hexachlorophene or
pyrithione.140
OTHER DISORDERS AFFECTING THE SWEAT

DUCTS. Abnormalities of the epidermal portion of
the spiraling sweat duct (acrosyringium) with altered

sweat delivery to the skin surface are present in several disorders with immunohistologic evidence of
neurogenic inflammation of skin. The presence of
vanilloid receptors and neuropeptide fibers containing
substance P and calcitonin-gene related protein in the
acrosyringium may explain the presence of mast cell
and other mediators of inflammation with subsequent
impairment of sweating.142144
DISORDERS WITH ALTERED

COMPOSITION OF SWEAT
ATOPIC DERMATITIS. Dermcidin is a recently discovered antimicrobial peptide with a broad spectrum
of activity. It is constitutively expressed in human
eccrine sweat glands and secreted into sweat. Recent
evidence suggests deficient amounts of sweat-derived
antimicrobial peptides may play a role in skin inflammatory disorders characterized by increased bacterial
colonization of the skin, such as atopic dermatitis.143,145
Dermcidin and other antimicrobial proteins and
peptides may have a therapeutical potential as topical anti-infectives in several skin diseases because of
their broad spectrum of antimicrobial activity, the low
incidence of bacterial resistance and their function as
immunomodulatory agents.118,146,147
CYSTIC FIBROSIS. Sweat chloride ion concentration
can determine the integrity of the CFTR Cl channel and
provide diagnostic information for cystic fibrosis.15 This
in vivo assay may prove useful in studying the effectiveness of CF gene therapy. In vitro studies of the CFTR Cl
activity from sweat glands obtained via skin biopsy are
presently under evaluation as markers of the efficiency
of CF-gene delivery and expression in sweat gland epithelial cells.148 The saltier sweat may be responsible for
the frequent observation of the aquagenic wrinkling of
the palms (AWP) syndrome in CF patients.149,150
AQUAGENIC WRINKLING OF PALMS
(AWP) SYNDROME. AWP is an uncommon dis-
946
Figure 84-5 Miliaria crystallina. Note the delicate, droplike vesicles without erythema.
ease characterized by the rapid and transient formation of edematous whitish plaques on the palms on
exposure to water.151 Although the exact cause of this

condition is unknown, hyperplastic glandular epithelium and aberrant AQP5 staining in the patients
sweat glands suggest that AWP stems from dysregulation of sweating.
KEY REFERENCES
14
Chapter 85
::
Disorders of the Apocrine Sweat Glands
3. Fealey RD: Thermoregulatory sweat test. In: Clinical

Autonomic Disorders, 3rd edition, edited by PA Low, EE
Benarroch. Philadelphia, PA, Lippincott Williams &
Wilkins, 2008, pp. 244-263
13. Morgan CJ et al: Cutaneous microdialysis as a novel
means of continuously stimulating eccrine sweat glands
in vivo. J Invest Dermatol 126(6):1220-1225, 2006
14. Kennedy WR, Wendelschafer-Crabb G, Brelje TC: Innervation and vasculature of human sweat glands: An
immunohistochemistry-laser scanning confocal fluorescence microscopy study. J Neurosci 14(11 Pt 2):6825-6833,
1994
16. Eisenach JH, Atkinson JL, Fealey RD: Hyperhidrosis:
Evolving therapies for a well-established phenomenon.
Mayo Clin Proc 80(5):657-666, 2005
17. Hornberger J et al: Recognition, diagnosis, and treatment of primary focal hyperhidrosis. J Am Acad Dermatol
51(2):274-286, 2004
33. Miller DL et al: Effect of sympathectomy level on the
incidence of compensatory hyperhidrosis after sympa-
thectomy for palmar hyperhidrosis. J Thorac Cardiovasc

Surg 138(3):581-585, 2009
36. Atkinson JL, Fode-Thomas NC, Fealey RD, Eisenach JH,
Goerss SJ: Endoscopic transthoracic limited sympathotomy for palmar-plantar hyperhidrosis: Outcomes and
complications during a 10-year period. Mayo Clin Proc
86(8):721-729, 2011
38. Weksler B et al: Transection of more than one sympathetic chain ganglion for hyperhidrosis increases the
severity of compensatory hyperhidrosis and decreases
patient satisfaction. J Surg Res 156(1):110-115, 2009
61. Kreyden OP, Scheidegger EP: Anatomy of the sweat
glands, pharmacology of botulinum toxin, and distinctive syndromes associated with hyperhidrosis. Clin Dermatol 22(1):40-44, 2004
90. Nolano M et al: Ross syndrome: A rare or a misknown
disorder of thermoregulation? A skin innervation study
on 12 subjects. Brain 129(Pt 8):2119-2131, 2006
107. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy
in the diagnosis of small fiber neuropathy. Report of a
joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher
Nerv Syst 15(2):79-92, 2010
130. Horsefield R et al: High-resolution x-ray structure of
human aquaporin 5. Proc Natl Acad Sci U S A 105(36):1332713332, 2008
143. Jarvikallio A, Harvima IT, Naukkarinen A: Mast cells,
nerves and neuropeptides in atopic dermatitis and nummular eczema. Arch Dermatol Res 295(1):2-7, 2003
145. Rieg S et al: Deficiency of dermcidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis
correlates with an impaired innate defense of human
skin in vivo. J Immunol 174(12):8003-8010, 2005
Chapter 85 :: D
isorders of the Apocrine
Sweat Glands

:: Christos C. Zouboulis & Fragkiski Tsatsou
Apocrine glands are adnexal glands that are distributed
in the scalp, the axillae, the anogenital region, the eyelids (Molls glands), the external auditory meatus (ceruminous glands), and the mammary glands. Apocrine
glands can also be found in a more limited distribution
on the face and abdomen. Apocrine glands are quiescent
until puberty. Embryologically, apocrine glands develop
from the upper bulge of the hair follicle late in the fourth
month of gestation, with continued development as
long as hair follicles develop. A primary epithelial germ
(hair germ) grows down from the epidermis and forms
an apocrine gland, sebaceous gland, and hair follicle.
Apocrine glands are composed of three components:
(1) the intraepithelial duct, (2) the intradermal duct,
and (3) a coiled gland in the deep dermis or at the junction of the dermis and subcutaneous fat, which contains
the secretory portion. The coiled gland consists of one
layer of secretory cells around a lumen that is about ten
times the diameter of its eccrine counterpart. Contrac-
tile myoepithelial cells, a hyaline basement membrane,

and connective tissue surround the coiled gland. The
predominant mode of apocrine secretion is decapitation, a process where the apical portion of the secretory
cell cytoplasm pinches off and enters the lumen of the
gland. Apocrine sweat consists mainly of sialomucin.
Apocrine sweat is more viscous and produced in much
smaller amounts than eccrine sweat (which actually is
the wet portion of axillary sweat). The exact function of
apocrine glands is unclear, although they are thought
to represent scent glands. Their primary sympathetic
stimulation is adrenergic.1
Four disorders are considered in this chapter: two

primary disorders of the apocrine glands, namely (1)
apocrine bromhidrosis and (2) apocrine chromhidrosis; and two secondary disorders, (1) FoxFordyce
disease and (2) hidradenitis suppurativa (acne
inversa), in which apocrine glands become secondarily affected.
947
14
APOCRINE BROMHIDROSIS
APOCRINE BROMHIDROSIS
AT A GLANCE
Apocrine bromhidrosis refers to an offensive or
unpleasant body odor arising from apocrine
gland secretions.
Chronic disorder, most often developing in
the axillae, but may also involve the genitals
or plantar aspect of the feet.
Section 14 ::
The best-characterized short chain fatty acid

causing odor is -3-methyl-2-hexenoic acid.
Should be distinguished from eccrine
bromhidrosis.
Surgical removal of affected glands may be

effective.
CLINICAL FINDINGS
Body odor, osmidrosis, is a common phenomenon in a
postpubertal population. Bromhidrosis refers to body
odor, which is excessive or particularly unpleasant
and apocrine bromhidrosis to such an offensive odor that
arises from apocrine glands. It is most often mentioned
in the axillae. This condition may contribute to impairment in an individuals psychosocial functioning. The
terminology in the literature is sometimes confusing,
using osmidrosis to imply offensive odor, and bromhidrosis to imply osmidrosis in the setting of concomitant
hyperhidrosis.2
EPIDEMIOLOGY
Disease onset after puberty is common and tends to be
more prevalent in African-American populations. There
is no geographic predilection, although summer months
or warm climates may aggravate the disease. Poor personal hygiene may also be a contributing factor.3
948
Moreover, the axilla hosts many different bacteria,

most of which are Gram-positive ones. Bromhidrosis has been particularly associated with the action
of aerobic Corynebacterium species. Eccrine bromhidrosis may develop from the action of bacteria
on keratin that has been softened by eccrine secretions. In addition, the bacterial action on apocrine
secretions produces ammonia and short chain fatty
acids. The best-characterized short chain fatty acid is
-3-methyl-2-hexenoic acid.7 This acid is delivered to
the surface of the skin on two binding proteins, apocrine-secretion binding proteins (ASOB1 and ASOB2).
ASOB2 has been identified as apolipoprotein D.8
The effect of hyperhidrosis (excessive eccrine sweat
secretion) on osmidrosis and bromhidrosis is unclear.
Some have advocated that excessive eccrine sweat
improves apocrine bromhidrosis by flushing away
excessive apocrine secretions. Others have postulated
that eccrine sweat augments apocrine bromhidrosis by
encouraging local spread of apocrine sweat components and enhancing the moist environment in which
bacteria flourish.3
Apocrine secretions are responsible for odor production, primarily through bacterial action on its components. It is accepted that the odorous steroids, the
so-called pheromones, among them 16-androstenes,
5-androstenol, and 5-androstenone, contribute
to osmidrosis.4,5 5-Reductase type I is expressed in
apocrine glands. Individuals with osmidrosis have
increased levels of 5-reductase in their apocrine
glands. Because this enzyme catalyzes the conversion
of testosterone to 5-dihydrotestosterone, levels of
5-dihydrotestosterone may be greater than testosterone in the skin of affected individuals.6 The biotransformation of these steroids is complex and further
research is required to delineate these pathways.
HISTORY. Patients complain of an unpleasant body

odor. The axillae are the most common affected site,
although the genitals or plantar feet may also be
affected. The diagnosis is usually clinical. What constitutes a normal amount of body odor varies considerably among individuals and ethnic groups. In Asian
populations, only slight odor is often considered diagnostic.9,10
CUTANEOUS LESIONS. Physical examination of
the affected individual is usually unremarkable.
LABORATORY TESTS. There are no associated lab-
oratory abnormalities.
PATHOLOGY. Although some reports do not reveal

any abnormalities in the apocrine glands of affected
individuals, an increase in the numbers and size of
apocrine glands has also been reported.9
Apocrine bromhidrosis should be distinguished from
eccrine bromhidrosis, which is far less common (see
Chapter 84). Eccrine secretions are distributed in a
generalized fashion, are usually odorless, and serve
a thermoregulatory function. A plantar location is
characteristic for eccrine bromhidrosis. Certain foods
(garlic, curry, alcohol), drugs (bromides), toxins, or
metabolic causes (disorders of amino acid metabolism)
may result in eccrine bromhidrosis (Box 85-1).
TREATMENT
GENERAL MEASURES. Frequent washing of
the axillae, use of a deodorant or antiperspirant

of Apocrine Bromhidrosis
NONSURGICAL THERAPY. The injection of botulinum toxin A has been reported to successfully treat
genital11 and axillary bromhidrosis.12 The frequencydoubled, Q-switched Nd:YAG laser has also been
reported to be an effective noninvasive therapy for
axillary bromhidrosis.13
SURGERY. Several surgical measures have been
investigated in the treatment of apocrine bromhidrosis.
Patient selection is important because surgery is potentially associated with postoperative scar formation,
prolonged healing times, infection, and other complications. Upper thoracic sympathectomy has been
successful in treating apocrine bromhidrosis either in
isolation or in association with palmar hyperhidrosis.2
Surgical removal of the culprit apocrine glands can be
achieved either by the removal of subcutaneous tissue
in isolation or in combination with axillary skin.1416
Surgical subcutaneous tissue removal has also been
used in association with CO2 laser ablation.17 Although
surgical excision may be highly efficacious, depending
on the depth of tissue removed and surgical technique
used, regeneration and return of apocrine function/
osmidrosis and bromhidrosis may develop. Superficial
liposuction,18 tumescent superficial liposuction with
curettage,19 and ultrasound-assisted liposuction20 have
efficacy in the management of apocrine bromhidrosis.
In a series of 375 patients, more than 90% reported a
satisfactory reduction in odor.20 Another technique
with reported efficacy is ultrasonic surgical aspiration
of axillary apocrine glands with endoscopic confirmation.21 This technique uses ultrasound to liquefy fat
Apocrine bromhidrosis is a chronic and nonremitting

condition. Patients with apocrine bromhidrosis often
feel self-conscious and embarrassed by their condition
and may develop impairment with psychosocial functioning.
APOCRINE CHROMHIDROSIS
APOCRINE CHROMHIDROSIS
AT A GLANCE
Rare, chronic condition characterized by the
secretion of colored sweat.
Axillary and facial involvement is most
common. Areola involvement has been
reported.
Caused by an increased number of lipofuscin
granules in the luminal secretory cells of the
apocrine glands.
Secretions may be yellow, blue, green,
brown, or black.
Woods light examination may demonstrate
fluorescence of secretions and stained
clothes.
(aluminum chloride), perfumes, and changing of

soiled clothing can help. Removal of axillary hair may
minimize odor by preventing bacteria and sweat accumulation on the hair shafts. Antibacterial soaps or topical antibacterial agents may also be of benefit.
::
From Rehmus W et al: Bromhidrosis. In: emedicine, edited by

T McCalmont et al (http://www.emedicine.com), 2005.
14
Chapter 85
Eccrine bromhidrosis
Fish odor syndrome (trimethylaminuria)
Phenylketonuria
Sweaty feet syndrome
Odor of cat syndrome
Isovaleric acidemia
Hypermethioninemia
Food, drug, toxin ingestion
Liver failure (fetor hepaticus)
Renal failure
Nasal foreign body in children
Poor hygiene
Olfactory hallucinations
Body dysmorphic disorder
and sweat glands. In contrast, laser hair removal may

be associated with intensification of bromhidrosis.22
Adequate therapy is lacking. Reports of

efficacy with manual expression, capsaicin,
and botulinum toxin.
Apocrine chromhidrosis is a rare condition characterized by the secretion of colored apocrine sweat. Two
variants of apocrine chromhidrosis are recognized: (1)
axillary and (2) facial. Involvement of the mammary
areola has also been described.23,24 Yonge first recognized facial chromhidrosis in 1709. Shelley and Hurley
described this entity in 1954 and associated it with an
increased number of lipofuscin granules in apocrine
glands.25
EPIDEMIOLOLGY
Apocrine chromhidrosis is a rare disease. The worldwide prevalence is unknown. Onset of apocrine
chromhidrosis is usually at puberty, at the time of
increased apocrine gland activity. The disease persists
throughout life, improving in the aged. It is reported
most commonly in African-Americans.26 Geographic
predilections have never been described. Most of the
949
14
cases reported in the literature involve women; however, there is a lack of sound scientific evidence supporting a female preponderance.
Section 14 ::
The pigment responsible for causing apocrine chromhidrosis is lipofuscins that are produced in the apocrine secretory cells and excreted to the skin surface.
Lipofuscin is a golden-colored pigment that is not specific to apocrine glands. In apocrine chromhidrosis, the
lipofuscin granules are in a higher state of oxidation,
thereby imparting various colors of pigment, such as
yellow, green, blue, or black. Higher states of oxidation
produce darker colors.23 It is uncertain why this only
develops in some individuals.27
One case of facial chromhidrosis was successfully
treated with capsaicin. Nerve endings with receptors
for substance P have been found around eccrine sweat
glands, suggesting that substance P, a potent vasodilator, may play a role in sweat production and apocrine
chromhidrosis.28
CLINICAL FINDINGS
HISTORY. Individuals with apocrine chromhidrosis
often describe a sensation of warmth, a prickling sensation, or tingling feeling before apocrine gland secretion.
Triggers for colored sweating are usually emotional
or physical stimuli.26 The morbidity associated with
apocrine chromhidrosis stems from the emotional distress experienced by affected individuals.29 Staining of
undershirts and handkerchiefs are common complaints.
950
CUTANEOUS LESIONS. Individuals with apocrine chromhidrosis develop colored sweat in the axillae or face (Fig. 85-1). Mammary areolar involvement
has also been described.23 The pigment produced
ranges in color from yellow, blue, green, brown, to
even black. The quantity of pigmented sweat produced is usually quite small (approximately 0.001
mL at each follicular orifice).30 The droplets are odorless and dry quickly. Dried secretions appear as dark
flecks within affected areas. Axillary involvement
causes staining of shirts and undergarments. Facial
chromhidrosis commonly develops close to the lower
eyelid, including the malar cheeks, and occasionally
the forehead.29,30 Colored sweat can also be manually
expressed by squeezing in the affected area. Such a
maneuver may also be therapeutic.26
SPECIAL TESTS. An examination of yellow, blue,
or green secretions using a Woods light (360 nm)
produces a characteristic yellow fluorescence. Black
or brown pigment rarely autofluoresces.26 Secretions
can be manually expressed if not present at the time of
examination. Stained clothing may also fluoresce with
Woods lamp examination.31 Apocrine glands can be
stimulated to produce colored secretions by the injection of epinephrine or oxytocin.
LABORATORY TESTS. It is reasonable to check a
complete blood cell count to exclude a bleeding diathesis, homogentisic levels in urine to exclude alkaptonuria, and bacterial and fungal cultures of affected areas
to exclude pseudo-eccrine chromhidrosis.27
Figure 85-1 (A) Blue-black sweat produced in a patient with facial apocrine chromhidrosis after gentle squeezing of the
cheeks (Reproduced with permission from Chang YC, Anderson N, Soeprono F. Bilateral facial pigmentation. Dermatology
Online J. 13(3):16, 2007), (B) blue-black apocrine pigmentation of the axilla and the inflammatory boils of a male patient
with hidradenitis suppurativa.
PATHOLOGY
Adequate therapy for chromhidrosis is lacking. Manual expression of colored secretions may result in a
temporary improvement in symptoms for the following 4872 hours.28 Botulinum toxin type A has reported
to be successful in one patient with facial chromhidrosis. This patient experienced a substantial reduction in

of Apocrine Chromhidrosis
Eccrine chromhidrosis
Quinine ingestion
Pseudo-eccrine chromhidrosis
Blue sweat with copper exposure
Extrinsic dyes, paints
Alkaptonuria (ochronosis)
Hyperbilirubinemia
Hematohidrosis (bleeding diathesis)
Chromogenic bacteria (e.g., Corynebacterium
species), pseudomonas
From June K et al: Chromhidrosis. In: emedicine, edited by G Burg
et al (http://www.emedicine.com), 2005.
Apocrine chromhidrosis is a chronic disease that

improves in old age as apocrine gland activity diminishes. Disease-associated morbidity is a result of psychosocial dysfunction experienced by affected individuals.
FOXFORDYCE DISEASE
FOXFORDYCE DISEASE AT A GLANCE
An uncommon eruption characterized by
pruritic skin-colored to pink papules localizing
mainly to axillae and genitofemoral area.
More than 90% of patients are female, and
onset tends to be after puberty.
Likely a result of intraluminal plugging of
follicular infundibula, causing apocrine duct
obstruction, rupture, and inflammation.
The most consistent pathologic finding is
hyperkeratosis and plugging of the follicular
infundibula.
Topical clindamycin, surgery, or other
treatments may be of benefit.
TREATMENT
::
Apocrine chromhidrosis must be distinguished from

eccrine chromhidrosis (Box 85-2; see Chapter 84).
True eccrine chromhidrosis is very rare and occurs
when water-soluble pigments are excreted from
eccrine glands after the ingestion of certain drugs,
such as quinines. Pseudo-eccrine chromhidrosis refers
to the development of colored sweat when surface
compounds or molecules mix with sweat to produce
pigment. A classic example of this type is the formation of blue sweat in copper workers.33 Extrinsic
dyes, paints, fungi, and chromogenic bacteria (e.g.,
Corynebacterium species) are other causes of pseudochromhidrosis.27
14
Chapter 85
The luminal cells of the apocrine sweat glands have

an eosinophilic cytoplasm, a large nucleus, and may
contain lipofuscin, iron, lipid, or periodic acid-Schiffpositive and diastase-resistant granules.32 Under light
microscopy using hematoxylineosin staining, an
increased number of (yellowbrown) lipofuscin granules may be present in the apical portion of luminal
secretory cells of the apocrine glands. The number
of granules varies. Additionally, autofluorescence of
paraffin-embedded nonstained sections can be demonstrated using a 360-nm wavelength.31 The granules are
positive on periodic acid-Schiff stains. Schmorl stain
may also be weakly positive.33
pigmented sweat and the results were sustained for

4 months.34 Capsaicin is a topical cream that depletes
and prevents reaccumulation of substance P levels in
unmyelinated, slow-conducting type C sensory fibers.
Case reports have demonstrated efficacy of capsaicin
in the treatment of facial chromhidrosis.28
FoxFordyce disease is an uncommon eruption characterized by pruritic follicular papules that localize to anatomic regions that bear apocrine glands.35
George Henry Fox and John Addison Fordyce originally described it in 1902 in two patients with axillary
involvement.36 In 1925, Fischer hypothesized that Fox
Fordyce was a disease of the apocrine glands.37 Shelley and Levy introduced the term apocrine miliaria as a
synonym for this disease.38
EPIDEMIOLOGY
Approximately 90% of patients with FoxFordyce disease are female. Age of onset tends to be after puberty,
with most patients between 13 and 35 years of age.38
The incidence of this disorder is unknown. There is no
reported ethnic or racial predilection.

FOLLICULAR PLUGGING. The triggers for the
development of FoxFordyce disease are largely
951
14
unknown. Shelley and Levy hypothesized that the

clinical manifestations of this disease are a result of
intraluminal keratin plugging of the follicular infundibula, causing obstruction of the apocrine duct, rupture, and inflammation.38 Although blockage of the
apocrine duct seems important in disease development, experimentally plugging the duct has not clinically reproduced disease manifestations.39 One case
report detailed the development of FoxFordyce disease associated with obstruction of apoeccrine sweat
glands.40
Section 14 ::
GENETICS. Genetics likely plays a role in disease

development. This disease has been reported in two
patients with Turner syndrome41 and one patient with
a small deletion on chromosome 21.42 The disease has
also been reported in identical male twins,43 one set of
siblings,44 and in father and daughter.45
HORMONES. Hormonal influences on disease

have been debated. Disease onset after puberty and
improvement with pregnancy and estrogens lends
support to a hormonal influence.36,46 However, hormonal studies in one patient with FoxFordyce did not
reveal any abnormalities.47 Additionally, development
before puberty has also been described.48
CLINICAL FINDINGS
HISTORY. Patients describe the development of
pruritic papules at the time of puberty with gradual
worsening. Pruritus can be triggered by emotional
excitement or sweating.
CUTANEOUS LESIONS. FoxFordyce disease
manifests as numerous symmetrically distributed
skin-colored to slightly yellow or red follicular,
dome-shaped papules that are equidistant from one
another and characteristically intensely pruritic (Fig.
85-2). These papules may resemble lichen planus,
lichen nitidus, folliculitis, or syringomas (Box 85-3).
Excoriations may be prominent. Apocrine-rich areas
are affected, most commonly the axillae. Other areas
involved include the pubic area and perineum, mammary areola,7 presternal area, periumbilical area, and
upper inner thighs. Only sparse hair growth is seen in
the affected area. Apocrine sweat is not produced in
affected areas.

of FoxFordyce Disease

952
Lichen planus
Lichen nitidus
Folliculitis
Multiple syringomas
Figure 85-2 Numerous skin colored to browning papules

involving the axilla a woman with Fox-Fordyce disease (Reproduced with permission from Chae KM, Marschall MA,
Marschall SM. Axillary Fox-Fordyce disease treated with
liposuction-assisted curettage. Arch Dermatol. 138:452454, 2002.)
PATHOLOGY
Although the clinical features in patients with
FoxFordyce disease are quite uniform, pathologic
findings can vary considerably. The most distinct,
relatively consistent pathologic finding is perifollicular foamy macrophages (xanthomatous infiltrates).49
These cells expressed CD68 but lack expression of
carcinoembryonic antigen, gross cystic disease fluid
protein 15, and periodic acid-Schiff with diastase
digestion. Perifollicular mucin, fibrosis, and mast
cells in the infiltrate can also be observed. Dilation
and hyperkeratosis of the follicular infundibula can
also be seen and were previously considered as a
histological sign of FoxFordyce disease. Other findings include spongiosis and solitary dyskeratotic
cells throughout the infundibular epidermis, vacuolar changes at the dermalepidermal junction in conjunction with some lymphocytes, cornoid lamella in
the follicular infundibula with eosinophilic keratinocytes directly below the parakeratotic column,
and few lymphocytes in the dermis surrounding the
infundibula.35 It has been suggested that transverse
histologic sectioning of the specimen is the most
effective and efficient method to demonstrate the
characteristic pathologic features of FoxFordyce
disease.50
TREATMENT
SURGERY.
FoxFordyce disease is a chronic disease characterized

by intermittent flares. It rarely remits. Infection or folliculitis may develop secondary to trauma caused by
scratching.
HIDRADENITIS SUPPURATIVA/
ACNE INVERSA
HIDRADENITIS SUPPURATIVA
AT A GLANCE
Common disorder with a point prevalence of
1.0% and female preponderance.
A chronic and recurrent disorder, usually
developing after puberty and most
commonly involving the genitofemoral area
or axillae.
Primary pathogenic event is believed to
be follicular occlusion with subsequent
inflammation, secondary adnexal gland
involvement, fibrosis, and scarring.
Pathologic features may include follicular
hyperkeratosis, folliculitis, abscess
formation, sinus tract formation, fibrosis,
and granuloma formation.
Surgery may sometimes be curative;
clindamycin/rifampicin, hormonal
treatments, some immunosuppressive
medications and certain biologics (infliximab,
adalimumab) may benefit some patients.
Conflicting reports have provided a varying assessment of HS epidemiology. A current study recorded
an HS prevalence of 1% in a representative sample
of the French population (n = 10,000).62 In a previous study, a point prevalence of up to 4.1% based
on objective findings, and a 1-year prevalence of 1%
based on patient recall was found.63 It seems to be
more common in females, with reported femalemale
ratios ranging from 2:1 to 5:1. The reason for female
preponderance is unknown. HS rarely develops
before puberty or after menopause, although persistence into menopause is not uncommon.64 The average age of onset is 23 years.65 Although the disease
may develop in any apocrine gland-bearing skin,
genitofemoral lesions are more prevalent in women,
whereas axillary involvement does not demonstrate a
gender predilection.63,66,67
::
Electrocoagulation,58 surgical excision,59

and liposuction-assisted curettage60 have all demonstrated efficacy.
EPIDEMIOLOGY
14
Chapter 85
NONSURGICAL THERAPY. Treating FoxFordyce

disease is difficult. Avoidance of excessive sweating or
heat may minimize symptoms and flares. Clindamycin with propylene glycol has demonstrated efficacy
in small case series in both eliminating symptoms and
resolving papules.44,51 Topical tretinoin 0.1%, although
potentially irritating, has also demonstrated efficacy.52
Topical pimecrolimus ointment has been shown effective.53 Systemic isotretinoin led to almost complete
clearance of lesions, but lesions recurred within 3
months after isotretinoin discontinuation.42 Other
reported medical therapies include oral contraceptives,54 testosterone,55 topical or intralesional corticosteroids,56 ultraviolet light,57 and X-rays.47
Hidradenitis suppurativa/acne inversa (HS) is a

rather common, multifactorial, chronic and debilitating inflammatory skin appendage disorder with a
notoriously underestimated burden of disease. The
first International Hidradenitis Suppurativa Research
Symposium (2006, Dessau, Germany) formulated the
following definition: HS is a chronic, inflammatory,
recurrent, debilitating skin disease (of the hair follicle)
that usually presents after puberty with painful, deepseated, inflamed lesions in the apocrine gland-bearing
areas of the body, most commonly the axillary, inguinal, and anogenital regions.61
HS is a disease of the terminal hair follicle associated

with lymphohistiocytic inflammation, granulomatous
reactions, sinus tracts, and scarring.61,68 A consistent
finding in histological studies of HS is a follicular
occlusion due to hyperkeratosis, regardless of disease
duration, whereas an isotopic hyperplasia of follicular epithelium is evident.69 This leads to occlusion of
the apocrine gland with subsequent follicular rupture, perifollicular inflammation and possible secondary infection, giving rise to clinical findings.6971 The
concept of the follicular occlusion tetrad stems from
the concept that HS, acne vulgaris, pilonidal sinus,
and dissecting cellulitis share follicular occlusion as
an inciting event that eventually leads to disease
expression.
ADNEXAL STRUCTURES. Classically, HS was

thought to represent a primary disorder of apocrine
glands, and was also referred to as apocrinitis.72 The
anatomic location of disease in apocrine-bearing skin
has supported this concept. Shelley and Cahn provided additional support of this concept by hypothesizing that poral occlusion of the apocrine duct
reproduced the clinical and pathologic lesions using
their experimental model.73 More recent publications
have refuted the concept that this primary event in HS
953
14
Section 14 ::
954
is apocrine gland inflammation and postulate that apocrine glands become secondarily affected.
GENETIC FACTORS. A family history of HS may

be elicited in 26% of patients.74 Several studies have
not demonstrated HLA associations.75,76 Others studies
have suggested an autosomal dominant mode of inheritance with single gene transmission.7789 The group
of experts, who participated at the first International
Symposium has accepted that HS has to be a polygenic
disease with sporadic cases having defects in a number of critical genes involved in its pathogenesis and
familial cases with probably highly penetrant defect(s)
in one of these genes.61 A genome-wide scan in a fourgeneration Chinese family identified a first locus for
HS at chromosome 1p21.11q25.3 into a 76-Mb region
flanked by the markers D1S248 and D1S2711.90 This
locus could not be confirmed by others groups.68,91
In a study of six Han Chinese families with familial disease, frameshift or termination mutations in the
-secretase complex were identified at 19p13 suggesting that haplosufficiency might play a role in HS in
familial cases.92
ASSOCIATED DISEASES. The coexistence of HS and
Crohn disease, particularly with perianal involvement,
has been associated with a more fulminant course.8083
Perianal Crohn disease may be clinically indistinguishable from perianal HS. A pilot study carried on ten HS
patients detected no CARD15/NOD2 polymorphisms,
found to be associated with Crohn disease.93 This finding adds evidence to the fact that HS has to be distinguished from Crohn disease and its HS-like cutaneous
manifestations.94 Other reported associations include
pyoderma gangrenosum,84 nephrotic syndrome, and
amyloidosis,85 DowlingDegos disease,86 and arthropathy.8789 A current systematic literature review reported
that follicular occlusion disorders, inflammatory bowel
diseases, especially Crohn disease, spondyloarthropathy, other hyperergic diseases, genetic keratin disorders
associated with follicular occlusion and squamous cell
carcinoma are the most common HS comorbid diseases.
A first classification of these major comorbidities and
their possible genetic background revealed a list of chromosome loci and genes, which could be HS candidates.
Most of these diseases belong to the group of autoinflammatory disorders, where Th17 cell cytokines seem
to play a central role.95
HORMONES AND ANDROGENS. The tendency of HS to develop at puberty or postpuberty
suggests an androgen influence. Additionally, disease
flares have been reported postpartum,86,96 in association with the oral contraception pill, and in the premenstrual period (approximately 50% of patients).97
Antiandrogen therapy has also demonstrated therapeutic benefit in some studies.98101 However, no biochemical evidence of hyperandrogenism was found
in 66 women with HS.102 Additionally, unlike the sebaceous glands, the apocrine glands are not affected by
androgens. Thus, the influence of androgens on HS
is unclear.
OBESITY. Obesity is unlikely to be a causal factor

in HS but is often regarded as an exacerbating factor
by increasing shearing forces, occlusion, keratinocyte
hydration, and maceration.86,103,104 Obesity may also
exacerbate disease by creating a state of androgen
excess.77 Weight reduction is recommended for overweight patients and may help to control disease.66 A
current multivariate analysis showed a strong association with body mass index [odds ratio = 1.1 (1.11.2)].62
BACTERIAL INFECTION. The role of bacterial infection in HS is unclear. It is believed that the
pathogenic role is indirect, similar to the role of bacteria in acne. Bacterial involvement is thought by
some authors to occur secondarily. Routine cultures
are often negative, but numerous bacteria have been
recovered from lesions. Staphylococcus aureus and
coagulase-negative Staphylococci are most frequently
isolated.105,106 However, other bacteria, including
Streptococci, Gram-negative rods, and anaerobes, have
also been identified. These are likely to be colonizing
bacteria rather than causative bacteria,86,107 a concept
that could explain the increased expression of Tolllike receptor 2 as well as of -defensin 2 and psoriasin
in HS lesions.108,109
SMOKING. The use of tobacco products is more common in HS patients than in healthy controls.110,111 One
study determined that 70% of their 43 patient cohort
with perineal HS were smokers.112 It is postulated that
smoking affects polymorphonuclear cell chemotaxis.64
Multivariate analysis showed a strong association with
current smoking (odds ratio = 12.6, 95% CI 8.618.4).62
Smoking cessation may improve the clinical course of
the disease.
CLINICAL FINDINGS
HS is a chronic disease with a variable clinical
course.113115 The diagnosis of HS is clinical, and a
biopsy is rarely needed (Box 85-4). Clinical diagnostic
criteria are wide and include recurrent disease, scarring, and multifocal location.66
One of the most obvious hallmarks of the disease is
the restriction to the skin areas affected.113115 The disease is essentially limited to the intertriginous areas,
although aberrant lesions may occur. The sites affected
in order of decreasing frequency include: axillary,
inguinal, perineal and perianal, mammary and inframammary, buttocks, pubic region, chest, scalp, retroauricular, and eyelid.64 HS is not acne: closed comedones
are not seen, since the deep part of the follicle appears
to be involved and not its superficial compartments,
as seen with acne affecting convex skin surfaces. HS
inflammatory lesions are initially transient, but gradually become intransigent and associated with significant scarring.61,115
SEVERITY. Three stages of disease are recognized

and named after Hurley (IIII)116 In the primary stage,
abscesses develop in isolated locations. The secondary
14

of Hidradenitis Suppurativa
Figure 85-3 A ruptured draining abscess involving the

groin of a male patient with hidradenitis suppurativa.
LABORATORY TESTS. Patients with acute

lesions of HS may demonstrate an increase in the
erythrocyte sedimentation rate or C-reactive protein. If there is any concern over infection, then deep
cultures (not skin surface) from lesions should be
conducted and submitted for bacterial, tuberculosis,
and fungal cultures.117
Figure 85-5 Large scars and fistule pseudo-comedones

at the buttocks of a male patient with severe hidradenitis
suppurativa involving the anogenital area.
stage involves the development of sinus tracts with

scars bridging individual lesions. The tertiary stage
shows coalescing lesions with scarring and sinus tracts,
inflammation, and chronic discharge.
The disease onset is insidious and shows variable
severity. Otherwise healthy postpubertal individuals
initially may experience slight discomfort or pruritus.
After this, a tender papule or deep-seated nodule (0.5
to 2.0 cm) ensues (eFig. 85-2.1 in online edition). Pustules may also be visualized (eFig. 85-2.2 in online edition). This nodule may slowly resolve or may expand
and coalesce with surrounding nodules to form large
painful inflammatory abscesses. These abscesses are
rounded without central necrosis and may resolve
or rupture spontaneously, producing a purulent discharge (Fig. 85-3). Eventual healing may result in scarring with fibrosis (Fig. 85-4), dermal contractures and
rope-like elevation of the skin (Fig. 85-5), and doubleended comedones (eFig. 85-5.1 in online edition). Sinus
tracts may also develop (Fig. 85-6). Sinuses have been
reported to involve deep tissue, including muscle and

fascia, urethra, and bowel. The process then recurs in
an adjacent area or different apocrine-bearing site.66
::
From Jovanovic M et al: Hidradenitis suppurativa. In: emedicine,

edited by D Siegel et al (http://www.emedicine.com), 2006.
Figure 85-4 Area of scarring with associated fistules involving the axilla of a male patient with hidradenitis suppurativa.
Chapter 85
Abscesses (including from methicillin-resistant

Staphylococcus aureus)
Furuncles/carbuncles
Actinomycosis
Cat scratch disease
Donovanosis
Lymphadenitis
Infected Bartholin cyst
Crohn disease
Ulcerative colitis
Tuberculosis
Tularemia
Ruptured epidermal cyst
955
14
measured by the Dermatology Life Quality Index.123

The highest scores relate to disease-associated pain.
Quality of life measurements are lower than other dermatologic diseases that have been investigated using
this tool.124 Loss of workdays is a socioeconomic consequence. Women lose significantly more days of work
(mean, 2.9 days) than men (mean, 1.7 days).117 A significant positive correlation of fair degree between HS
severity and life quality index was detected.125
Section 14 ::
Figure 85-6 Sinus tract formation developing in the vulva

of a woman with hidradenitis suppurativa. (Used with permission from Dr. L. Edwards.)
SPECIAL TESTS. Ultrasonography of the follicles

and dermis may reveal abscess formation and abnormalities in the deep part of the follicle, but is rarely
indicated.117 Magnetic resonance imaging features of
the skin and subcutaneous tissue have been described.
Such features included marked thickening of the skin,
induration of the subcutaneous tissues, and multiple
subcutaneous abscesses.118
PATHOLOGY
The early lesions of HS demonstrate follicular hyperkeratosis. Epidermal psoriasiform hyperplasia and
subepidermal interfollicular inflammatory infiltrate
have been additionally observed in a current report.69
The deep part of the follicle appears to be involved.
Dermal features include perifolliculitis, active folliculitis or abscess, sinus tract formation, fibrosis, and
granuloma formation. There is evidence of an inverse
relationship between fibrosis and inflammation, supporting the concept that fibrosis corresponds to areas
of chronic involvement.119 Histologic feature examination of adnexal structures reveals inflammation of the
apocrine glands in only one-third of cases. Interestingly, involvement of eccrine glands (25%) has been
reported to be more common than apocrine glands
(12%).120,121 Poral occlusion or cyst formation may be
noted. The subcutis may demonstrate some fibrosis, fat
necrosis, or inflammation.70,71
A reduction in the percentage of NK cells over time
and a lower monocyte response to triggering by bacterial components was observed in patients with HS.122
Compared with normal skin, increased numbers of
TLR2-expressing infiltrating macrophages (CD68+)
and dermal dendrocytes (CD209+) was detected in HS
lesions.108 In addition, a striking CD8+ lymphocyte epitheliotropism was identified.69
COMPLICATIONS
956
QUALITY OF LIFE. Patients with HS experience a

significant degree of morbidity when quality of life is
SYSTEMIC COMPLICATIONS. Local infection

may develop and lead to septicemia. A case of lumbosacral epidural abscess has been reported.126 Anemia or
leukocytosis may be detected, but does not tend to be
significant clinically.127,128
LOCAL COMPLICATIONS. Scarring may limit
mobility. Anal, urethral, or rectal strictures may
develop from chronic genitofemoral inflammation.
Urethral fistulas have also been reported.129 Additionally, disfiguring persistent penile, scrotal, or vulvar
lymphedema due to blockade or destruction of local
lymph drainage routes subsequent to chronic and
recurrent inflammation may develop,130 giving rise to
significant functional impairment. Once this complication appears, no medical treatment is effective and
surgical reconstruction may be necessary.131 Squamous
cell carcinoma (SCC) may rarely develop in chronically inflamed and scarred areas in individuals with
long-standing disease.132,133 SCC has been reported in
3.2% of patients with perianal HS lasting 2030 years.
Malignant transformation affects mainly men with a
long-term history of genitoanal HS, whereas HPV has
been detected in these genitoanal tumoral lesions,
principally HPV-16.133 These carcinomas tend to be
more aggressive locally and are associated with a high
incidence of metastatic disease and mortality (up to
50%). One case of paraneoplastic neuropathy has been
described in association with SCC complicating severe
perineal HS.134 Clinicians should have a low threshold
for biopsying any nonhealing lesion localizing to an
area of chronic HS. One case-controlled Swedish study
found that the overall incidence of malignancy, including nonmelanoma skin cancer, is increased in patients
with HS.135
TREATMENT
The objective of patient management is prevention of
the development of primary lesions as well as resolution, amelioration, or regression of secondary disease
features such as scarring or sinus tract formation. The
literature reveals only few randomized controlled
studies, several case series, and a plethora of case
reports.
Assessing severity is a prerequisite to manage individual patients; the classification of Hurley113 is still
useful: stage I is manageable with systemic drugs,
stage II may benefit from medical treatment and from
limited excisions of locally recurring lesions, stage III
requires radical surgery (Box 85-5). On the other hand,
the modified Sartorius score is more sensitive and
Box 85-5 Proposal for a Global Algorithm of Treatment of Hidradenitis

Suppurativa/Acne Inversa
Treatment
Hurley stage I
Clindamycin 300 mg 23/day (alternatively minocycline 100 mg/day) and rifampicin 300 mg 2/
day p.o. for 412 week (to potentate: clindamycin 300 mg 23/day iv during the first 5 days of
treatment)
For females with signs of hyperandrogenism/hyperandrogenemia (additionally): hormonal antiandrogen with cyproterone acetate (up to 100 mg/day)
Hurley stage II
Step 1: As stage I
Step 2: Limited excisions of locally recurring lesions
Hurley stage III
Step 1: As stage I
Step 2: Infliximab (5 mg/kg) (alternatively adalimumab 40 mg) once or twice
(Step 3: Ultrasonography of the area to be excised)
Step 4: Wide excision of the involved area
Chapter 85
HS stage
14
::
MEDICAL TREATMENT. Treatment is often disappointing, which has a significant negative impact
on the patients quality of life. Although topical and
systemic antibiotics are effective, supportive evidence
for bacterial etiology is lacking. In an evidence-based
analysis of standard treatments and recent advances in
the therapy of HS, only treatment with topical clindamycin 1% solution,136 oral clindamycin and rifampicin,
or with the hormonal antiandrogen cyproterone acetate 100 mg/day achieved an evidence level 2 and a
recommendation grade B.137 In three retrospective
studies, 164 HS patients have received clindamycin
300 mg 2/day and rifampicin 300 mg 2/day for
1012 weeks.138140 Thirty-two experienced complete
remission of HS of between 1 and 4 years after only

one course of treatment, and further two patients
achieved remission after substituting clindamycin
with minocycline (100 mg/day) because of transient
diarrhea. Twenty-one patients were unable to complete the course of treatment because of side effects,
mostly diarrhea. Most responders have not subsequently relapsed. A randomized controlled study comparing topical clindamycin with systemic tetracycline
did not reveal a statistical difference.141
Intralesional corticosteroids may be of benefit for
patients with an isolated number of tender lesions.142
Practically, such treatment may not be appropriate for
individuals with extensive disease and is not appropriate for areas of chronic inflammation.
Oral isotretinoin is ineffective in the treatment of
HS. In a study with 358 HS patients interviewed and
useful in evaluating disease severity in clinical studies125

(Box 85-6).
BOX 85-6 Modified Sartorius Score for Evaluation of Disease Severity

Number
Factor
Total
_______
3=
_______ _______
_______
1=
_______ _______
_______
6=
_______ _______
3. Longest distance between two relevant lesions (per region)

<5 cm = 1; 510 cm = 3; >10 cm = 9
_______
_______
4. All lesions are separated by normal skin (per region)

yes = 0; no (Hurley III) = 9
_______
_______
1. Number of regions involved, namely axillary area, (right/left),

groin (right/left), gluteal area (right/left), other
2. Number of lesions (per region)
Number of nodules (painful or sensitive)
Number of fistules (all purulent lesions, spontaneously or
after pressure)
Total
_______ _______ _______
From Sartorius K, Emtestam L, Jemec GB, Lapins J: Objective scoring of hidradenitis suppurativa reflecting the role of tobacco smoking and
obesity. Br J Dermatol 161:831, 2009.
957
14
Section 14 ::
examined for the effect of previous treatment with oral

isotretinoin, only 16.1% declared an improvement.143
In a previous study with 68 patients, 23.5% were
cleared during therapy, whereas only 16.2% maintained improvement during a follow-up period of up
to 6 months.144 One case report described an individual with severe vulvar HS who, after treatment with
prednisolone and then long-term isotretinoin (more
than 1 year), remained disease free at 10 months posttreatment.145 The other systemic retinoids, acitretin and
etretinate, have also demonstrated limited efficacy in
disease management.146,147
Hormonal therapy does have some reported success.
In a double-blinded study, the antiandrogen, cyproterone acetate (50 mg), in conjunction with ethinyl estradiol (50 g), resulted in complete or partial clearance
at 18 months posttreatment in 50% of patients.99,100 In a
retrospective study with 64 female HS patients antiandrogen therapy was superior to oral antibiotic therapy
(55% vs. 26%). Female patients presenting with HS
should prompt investigations for underlying PCOS
and insulin resistance.148 The 5-reductase inhibitor,

finasteride (1 mg), may also have a weak limited effect
on disease management.101,149
Intramuscular human immunoglobulin (HIG; 1,320
1,980 mg sc/m) administered in five HS patients led to
>50% improvement in four patients.150
In a pilot study, 22 patients with Hurleys grade I
and II were treated with 90 mg/day zinc gluconate;
8 complete remissions (CR) and 14 partial remissions
were observed. When CR was obtained, the treatment
was progressively decreased; 4 out of 22 patients experienced side effects, mainly gastrointestinal.151
Emerging data on the efficacy of biologics as monotherapy152154 did not fulfill the expectations initially,
since etanercept and efalizumab showed a minor effectiveness in a few open and was ineffective in one controlled study (Box 85-7).155160 In contrast, infliximab, a
chimeric monoclonal antitumor necrosis factor antibody, has demonstrated efficacy in several case reports
with severe HS patients in both open and a controlled study, although the results seem transient and
Box 85-7 Treatment of Hidradenitis Suppurativa/Acne Inversa with

Biologic Agents (studies with 3 patients; patients with Crohns disease
were excluded)
Result
Agent reference
168171
No. of
patients
Adalimumab
12
Efalizumab160
Etanercept155158
34
Infliximab161167
40
Improvement
50%
Schema
40 mg/2nd
week-40
80 mg/week
1.0 mg/kg/
week
25 mg sc 2/
week
510 mg/kg
0, 2, 6 week
Duration
no yes
0
3 months
12 (100%)
Relapse after A Discontinution or Surgical

Treatment Required
5/6 (83%)
0 (0%)
310 months 19
15 (44%)
10/14 (71%)
2.572
months
19 (48%)
11 (53%)
21
Randomized, prospective, double-blind, placebo-controlled studies

Result
Agent reference
159
958
No. of
patients
Improvement
50%
Schema
Relapse After A Discontinution or Surgical

Treatment Required
Duration
no yes
No significant difference compared

with placebo
Yes
Significant
improvement
under infliximab
(p < 0.001) (27%
>50% improvement
under infliximab:
5% under placebo)
Etanercept
20 (crossover) 50 mg sc 2/
week
Infliximab168
33 (crossover) 5 mg/kg
0, 2, 6 week
2.5
14
RADIOTHERAPY. Several authors have reported

radiotherapy to be successful in the treatment of HS.
Given the often young patient population with HS,
long-term side effects must be considered.209,210
BIOMARKERS. Soluble interleukin-2 receptor (sIL2R) and tumor necrosis factor- serum levels were
found increased in HS and especially sIL-2R correlated
well with Hurleys grade.211,212 Both serologic markers
may be used as a valuable marker for disease staging
and evaluation of treatment in patients with HS.
::
KEY REFERENCES
12. Heckmann M, Teichmann B, Pause BM: Amelioration of
body odor after intracutaneous axillary injection of botulinum toxin A. Arch Dermatol 139:57, 2003
34. Matarasso SL: Treatment of facial chromhidrosis with
botulinum toxin type A. J Am Acad Dermatol 52:89, 2005
49. Bormate AB Jr, Leboit PE, McCalmont TH: Perifollicular
xanthomatosis as the hallmark of axillary Fox-Fordyce
disease: An evaluation of histopathologic features of 7
cases. Arch Dermatol 144:1020, 2008
61. Kurzen H et al: What causes hidradenitis suppurativa?
Exp Dermatol 17:455, 2008
62. Revuz JE et al: Prevalence and factors associated with
hidradenitis suppurativa: Results from two case-control
studies. J Am Acad Dermatol 5:596, 2008
95. Fimmel S, Zouboulis CC: Comorbidities of hidradenitis
suppurativa (acne inversa). Dermatoendocrinol 2:9, 2010
113. Alikhan A, Lynch PJ, Eisen DB: Hidradenitis suppurativa: A comprehensive review. J Am Acad Dermatol 60:539,
2009
114. Revuz J: Hidradenitis suppurativa. J Eur Acad Dermatol
Venereol 23:985, 2009
125. Sartorius K et al: Objective scoring of hidradenitis suppurativa reflecting the role of tobacco smoking and
obesity.Br J Dermatol 161:831, 2009
152. Haslund P, Lee RA, Jemec GB: Treatment of hidradenitis
suppurativa with tumour necrosis factor-alpha inhibitors. Acta Derm Venereol 89:595, 2009
186. Kagan RJ et al: Surgical treatment of hidradenitis suppurativa: A 10-year experience. Surgery 138:734, 2005
SURGERY. Surgical removal of all involved tissue,

beyond clinically involved margins, is an effective
treatment modality.186190 Postoperative recurrences
may occur. Some authors have advocated the use of
CO2 laser191,192 or the neodymium-doped yttrium aluminum garnet laser193,194 for surgical ablation of tissue.
The modality of closure has been a topic of debate.
Overall, healing by secondary intent is thought to
provide the best outcome. Primary closure, grafting,
or flaps have been extensively used, but may be associated with poorer results.195201 In one series of 106
patients, there was a 70% recurrence rate requiring
subsequent operation in the primary closure cohort
and no recurrence in the split-thickness graft and flap
groups.202 A more limited surgical approach also plays
a role in disease management. Deroofing or marsupializing of recurrent troublesome lesions or sinus tracts
may aid with local control.203 Lancing an inflammatory lesion is of limited benefit and should be discouraged.195,204,205 A study with 200 patients has shown that
enclosure of gentamicin after primary excision of HS

lesions can reduce the number of complications 1 week
postoperatively but it was ineffective on the long-term
recurrence rate.206 Ultrasonography can identify the
true extent of lesions in HS, which may be of use in the
preoperative planning.207,208
Chapter 85
are associated with significant toxicity as long-term

treatment.161168 Small case series with adalimumab
exhibited even more promising results but controlled
studies are still missing.169171
Case reports or small case series have also shown
therapeutic success with other systemic therapies,
including systemic corticosteroids, azathioprine, cyclosporine, dapsone, and methotrexate.86,172176
Local therapies have also been recently examined.
A single patient with aggressive perianal HS has
responded favorably to wide surgical excision in conjunction with perilesional granulocyte-macrophage
colony-stimulating factor injections.177 A small case
series demonstrated the efficacy of treatment of persistent painful nodules with cryotherapy. Healing
time in these patients was lengthy (1842 days).178
Finally, the first case of botulinum toxin A successfully
treating HS has been reported. In this case, injections
into the axillae resulted in a 10-month remission.179
Topical 15% resorcinol peel in 12 women with HS
Hurley stage I or II led to a significant decrease in
pain and a reduction in mean duration of the painful
abscesses.180
Photodynamic therapy (PDT) as treatment for HS
has recently been described in three small case series,
but is neither established nor has been standardized.181184 Moreover, pulsed dye laser-mediated photodynamic therapy was not successful in a pilot study
with four self-controlled cases.185
959
Disorders of the Hair and Nails
Chapter 86 :: Biology of Hair Follicles

:: George Cotsarelis & Vladimir Botchkarev
BIOLOGY OF HAIR FOLLICLES
AT A GLANCE
The primary purpose of hair in humans is to
influence social interactions.
Hair follicle development depends on
interactions between epithelial and
mesenchymal cells. The genes important for
this interaction are slowly being elucidated.
Genes important for hair follicle
development also play a role in hair follicle
cycling.
The hair follicle bulge possesses stem cells
important for the continual regeneration of
the follicle during cycling.
Hair pigmentation depends on melanocyte
stem cells and differentiated cells in
the follicle. Many genes important for
melanocyte behavior and hair pigmentation
have been defined.
EVOLUTION AND
FUNCTION OF HAIR
Hair is found only in mammals, where during the
course of evolution its primary roles were to serve as
insulation and protection from the elements. However, in contemporary humans, hairs main purpose
revolves around its profound role in social interactions. Loss of hair (alopecia) and excessive hair
growth in unwanted areas (hirsutism and hypertrichosis) can lead to significant psychological and
emotional distress that supports a multibillion-dollar
pharmaceutical and cosmetic effort to reverse these
conditions.
Fundamental understanding of hair growth and its
controls is increasing and result in new treatments for
alopecia.1,2 These advances resulted from the interest
of developmental biologists and other investigators in

the hair follicle as a model for a wide range of biologic
processes. As each hair follicle cyclically regenerates, it
recapitulates its initial development. Many growth factors and receptors important during hair follicle development also regulate hair follicle cycling.310 The hair
follicle possesses keratinocyte and melanocyte stem
cells (MSCs), nerves, and vasculature that are important in healthy and diseased skin.1113 To appreciate this
emerging information and to properly assess a patient
with hair loss or excess hair (see Chapter 88), an understanding of the anatomy and development of the hair
follicle is essential.
EMBRYOLOGY
Morphologically, hair follicle development has been
divided into eight consecutive stages, several of which
are illustrated in Fig. 86-1. Each stage is characterized
by unique expression patterns for growth factors and
their receptors, growth factor antagonists, adhesion
molecules, and intracellular signal transduction components.1416 Promising advances in understanding
the molecular mechanisms behind hair follicle development arose through the discovery that mammalian counterparts (homologs) of genes important for
normal Drosophila (fruit fly) development also affect
hair follicle development. Decapentaplegic [Dpp/bone
morphogenetic protein (BMP)], Engrailed (en), Homeobox
(hox), hedgehog/patched (hh/ptc), notch, wingless/armadillo
(wg/wnt/catenin) genes are all critical for hair follicle and
vertebrate development in general.1719 These genes were
all first discovered in Drosophila, thus, most of the
names assigned to them describe the peculiar appearance (phenotype) of the flies carrying mutations in
these genes.20
Follicle formation begins on the head, and then
moves downward to the remainder of the body
in utero. The first hairs formed are lanugo hairs,
which are nonpigmented, soft, and fine. Lanugo
hair is typically shed between the 32nd and 36th
weeks, although approximately one-third of newborns still retain their lanugo hair for up to several
weeks after birth.
Patterning genes, called homeobox genes, which are
precisely organized in the genome so that they are
15
Molecular regulation of hair follicle morphogenesis
Stage 1
Stage 2
Hair placode (hair germ)
Hair peg
Wnt10b, -catenin, Lef-1

EDA, EDAR
Lhx2, BMP-2, BMPR-IA
TGFR-II, Msx-2
P-cadherin
Loss of E-cadherin
SHH, Ptc1
PDGF-
neurotrophins
TGFbR-II
N-CAM
Differentiating
inner root
sheath
TCF3
BMPR-IA
Bulge
CK15, CK19
BMP6, Gremlin
CK1, CK10
Loricrin
Involucrin
Trichohyalin
Transglutaminases
EGFR
Gata3, Cutl1
Foxn1
Notch, Jagged 1/2
Differentiating
Hair shaft
Hair keratins
Lef-1
Hoxc13
Foxn1, Msx-2
Notch
Jagged 1/2
Dermal papilla
Arrector pili
muscle
Inner root sheath
Hairshaft
Outer root sheath
Melanogenic area
BMP-2, BMP-4
Noggin, BMPR-IA
KGF, HGF, SCF
Versican
Alkaline phosphatase
Biology of Hair Follicles
Wnt-5, Lef-1
Ptc1, Gli1
PFGF-Ra
Noggin
Versican
p75 kd neurotrophin
receptor
CK5, CK14
Sebaceous gland
::
Mesenchymal
condensation
Differentiating outer
root sheath
Stage 8
Chapter 86
Mesenchymal condensation
BMP-4, Noggin, Activin
Versican
p75 kd neurotrophi
receptor
Stage 5
Figure 86-1 Molecular regulation of hair follicle morphogenesis. The scheme shows the expression of different growth
factors, their receptors, adhesion, and cell matrix molecules, transcriptional regulators in hair follicle epithelium, and mesenchyme during distinct stages of hair follicle development. BMP = bone morphogenetic protein; BMPR-IA = bone morphogenetic protein receptor, type IA; CK = keratin 5; Cutl1 = cut-like 1; E-cadherin = epithelial cadherin; EDA = ectodysplasin; EDAR = ectodysplasin receptor; EGFR = epidermal growth factor receptor; Foxn1 = forkhead box N1; Gata3 = GATA
binding protein 3; Gli1 = glioma-associated oncogene homolog 1; HGF = hepatocyte growth factor; Hoxc13 = homeobox
C13; KGF = keratinocyte growth factor; Lef-1 = lymphoid enhancer factor 1; Lhx2 = LIM homeobox 2; N-CAM = neural cell
adhesion molecule; P-cadherin = placental cadherin; PDGF- = platelet-derived growth factor polypeptide; PFGF-R =
platelet-derived growth factor receptor ; Ptc1 = patched1; SCF = stem cell factor; Shh = sonic hedgehog; TCF3 = transcription factor 3; TGF-R-II = transforming growth factor- receptor 2.
expressed in strict temporal sequences and spatial patterns during development, likely are responsible for
the nonrandom and symmetric distribution of hair
follicles over the body.21,22 In adult mice, homeobox
gene expression reappears in hair follicles and serves
to maintain normal hair shaft production.6 Engrailed,
a type of homeobox gene, is responsible for dorsal
ventral patterning, and mice lacking engrailed develop
hair follicles on their footpads.23
Although hair follicles and hairs all share the same
basic anatomy, their growth, size, shape, pigmentation, and other characteristics differ widely, based on
body location and variation among individuals. Many
of these characteristics are established during development but are then profoundly altered by hormonal
influences later in life. We are beginning to understand
the genes controlling hair length, curl and distribution because of elegant genetic studies on dogs. These
studies reveal that fibroblast growth factor-5 (FGF-5),
Keratin 71, and R-spondin 2 influence length, curl and
distribution respectively.24 In humans, thicker hair
found in Asians is associated with increased activity of
ectodysplasin receptor (EDAR),25 the receptor of ectodysplasin (EDA) (see below).
The size of many types of follicles changes drastically several times throughout life. For example,
lanugo hair follicles, which produce hair shafts several centimeters long, convert to vellus follicles that
produce small hairs that protrude only slightly from
the skin surface. Later in life, vellus follicles on the
male beard enlarge into terminal follicles that generate thick, long hairs. On the scalp of genetically
961
15
predisposed individuals, terminal follicles miniaturize and form effete, microscopic hairs.
EPITHELIAL PLACODE OR
PRIMARY HAIR GERM
Section 15
:: Disorders of the Hair and Nails
962
In the human fetus, hair follicles develop from small

collections of cells, called epithelial placodes, which correspond to stage 1 of hair follicle development and first
appear around 10 weeks gestation (see Fig. 86-1). The
epithelial placode then expands to form the primary
hair germ whose progeny eventually generate the
entire epithelial portion of the hair follicle.26
The cells of the hair placode and germ express placental cadherin and become oriented vertically, losing
their desmosomes, hemidesmosomes, and epithelial cadherin, which decreases their adhesion to their
neighbors.2729 Dermal cells beneath the hair placode
form a cluster (or condensate), which later develops
into the dermal papilla.30
Hair follicle formation depends on a series of mesenchymal/epithelial interactions.30 An initial signal arises
in the mesenchyme (primitive dermis) and instructs
the overlying epithelium to form an appendage, indicated by the appearance of regularly spaced placodes
(see Fig. 86-1). The second signal arises from the epithelial placode and causes an aggregation of cells in
the underlying mesenchyme that will eventually form
the dermal papilla. Finally, a signal from this primitive
dermal papilla initiates proliferation and differentiation of placode cells, ultimately leading to formation of
a mature follicle. These reciprocal signals pass through
the intervening basement membrane, which undergoes alterations in its morphology and chemical composition that may alter its ability to sequester growth
factors and binding proteins, thus possibly modulating the epithelial/mesenchymal interactions.
Many of these regulatory molecules important for
the formation of the hair follicle have been defined, but
how they interact to generate hair follicles in an otherwise homogeneous epithelium is yet to be determined.
In one model, the spacing and size of placodes are
regulated by a dermal signal, which varies in character in different body regions. The dermal signal occurs
uniformly within each body region and triggers the
activation of promoters and repressors of follicle fate
in the epithelium that then compete with one another,
resulting in the establishment of a regular array of
follicles.15,31 Differences in the levels of promoter and
repressor activation could account for regional differences in the size and spacing of follicles. Consistent with this model, several positive and negative
regulators of hair follicle fate are initially expressed
uniformly in the epidermis and subsequently become
localized to placodes.
One of the earliest molecular pathways that positively
regulates hair follicle initiation is the WNT/-catenin
pathway. -Catenin is the downstream mediator of
WNT signaling. WNT proteins bind to receptors on the
cell membrane and, through a series of signals, inhibit
the degradation of cytoplasmic -catenin. -Catenin
then translocates to the nucleus, forming a complex
with the LEF/TCF family of transcription factors and

resulting in expression of downstream genes.15,31 Activation of this -catenin pathway appears necessary for
establishing epithelial competencea state in which
the epithelial tissue has the potential to form a hair
follicle. Normally, the -catenin pathway is inactive
in the adult epidermis, but by artificially activating
-catenin in epidermal basal cells of adult transgenic
mice, hair follicles develop de novo.32 This remarkable finding could eventually have therapeutic implications, although constant activation of this pathway
in the hair follicle also results in pilomatricomas and
trichofolliculomas, two types of relatively rare cutaneous tumors.32,33
EDA, a molecule related to tumor necrosis factor,
and its receptor (EDAR) also are part of another major
pathway that stimulates early follicle development in
both mice and humans.34 EDA gene mutations cause
X-linked anhidrotic ectodermal dysplasia, a syndrome associated with decreased numbers of hair follicles, and defects of the teeth and sweat glands (see
Chapter 142).35 The EDAR gene is mutated in autosomal recessive and dominant hypohidrotic ectodermal dysplasias, causing identical phenotypes to those
resulting from EDA mutations. The mouse Edar gene is
expressed ubiquitously in the epithelium before placode formation, and then becomes restricted to placodes, whereas the Eda gene is ubiquitously expressed
even after placode formation.36 Mice with mutations in
these genes have the same phenotype as humans with
similar mutations, and mice overexpressing Eda in the
epidermis show formation of the fused follicles due
to the loss of proper spacing between neighboring hair
placodes.37,38 Humans with more active EDAR genes
have thicker hair.25
In contrast to EDA and EDAR, which promote hair
follicle development, members of the BMP family
inhibit follicle formation. Bmp2 is expressed diffusely
in the ectoderm, but then localizes to the early placode
and underlying mesenchyme, while Bmp4 is expressed
in the early dermal condensate.39,40 BMP signaling
inhibits placode formation, whereas neutralization of
BMP activity by its antagonist Noggin promotes placode fate, at least in part via positive regulation of lymphoid enhancer factor 1 (Lef-1) expression.39,4143 Mice
lacking Noggin have fewer hair follicles than normal
and retarded follicular development.43 The Notch
pathway also appears to play a role in determining
the follicular pattern. The Notch ligand -1 is normally expressed in the mesenchyme underlying the
placode4446 and, when misexpressed in a small part of
the epithelium, promotes and accelerates placode formation while suppressing placode formation in surrounding cells.44,47
Another secreted protein present in the follicular
placode that plays a major role in epithelial-mesenchymal signaling is sonic hedgehog (Shh).48,49 Skin
from mice lacking Shh have extremely effete hair
follicles with poorly developed dermal papillae.5052
Patched1 (Ptc1), the receptor for Shh, is expressed
in the germ cells and the underlying dermal papilla,
suggesting that Shh may have both autocrine and
paracrine inductive properties necessary for hair
germ and dermal papilla formation.53 Patched is

the gene deficient in basal cell nevus syndrome (see
Chapter 116).19
THE BULBOUS PEG OR HAIR BUD
HAIR TYPES
After formation of the lanugo hair that is characteristic of the prenatal period, there are two major types
of hair classified according to size (Table 86-1). Terminal hairs are typically greater than 60 m in diameter,
possess a central medulla, and can grow to well over
100 cm in length. The duration of the growing stage
(anagen) determines the length of the hair. The hair
bulb of terminal hairs in anagen is located in the subcutaneous fat. In contrast, vellus hairs are typically less
than 30 m in diameter, do not possess a medulla, and
are less than 2 cm in length. The hair bulb of vellus
hairs in anagen is located in the reticular dermis. Terminal hairs are found on the scalp, eyebrows, and eyelashes at birth. Vellus hairs are found elsewhere, and,
at puberty, vellus hair follicles in the genitalia, axillae,
trunk, and beard area in men transform into terminal
hair follicles under the influence of sex hormones. Terminal hair follicles in the scalp convert to vellus-like or
miniaturized hair follicles during androgenetic alopecia (see Chapter 88).1,69
The curvature of the hair varies greatly among different individuals and races, and ranges from straight
to tightly curled. Curved hair shafts arise from curved
hair follicles. The shape of the inner root sheath is
thought to determine the shape of the hair. Curled
The central lumen where the hair shaft will emerge is

formed by necrosis and cornification of epithelial cells
in the infundibulum. As the hair shaft is produced,
several signaling pathways are involved in the control
of its differentiation. Wnt/-catenin/Lef-1 signaling
plays an important role in hair shaft formation, and
ectopic expression of Wnt3 in the hair follicle outer root
sheath causes hair shaft fragility.57,58 Hair shaft keratin
genes contain binding sites for Lef-1,59 which translocates to the nucleus after activation of the WNT/catenin pathway. WNT signaling probably regulates
expression of hair shaft keratin genes, because nearly
::
MATURE HAIR FOLLICLE
ANATOMY
15
Chapter 86
In the next stage of development, the bulbous peg or

hair bud (or stage 2 of hair follicle development, see
Fig. 86-1) is formed by elongation of the hair germ
into a cord of epithelial cells. The mesenchymal cells
at the sides of the peg will develop into the fibrous
sheath of the hair follicle, and those at the tip of the
peg will develop into the dermal papilla. The deepest portion of the follicle peg forms a bulbous structure that surrounds the underlying mesenchymal
cells destined to become the dermal papilla. These
epithelial cells will become the matrix of the hair follicle, which gives rise to the hair shaft and inner root
sheath. The outer root sheath forms two bulges on
the side of the hair follicle forming an obtuse angle
with the surface of the skin. The superficial bulge will
develop into the sebaceous gland. The deeper bulge
serves as the future site of epithelial stem cells that
generate the new lower follicle during hair follicle
cycling. The arrector pili muscle usually attaches in
the bulge area, and contraction of the muscle causes
a more vertical orientation of the hair shaft leading
to goose bumps. In the axillae, anogenital region,
areolae, periumbilical region, eyelids (the specialized
glands of Moll), and external ear canals, a third bulge
develops superficial to the sebaceous gland bud and
gives rise to the apocrine gland.
As the hair follicle bulb appears during the bulbous
peg stage, at least eight different cell layers constituting all of the components of the mature hair follicle
are formed. Understanding which genes determine
specific cell lineages within the follicle is an important
question. GATA-3 is important in inner root sheath differentiation.54 Notch1, a membrane protein involved
in determining cell fate through cellcell interactions
and intracellular signal transduction, and its ligands
Serrate1 and Serrate2 are expressed in matrix cells destined to form the inner root sheath and hair shaft.46,55
Notch1 appears to control the phenotype of keratinocytes as they leave the bulb matrix and differentiate
into specific cell types.56
all of these genes contain Lef-1 binding sites in their

promoter regions.60
BMP signaling is also essential for proper differentiation of the inner root sheath and hair shaft, because
conditional deletion of BMP receptor type 1A in keratinocytes results in profound alterations of the inner
root sheath and hair shaft formation.6163 Several other
putative transcription factors control hair shaft differentiation, including HOXC13,6 a homeobox protein,
and the WHN gene,6466 which is mutated in nude mice
and rarely in humans with hair, nail, and immune
defects.67,68
This process of hair follicle formation is repeated in
several waves, with the formation of secondary follicles alongside the initial follicle. The follicles are primarily clustered into groups of three and possess an
oblique orientation with a similar angle to their neighbors.
TABLE 86-1
Hair Types and Characteristics

Type of Hair
Anagen
Duration
Size (Diameter,
Length)
Lanugo
13 months
40 m, 12 cm
Vellus
12 weeks
<30 m, <2 cm
Terminal
>1 year
>60 m, 10>100 cm
Miniaturized
<1 week
<30 m, <2 cm
963
15
hair in cross section is more elliptical or flattened in

comparison with straight hair, which is more round.
Several genes influencing hair shape have been identified. Mutations in the epidermal growth factor receptor (EGFR) pathway and in insulin-like growth factor
binding protein 5 result in curly hair in mice.70,71
MICROSCOPIC ANATOMY
Section 15
The upper follicle consists of the infundibulum and the

isthmus, and the lower follicle consists of the suprabulbar and the bulbar areas (Fig. 86-2).14,66 The upper
follicle is permanent, but the lower follicle regenerates
with each hair follicle cycle. The major compartments
of the hair from outermost to innermost include the
connective tissue sheath, the outer root sheath, the
inner root sheath, the cuticle, the hair shaft cortex, and
the hair shaft medulla, each characterized by distinct
expression of the hair follicle-specific keratins (Table
86-2).72,73
OUTER ROOT SHEATH. The outer root sheath is

continuous with the epidermis (see Fig. 86-2) at the
infundibulum and continues down to the bulb. The
cells of the outer root sheath change considerably
throughout the follicle. The outer root sheath in the
infundibulum resembles epidermis and forms a granular layer during its keratinization. In the isthmus,
the outer root sheath cells keratinize in a trichilemmal
fashion, lacking a granular layer. Trichilemmal keratinization occurs where the inner root sheath begins
to slough. Desmoglein expression markedly changes
here as well and trichilemmal or pilar cysts retain these
characteristics.74 Keratinocytes in the outer root sheath
form the bulge at the base of the isthmus (see Section
Hair Follicle Stem Cells). These cells generally possess a higher nuclear to cytoplasmic ratio compared
with other areas of the follicle. Moving downward, the
outer root sheath cells become much larger and contain abundant glycogen in the suprabulbar follicle. In
the bulb, the outer root sheath consists of only a single,
Hair cycle and anatomy
Catagen
Telogen
Outer root
sheath
Anagen stage
Anagen
Infundibulum
Epidermis
Hair
Sebaceous
gland
Bulge
Exogen
Bulge
Sec Grm
Matrix
Dermal papilla
Bulge
Bulge
Suprabulbular
area
Bulb
Hair medulla
Hair cortex
Hair cuticle
Companion layer
Huxleys layer
Henles layer
Inner root sheath
Cuticle
Outer root sheath
Connective tissue sheath
964
Figure 86-2 Hair cycle and anatomy. The hair follicle cycle consists of stages of rest (telogen), hair growth (anagen), follicle regression (catagen), and hair shedding (exogen). The entire lower epithelial structure is formed during anagen and
regresses during catagen. The transient portion of the follicle consists of matrix cells in the bulb that generate seven different cell lineages, three in the hair shaft and four in the inner root sheath. B = bulge; E = epidermis; DP = dermal papilla;
H = hair shaft; M = matrix; ORS = outer root sheath; S = sebaceous gland; Sec Grm = secondary germ.
15
TABLE 86-2
Expression of Keratin Genes in Distinct Hair Follicle (HF) Compartments

HF Compartments
Type I Keratins, New

Type II Keratins, New
Nomenclature (Old Nomenclature) Nomenclature (Old Nomenclature)
Outer root sheath
K14 (K14), K15 (K15), K16 (K16), K17 (K17),

K19 (K19)
K5 (K5)
Inner root sheath, companion layer
K16 (K16), K17 (K17)
K75 (K6hf ), K6 (K6)
Hair matrix/precortex
K35 (Ha5)
K85 (Hb5)
K71 (K6irs1)
K25 (K25irs1), K27 (K25irs3), K28 (K25irs4)
K71 (K6irs1), K74 (K6irs4)
Inner root sheath, cuticle
K25 (K25irs1), K26 (K25irs2), K27 (K25irs3),

K28 (K25irs4)
Hair, cuticle
K32 (Ha2), K35 (Ha5)
K82 (Hb2), K85 (Hb5)
Hair, mid-/upper cortex
K31 (Ha1), K33a (Ha3-I), K33b (Ha3-II),

K34 (Ha4), K35 (Ha5), K36 (Ha6), K37 (Ha7),
K38 (Ha8)
K81 (Hb1),a K83 (Hb3), K85 (Hb5), K86 (Hb6)a
Hair, medulla
K16 (K16), K17 (K17), K25 (K25irs1), K27

(K25irs3), K28 (K25irs4), K33 (Ha3), K34 (Ha4),
K37 (Ha7)
K5 (K5), K6 (K6), K75 (K6hf ), K81 (Hb1)a
::
Inner root sheath, Huxleys layer
Autosomal dominant mutations of K81 and K86 lead to monilethrix (alopecia due to increased hair fragility).
Data from Langbein L et al: K25 (k25irs1), K26 (k25irs2), k27 (k25irs3), and k28 (k25irs4) represent the type I inner root sheath keratins of the
human hair follicle. J Invest Dermatol 126:2377, 2006; and Langbein L, Schweizer J: Keratins of the human hair follicle. Int Rev Cytol 243:1, 2005.
INNER ROOT SHEATH. The inner root sheath

extends from the base of the bulb to the isthmus and
contains four parts from outermost to innermost: companion layer, Henle layer, Huxley layer, and the inner
root sheath cuticle. The companion layer (see Fig.
86-2) has been referred to as the innermost layer of the
outer root sheath, but recent evidence indicates that it
is more like inner root sheath than outer root sheath.75
The companion layer attaches to Henle layer and
moves upward with the rest of the inner root sheath;
thus, it provides a slippage plane between the outer
root sheath, which is stationary, and the inner root
sheath.76 The companion layer is prominent in some
follicles (e.g., the beard) compared with others. The
cells of the companion layer are flat compared to the
cuboidal outer root sheath cells and express a type II
cytokeratin, K6hf.75 Henle layer is one-cell-layer thick
and is the first to develop keratohyalin granules and
the first to keratinize. Huxley layer is two to four cell
layers thick and keratinizes above Henle layer at the
region known as Adamson fringe. Some cells within
Huxleys layer protrude through Henle layer and
attach directly to the companion layer. These cells are
called Fluegelzellen or wing cells.77 The cells of the inner
root sheath cuticle partially overlap, forming a shingled roof appearance, and they intertwine precisely
with the cuticle cells of the hair shaft. This association
between the two cuticles anchors the hair shaft tightly
to the follicle. The inner root sheath, composed of
hard keratins and associated proteins (see Table 86-2),
flattened cell layer that can be traced to the base of the

follicle.
Chapter 86
Inner root sheath, Henles layer
is thought to dictate hair shape by funneling the hair

shaft cells as they are produced. The transcription factor, GATA-3, is critical for inner root sheath differentiation and lineage. Mice lacking this gene fail to form
an inner root sheath.54
HAIR SHAFT. The hair shaft (and inner root sheath)

arises from rapidly proliferating matrix keratinocytes
in the bulb, which have one of the highest rates of proliferation in the body. The cells of the future hair shaft
are positioned at the apex of the dermal papilla and
form the medulla, cortex, and hair shaft cuticle (see
Fig. 86-2). Immediately above the matrix cells, hair
shaft cells begin to express specific hair shaft keratins
in the prekeratogenous zone. The differentiation of
hair shaft cells in this zone is dependent on the Lef-1
transcription factor. Lef-1 binding sites are present in
most hair keratin genes. BMP receptor type 1a is also
critical for matrix cell differentiation into the hair shaft,
because loss of this receptor prevents hair shaft differentiation.6163
The hair shaft cuticle covers the hair, and its integrity
and properties greatly impact the appearance of the
hair. Once the hair exits the scalp, the cuticle endures
weathering, and it is often completely lost at the distal
ends of long hairs. Inside the cuticle, the cortex comprises the bulk of the shaft and contains melanin. The
cortex is arranged in large cable-like structures called
macrofibrils. These, in turn, possess microfibrils that
are composed of intermediate filaments. The medulla
sits at the center of larger hairs, and specific keratins
expressed in this layer of cells (see Table 86-2) are
under the control of androgens.78
965
15
Section 15
966
DERMAL PAPILLA. The dermal papilla (see Fig.

86-1) is a core of mesenchymally derived tissue enveloped by the matrix epithelium. It is comprised of
fibroblasts, collagen bundles, a mucopolysacchariderich stroma, nerve fibers, and a single capillary loop.
It is continuous with the perifollicular sheath (dermal
sheath) of connective tissue that envelops the lower
follicle.
Tissue recombination experiments have shown that
the dermal papilla has powerful inductive properties,
including the ability to induce hair follicle formation
when transplanted below nonhair-bearing footpad
epidermis.76,79 This shows that the tissue patterning established during the fetal period can be altered
under appropriate conditions. In human follicle, the
volume of the dermal papilla correlates with the number of matrix cells and the resulting size of the hair
shaft.80 In mice, sizes of the hair bulb and hair diameter strongly depend of the proliferative activity of the
matrix keratinocytes.81
Many soluble growth factors that appear to act in a
paracrine manner on the overlying epithelial matrix
cells originate from the dermal papilla. Specifically,
keratinocyte growth factor (KGF) is produced by the
anagen dermal papilla, and its receptor, FGF receptor
2 (FGFR2), is found predominantly in the matrix keratinocytes. Injections of KGF into nude mice produce
striking hair growth at the site of injection,82 suggesting that KGF is perhaps necessary for hair growth and
cycling. However, surprisingly, KGF knockout mice
develop morphologically normal hair follicles that
produce rough or greasy hair; thus, KGFs effects
on hair follicle morphogenesis and cycling appear dispensable or replaceable by other growth factors with
redundant functions.83
HAIR FOLLICLE INNERVATION. Myelinated sensory nerve fibers run parallel to hair follicles, surrounding them and forming a network.84
Smaller nerve fibers form an outer circular layer,
which is concentrated around the bulge of terminal
follicles and the bulb of vellus follicles. Several different types of nerve endings, including free nerve
endings, lanceolate nerve endings, Merkel cells, and
pilo-Ruffini corpuscles are found around hair follicles.85 Each nerve ending detects different forces and
stimuli. Free nerve endings transmit pain, lanceolate
nerve endings detect acceleration, Merkel cells sense
pressure, and pilo-Ruffini structures detect tension.
Perifollicular nerves contain neuromediators and
neuropeptides, such as substance P or calcitonin
gene-related peptide, that influence follicular keratinocytes and alter hair follicle cycling.8690 Conversely,
hair follicle keratinocytes produce neurotrophic factors that influence perifollicular nerves and stimulate
their remodeling in hair cycle-dependent manner.90,91
Merkel cells that are considered neuroendocrine
cells also produce neurotrophic factors, cytokines, or
other regulatory molecules. Because Merkel cells are
concentrated in the bulge area, some have postulated
that these secreted factors may influence the cycling
of the hair follicle.92
PERIFOLLICULAR SHEATH. The perifollicular

sheath envelops the epithelial components of the hair
follicle and consists of an inner basement membrane
called the hyaline or vitreous (glassy) membrane and an
outer connective tissue sheath. The basement membrane of the follicle is continuous with the interfollicular basement membrane. It is most prominent around
the outer root sheath at the bulb in anagen hairs. During catagen, the basement membrane thickens and
then disintegrates.
Surrounding the basement membrane is a connective tissue sheath comprised primarily of type III
collagen. Around the upper follicle, there is a thin connective tissue sheath continuous with the surrounding
papillary dermis and arranged longitudinally. Around
the lower follicle, the connective tissue sheath is more
prominent, with an inner layer of collagen fibers that
encircle the follicle surrounded by a layer of longitudinally arranged collagen fibers.66
When transplanted under the skin, this perifollicular
connective tissue has the remarkable ability to form a
new dermal papilla and induce new hair follicle formation.93 Even when the connective tissue sheath is
transplanted to another individual, these follicles survive without evidence of immunologic rejection.
HAIR FOLLICLE CYCLE

Each individual hair follicle perpetually traverses
through three stages: (1) growth (anagen), (2) involution (catagen), and (3) rest (telogen).12 The length
of anagen determines the final length of the hair and
thus varies according to body site; catagen and telogen duration vary to a lesser extent depending on site.
Scalp hair has the longest anagen of 2 years to more
than 8 years. Anagen duration in young males at other
sites is shorter: legs, 57 months; arms, 1.53.0 months;
eyelashes, 16 months; and fingers, 13 months. In contrast to most mammals, including mice and newborn
humans, in the adult human the hairs of the scalp grow
asynchronously. Approximately 90%93% of scalp
follicles are in anagen and the rest primarily in telogen.94 Applying these figures to the 100,000150,000
hairs on the scalp indicates that approximately 10,000
scalp hairs are in telogen at any given time. However,
because we lose only 50100 hairs per day, this indicates that telogen is a heterogenous state. The follicles
that are shedding their hair shaft are thus in exogen,
which comprises approximately 1% of the telogen hair
follicles (see Fig. 86-2 and below). Hair on the scalp
grows at a rate of 0.370.44 mm/day or approximately
1 cm/month.
HAIR FOLLICLE STEM CELLS

Because the lower portion of the follicle cyclically
regenerates, hair follicle stem cells were thought to
govern this growth. Historically, hair follicle stem cells
were assumed to reside exclusively in the secondary
germ (see Fig. 86-2), which is located at the base of the
telogen hair follicle. It was thought that the secondary
Relationship between epidermal and hair follicle stem cells during homeostasis and after wounding
A Homeostasis
EPU
B Re-epithelialization
Epidermis
EPU
15
C Days after wounding

Wound
8
Epidermis
EPU EPU
Epidermis
20
Chapter 86
Bulge:
Epithelial
Stem cells
50
::
Bulge-derived
Non bulge-derived
Figure 86-3 Relationship between epidermal and hair follicle stem cells during homeostasis and after wounding.
A. During normal conditions, epidermal renewal is dependent on cell proliferation within epidermal proliferative units
(EPUs), which are clonal populations of cells roughly arranged in hexagonally shaped columns that produce a single
outer squame. Epithelial stem cells in the hair follicle bulge do not contribute to epidermal renewal. B. After full-thickness
wounding, bulge cells contribute cells to the epidermis for immediate wound closure (blue upward arrow). Bulge cells also
are required for hair follicle cycling (blue downward arrow) C. Over time, bulge-derived cells diminish, whereas nonbulgederived cells (from the interfollicular epidermis and infundibulum) appear to predominate in the reepithelialized wound.
germ moved downward to the hair bulb during anagen and provided new cells for production of the hair.
At the end of anagen, the secondary germ was thought
to move upward with the dermal papilla during catagen to come to rest at the base of the telogen follicle.
This scenario of stem cell movement during follicle
cycling was brought into question when a population
of long-lived presumptive stem cells was identified
in an area of the follicle surrounding the telogen club
hair.95 Subsequently, it was shown that the secondary
germ is a transient structure that forms at the end of
catagen from cells in the lower bulge.96 The concept
that hair follicle stem cells are permanently located in
the bulge has now been confirmed using lineage analysis, which showed that the bulge cells give rise to all
epithelial layers of the hair follicle.11,97,98 In line with
this, ablation of bulge cells results in destruction of the
follicle.96 These findings support the notion that loss of
hair follicle stem cells in the bulge leads to permanent
or cicatricial types of alopecia (see Chapter 88).
Progress has been made in defining subsets of cells
within the hair follicle that serve as different stem
and progenitor populations. Markers that have been
shown through genetic lineage analysis to contribute
to the perpetual cycling of the hair follicle, include
cytokeratin 15 and Lgr5.96,99 Lgr5, although sometimes
touted as an exclusive marker of secondary germ cells,
Bulge:
Epithelial
Stem cells
also marks bulge cells. Lgr6, a gene related to Lgr5,

is expressed in an area above the bulge in the upper
isthmus. The cells marked by Lgr6 migrate to the epidermis during homeostasis and after wounding.100 In
addition to these markers, several others demonstrate
the heterogeneity of the hair follicle epithelium.101
Are bulge cells the ultimate stem cells within
the skin epithelium? For example, do they generate
epidermis and sebaceous glands during homeostasis
and after wounding? To answer these questions, lineage analysis and transgenic techniques were again
used. As illustrated in Fig. 86-3, bulge cells do not
normally move to the epidermis, but after full-thickness excision of the skin, bulge cell progeny migrate
into the wound during reepithelialization.11,96 These
cells comprise approximately 30% of the cells in the
regenerated epidermis. The role of bulge cells in sebaceous gland maintenance is still not clear, but is under
investigation.
ANAGEN
The formation of a new lower follicle and hair at anagen onset recapitulates folliculogenesis in the fetus.
Anagen can be divided into seven stages: (1) stage
Igrowth of the dermal papilla and onset of mitotic
967
15
Section 15
968
activity in the germ-like overlying epithelium; (2) stage

IIbulb matrix cells envelop the dermal papilla and
begin differentiation, evolving bulb begins descent
along the fibrous streamer; (3) stage IIIbulb matrix
cells show differentiation into all follicular components; (4) stage IVmatrix melanocytes reactivate;
(5) stage Vhair shaft emerges and dislodges telogen
hair; (6) stage VInew hair shaft emerges from skin
surface; and (7) stage VIIstable growth.102
During proliferation and migration of keratinocytes into the dermis to reform the new lower follicle,
enzymes such as proteases and collagenases appear at
the leading edge of the downgrowth, and growth factors and their receptors are upregulated similar to an
epithelial wound.12 Pathways of keratinocyte differentiation that are seen in the epidermis during wound
healing, such as expression of keratin 6, are activated.
Mice lacking Stat3, a regulator of cell migration in the
cutaneous epithelium, show defects in wound healing
and a failure of hair follicles to enter anagen,103 thus
further illustrating the similarity between wound healing and the early events of anagen. Remarkably, the
dermal papilla in the midst of this degradative milieu
survives and moves downward. Neurocutaneous and
vascular networks are remodeled.91,95 Melanocytes
proliferate and repopulate the new hair bulb.104 Finally,
a burst of endothelial proliferation and angiogenesis
in the dermal papilla marks the time point when the
lower follicle is completely restored and is actively
producing the new hair shaft.105
CATAGEN
The onset of catagen is marked by cessation of the
mitotic activity of the matrix cells and by wellcoordinated apoptosis in the cyclic portion of the hair
follicle.12,106 Pigment production by melanocytes ceases
before matrix cell proliferation stops, thus leading to a
nonpigmented proximal end in the telogen club hair
(see Fig. 86-2). Melanin is often found in the surrounding dermis and papilla where it is engulfed by macrophages. The perifollicular sheath collapses, and the
vitreous or glassy membrane thickens. The lower follicle retracts upward with the dermal papilla. The perifollicular sheath forms a fibrous streamer comprised of
fibroblasts, small blood vessels, and collagen.1 Eventually, the dermal papilla becomes situated immediately
below the bulge at the lower portion of the isthmus.
During catagen, the largest follicles, on the scalp for
example, shorten their length from 2- to 5-mm-long
structures whose deepest portion, the bulb, extends
down into the subcutaneous fat to truncated 0.25- to
0.5-mm follicles in telogen. As the basement membrane around the lower follicle thickens, the dermal
papilla, protected from the surrounding apoptosis
and destruction (perhaps because it expresses Bcl2, an antiapoptotic factor12) condenses and begins to
move upward to come to rest below the bulge during
telogen. The migration of the dermal papilla from the
subcutaneous fat to the dermis during catagen is necessary for continued follicle cycling. This is illustrated
by the syndrome of atrichia with papules.107,108 These
patients have mutations in either their hairless gene or

in their vitamin D receptor gene, in which case they
also have rickets. Mice with similar mutations have
the hairless phenotype. We know from these mice that
folliculogenesis is normal; however, when the follicles
enter catagen for the first time, the lower portion of the
follicle does not involute and contract properly, and
the dermal papilla remains stranded in the subcutaneous fat.95 Although bulge cells are still present, no
new anagen follicles ever form, presumably because
the stem cells cannot interact with the dermal papilla.95
The study of mouse mutants has also resulted in
several key findings that have increased our understanding of the molecular events at catagen onset.
Specifically, Hebert et al3 discovered that mice lacking
the Fgf5 gene have hair that is 50% longer than their
wild-type litter mates, and that mutations in this gene
are responsible for the angora phenotype that was
described more than 30 years ago. Although these findings were rather unexpected, careful evaluation of Fgf5
expression throughout the normal hair cycle demonstrated that its expression was upregulated in the outer
root sheath and hair matrix cells just before the onset
of catagen, suggesting that Fgf5 may trigger catagen
onset. Interestingly, the follicle still eventually entered
catagen, even in the absence of FGF-5, suggesting
redundancy in the FGF-5 pathway or an intrinsic finite
proliferative capability of the matrix cells.95 Further
studies also demonstrated that other FGF family members and their receptors are expressed during anagen,
and probably also play a role in the hair follicle cycle.109
The hair phenotype of FGF-5-deficient mice is substantially reversed by ectopic expression of the antiapoptotic gene bcl-xLx in the outer root sheath, suggesting
that regulation of cell survival in the outer root sheath
may play a role in control of the hair growth cycle.110
Although it has been known for many years that
exogenous EGF administered to sheep results in catagen induction,111 only through more recent transgenic
and knockout studies in mice has the importance of the
EGFR system in hair cycle regulation been realized.70,112
For example, knockout mice lacking transforming
growth factor- (TGF-), the major ligand for EGFR,
have abnormal hair follicle development and manifest
the waved hair phenotype.4,5 When EGFR is functionally downregulated in the basal layer of the epidermis
and hair follicle using a dominant negative transgenic
strategy, the resulting hair is not only waved, but also
longer than normal.70 The transition of the hair follicles
from anagen to catagen is delayed in these mice. Hair
follicles in mouse skin that completely lack EGFR also
do not progress from anagen to telogen.112 Thus, EGFR
and its ligand are required for normal hair follicle
development and cycling. Given the complexity of the
EGFR family, which includes four receptors (ErbB14)
and at least six ligands, future studies are needed to
clarify the role of individual family members in hair
follicle cycling.113
In addition to FGF-5 and EGF, neurotrophins and
TGF-1 induce premature catagen. Neurotrophin-3
and brain-derived neurotrophic factor transgenic mice
show premature catagen development, and brainderived neurotrophic factor overexpression leads to
the shortening of hair length by 15%, most likely via

stimulation of proapoptotic signaling through p75 kDa
neurotrophin receptor.114,115 TGF-1 induces premature
catagen in isolated human hair follicles and in mouse
skin in vivo, and TGF-1 knockout mice display delay
in catagen onset.116118
TELOGEN AND EXOGEN
HAIR MELANOCYTE DEVELOPMENT

Melanoblasts can be identified in the epidermis of
human embryos at 50 days of estimated gestational age
before the onset of hair follicle morphogenesis.126128
These follicular melanocytes originate in the neural
crest and migrate first to the dermis and then epidermis.129 New data reveal that melanocytes in the skin
arise from two sources: from neural crest cells migrating in the dorsolateral pathway and from Schwann cell
progenitors located in cutaneous nerves.129a Commitment of neural crest cells to the melanocyte lineage is
regulated by Pax3 and microphthalmia transcription
factors (Mitf), which stimulate the expression of dopa-
Hair becomes pigmented as a result of a tightly coordinated program of melanin synthesis and transport
from the hair bulb melanocytes to differentiating hair
shaft keratinocytes.122124 This process is strictly coupled to anagen and ceases during catagen and telogen.
Numerous signaling molecules, structural proteins,
enzymes, cofactors, and transcriptional regulators control hair pigmentation (Figs. 86-4 and 86-5).122,124,125
MSCs located in the hair follicle bulge generate progeny that repopulate the melanocytes in the new hair
bulb formed at the onset of anagen.103,134 MSCs express
Trp2, Bcl-2, Pax3, while other melanogenic enzymes
(tyrosinase, Trp1) and signaling molecules (c-kit,
endothelin receptor type B, SOX10, Mitf and Lef-1)135
are expressed at low levels. MSCs can be first detected
in the bulge area during late stages of hair follicle
morphogenesis and similarly to epithelial stem cells
they are quiescent.134136 TGF- signaling plays an
important role in controlling MSCs entering into a
noncycling (dormant) state during hair follicle (HF)
morphogenesis.137
Maintenance of MSCs during hair follicle cycling is
controlled by TGF- and Notch-signaling pathways.
Notch signaling plays a crucial role in the survival of
melanocyte stem cells and immature melanoblasts by
preventing apoptosis.138 Crosstalk between the TGF-
pathway and Bcl2 is also important for maintenance
of MSCs, and Bcl2 knockout mice show progressive
hair graying due to their depletion.135138 Bcl-2 plays a
key role in maintenance of MSCs, and Bcl-2 knockout
mice show progressive hair graying due to the depletion of MSCs.139141 However, Bcl-2 deficiency may be
compensated by overexpression of SCF, which rescues
loss of MSCs in the hair follicle bulge of Bcl-2 knockout mice.135
Melanogenically active melanocytes are located in
the hair bulb above the dermal papilla.104,124 These cells
synthesize and transport melanin to hair shaft keratinocytes and express a full set of enzymes and other
proteins involved in melanin biosynthesis including tyrosinase, Trp1, Trp2 (in mice), and pMel17 (in
humans).105,135 Keratinocytes, as pigment recipient
cells, produce Foxn1 and its target Fgf2 to identify
themselves as the targets for pigment transfer.142
::
HAIR PIGMENTATION
HAIR FOLLICLE MELANOCYTE STEM

CELLS AND PIGMENT-PRODUCING
MELANOCYTES
15
Chapter 86
Once the involution of catagen is complete and a club

hair is formed (see Fig. 86-2), the hair follicle prepares
the hair for expulsion from the scalp. About 1% of
telogen follicles are shed each day. Milner et al119 have
proposed distinguishing hair shedding as a separate
phase called exogen. Exogen is a highly controlled and
timed event in mammals that shed on a seasonal basis.
That exogen is an active stage is supported by Headingtons description of one type of telogen effluvium
he termed immediate telogen release.120 This type of hair
loss can be seen soon after starting medications, such
as minoxidil, or in response to rapid fluctuations in
light/dark cycles. It consists of an increase in shedding of club hairs within weeks of the precipitating
event (too soon to be caused by follicles prematurely
entering telogen from anagen), suggesting that club
hairs that are normally retained in the follicle can be
actively shed. The heterogeneity of telogen is further
supported by the work of Guarrera and Rebora,121 who
followed individual hairs in situ using macrophotographs for more than 2 years and showed that several
months could transpire between hair shedding and
regrowth. This lag period is normally not present or
is very short, but often lasts several months in patients
with androgenetic alopecia.
chrome tautomerase [or tyrosinase-related protein 2

(Trp2)], an enzyme involved in melanin biosynthesis
that also functions as an early melanoblast marker.128
Subsequent steps of melanoblast development (migration into the dermis and epidermis) are controlled by
signaling mechanisms activated through endothelin
receptor type B and c-kit oncogene (c-kit) receptor,
which are mutated in humans with Hirschprung disease and piebaldism, respectively, resulting in formation of unpigmented hairs129 (see also Chapter 72).
After entering the placode of the developing hair follicle, melanoblasts proliferate and become melanogenically active synchronously with the onset of hair fiber
formation.130 Experimental and genetic data suggest
that migration of melanoblasts into the hair follicle
and their development toward melanogenically active
forms depend on stem cell factor (SCF)/c-kit signaling.
SCF is a ligand that binds to its receptor, c-kit. Pharmacologic blockade of c-kit during embryogenesis, as
well as genetic ablation of SCF or c-kit in corresponding mouse mutants results in unpigmented hairs.131133
969
15
Section 15
Figure 86-4 Morphology and fluorescent microscopy of human hair follicle at distinct hair cycle stages. AD. Morphology
of human hair follicle during telogen (A), late anagen (B), and early and late catagen (C, D). E. Immunofluorescent visualization of the melanocytes (arrows) in the hair bulb of late anagen hair follicle with antimelanoma-associated antigen recognized by T cells antibody. F. Immunofluorescent detection of proliferative marker Ki-67 (arrows) and apoptotic TUNEL+
cells (arrowheads) in early catagen hair follicle. FP = follicular papilla; HM = hair matrix.
970
15
Hair cycle-dependent remodeling of the follicular pigmentary unit
Telogen
melanocyte
stem cell
Trp2+/Ki67-c-kit-
Melanocyte
stem cell
Early anagen
Undifferentiated
melanocytes
Trp2+/Ki67+c+kit+
Outer root sheath
Late anagen
Differentiated
melanocytes
Trp2+/Trp1+/Tyr+
Ki67-/c-kit+/MC-1R+
Hair bulb
Undifferentiated
melanocytes
::
Differentiated
pigment-producing
malanocytes
Hair follicle melanocytes undergo substantial remodeling during hair follicle cycling.104,124 In telogen, hair
follicle melanocytes are found in the bulge, secondary
hair germ, and connective tissue.104 In humans, melanocytes in the telogen hair follicle do not express Trp1
or tyrosinase and do not proliferate. Melanocytes can
be visualized by expression of pMel17.141 Some of these
cells also express c-kit receptor, whereas others remain
c-kit-negative and represent MSCs.104,134,135 TGF- signaling is activated in MSCs when they reenter the quiescent noncycling state during the hair cycle and this
process requires Bcl2 for cell survival.137
During early anagen, resting melanocytes proliferate, differentiate, and migrate within the hair follicle
synchronously with regeneration of the hair follicle
bulb. Hair follicle melanocytes are maximally proliferative during early and midanagen, and their transition to melanogenic competence is accompanied by
the appearance of Trp1 and tyrosinase proteins.104,143
However, this process is stringently controlled, and
Notch signaling is necessary to prevent differentiation
of melanoblasts into pigment-producing melanocytes
before they reach the hair bulb, as well as for their
proper positioning in the hair matrix.144
Similar to embryonic and early postnatal development, SCF/c-kit signaling plays a critical role in
repopulation of the bulb with pigment-producing
Figure 86-5 Hair cycle-dependent remodeling of the follicular pigmentary unit. A. Scheme illustrating localization of
distinct subpopulations of melanocytes in anagen hair follicle. B. Dynamics of the follicular melanocytes during anagen.
Expression of melanogenic markers and growth factor receptors indicated is based on the data obtained from murine
hair follicles. Note that human follicular melanocytes do not express tyrosinase-related protein 2 (Trp2). c-kit = c-kit oncogene. (From Ando H et al: Fatty acids regulate pigmentation via proteasomal degradation of tyrosinase: A new aspect of
ubiquitin-proteasome function. Botchkareva NV, Botchkarev VA, Gilchrest BA: Fate of melanocytes during development of
the hair follicle pigmentary unit. J Investig Dermatol Symp Proc 8:76, 2003 .
HAIR CYCLE-DEPENDENT CHANGES

IN MELANOCYTES
Chapter 86
Bulge/
secondary
germ
Mid-anagen
Undifferentiated
melanocytes
Trp2+/Trp1+
Ki67-/c-kit+
melanocytes. C-kit is expressed on proliferating, differentiating, and melanogenically active melanocytes,

whereas overexpression of SCF in the epidermis of
transgenic mice significantly increases the number of
hair follicle melanocytes and their proliferative activity.104 Similarly, administration of the ACK45 antibody
blocking c-kit signaling dramatically reduces melanocyte number in anagen hair follicles, resulting in hair
depigmentation.104 However, in the next hair cycle, the
previously treated animals grow fully pigmented hairs
with the normal number and distribution of melanocytes, suggesting that MSCs are not dependent on
SCF/c-kit.104
During catagen, melanogenic activity in the follicular melanocytes abruptly ceases. Immunohistochemical and electron microscopic data suggest that some
pigment-producing melanocytes located above the
follicular papilla undergo apoptosis, while others drop
into the dermal papilla of the follicle and migrate into
the dermis.145,146
MOLECULAR CONTROL
OF HAIR COLOR
Follicular melanocytes synthesize pigment via a
cascade of enzymatic conversions of phenylalanine
or tyrosine into brownblack eumelanin or yellow
pheomelanin that requires melanogenic enzymes
(tyrosinase, Trp1/2, -glutamyl transpeptidase,
971
15
Section 15
972
peroxidase) and essential cofactors, such as 6-tetrahydrobiopterin.122 The balance between black and yellow pigment synthesis (eumelanin and pheomelanin,
respectively) is regulated by signaling through the
melanocortin type 1 receptor (MC-1R) that has long
been implicated in the control of hair color.147,148 (See
Chapter 72.)
After binding to MC-1R, melanocyte-stimulating hormone (-MSH) stimulates adenylyl cyclase,
resulting in elevation of intracellular cyclic adenosine
monophosphate levels. This leads to increase of transcriptional activity of Mitf that stimulates synthesis of
melanogenic enzymes (tyrosinase, Trp1/2) involved in
eumelanin formation.149,150 Pheomelanin synthesis in the
hair follicle melanocytes of mice occurs when MC-1R
signaling is inhibited by Agouti signal protein (ASP)
that competes with -MSH in binding to MC-1R.148,149
In mice, ASP expression is positively regulated by BMP
signaling, and transgenic mice overexpressing BMP
antagonist Noggin show hair darkening.151 Although
ASP is expressed in human skin, its role in human pigmentation remains unclear.150
Recent data also demonstrate existence of fully functional proopiomelanocortin/MC-1R system in human
hair follicles: MC-1R is expressed by hair follicle melanocytes, whereas its ligands -MSH and adrenocorticotropic hormone are able to promote proliferation,
dentricity, and melanogenesis.152 Similar effects are
seen with another proopiomelanocortin-derived peptide, -endorphin that interacts with -opiate receptor
expressed by hair follicle melanocytes.152 However,
signaling through the -opiate receptor may regulate
hair pigmentation via modulating the activity of protein kinase C-, a known positive regulator of melanogenesis.153
Follicular melanocytes are sensitive to aging, which
results in their premature loss and hair graying.154 In
contrast to normally pigmented hair follicles, fewer
melanocytes are found in the bulbs of gray hairs;
however, these melanocytes still express tyrosinase,
synthesize and transfer melanin to keratinocytes.146
In addition, a population of melanogenically inactive
melanocytes (melanoblasts including stem cells) in
the outer root sheath is markedly reduced in the follicles producing gray hairs compared to pigmented
follicles (Commo et al, 2004). The fact that MSCs are
damaged in hair follicles producing gray hairs was
confirmed in mice by applying ionizing radiation,
which triggered premature differentiation of MSCs in
the follicular bulge into mature, pigment-producing
melanocytes followed by their depletion and irreversible hair graying.155 Deficiency of ATM-kinase, a
central transducer of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating
its role in protecting MSCs from their premature differentiation.155
However, hair graying is also mediated by H2O2induced oxidative damage in the entire hair follicle
including the hair shaft, which does not exclusively
affect follicle melanocytes, thus suggesting that accumulation of hydrogen peroxide in both keratinocytes
and melanocytes is one of the critical factors that
underlie biochemical changes in the follicular pigmentary unit of graying hairs.156
CONCLUSION
The hair follicle is formed as the result of a complex
interplay of signals between epithelium and mesenchyme. The nature of these signals is just now being
elucidated, with many molecular pathways important
in development also playing roles in hair follicle formation. The product of this process is a miniature organ
with distinctive vertical and concentric divisions. Both
epithelial stem cells and MSCs in the follicle are important for the constant regeneration of the follicle.
KEY REFERENCES
1. Cotsarelis G, Millar SE: Towards a molecular understanding of hair loss and its treatment. Trends Mol Med
7:293, 2001
11. Cotsarelis G: Epithelial stem cells: A folliculocentric
view. J Invest Dermatol 126:1459, 2006
12. Stenn KS, Paus R: Controls of hair follicle cycling. Physiol
Rev 81:449, 2001
15. Millar SE: Molecular mechanisms regulating hair follicle
development. J Invest Dermatol 118:216, 2002
16. Schmidt-Ullrich R, Paus R: Molecular principles of hair
follicle induction and morphogenesis. Bioessays 27:247,
2004
30. Hardy MH: The secret life of the hair follicle. Trends Genet
8:55, 1992
73. Langbein L, Schweizer J: Keratins of the human hair follicle. Int Rev Cytol 243:1, 2005
84. Paus R et al: Neural mechanisms of hair growth control.
Review. J Invest Dermatol Symp Proc 2:61, 1997
106. Botchkareva NV, Ahluwalia G, Shander D: Apoptosis in
the hair follicle. J Invest Dermatol 126:258, 2006
Chapter 87 :: K
eratosis Pilaris and Other Inflammatory
Follicular Keratotic Syndromes

:: Paradi Mirmirani & Maureen Rogers
KERATOSIS PILARIS AT A GLANCE
Common condition of keratotic follicular
plugging with variable erythema.
Two main patterns(1) early childhood

onset and (2) adolescent onset.
Usually improves gradually over years.
Nonspecific histology of follicular orifice
distended by keratin plug.
Variable response to keratolytics.
Variants:
Erythromelanosis follicularis faciei et
colli (EFFC): marked erythema and
hyperpigmentation.
Keratosis rubra pilaris (KRP): erythema
not limited to perifollicular area, may be
same as EFFC.
ASSOCIATIONS OF KERATOSIS PILARIS. Clinical ichthyosis vulgaris (see Chapter 49) is associated with
KP8; in one series KP was found in 74.3% of patients (Fig.
87-1).2 Other conditions in which KP is more prevalent
or more prominent are atopic disorders, hypothyroidism, Cushing syndrome, insulin dependent diabetes,
obesity or high body mass index, and Down syndrome.9
Follicular keratosis, which may simulate KP, can occur
in several nutritional deficiencies, although vitamin A
deficiency is most commonly cited (see Chapter 130).10
KERATOSIS PILARIS VARIANTS

ERYTHROMELANOSIS FOLLICULARIS
FACIEI ET COLLI
Follicular keratosis refers to orthokeratosis involving

the follicular ostium and infundibulum. Horny plugs
protrude from the orifices, producing a rough sensation on palpation of the skin. It may be isolated [keratosis pilaris (KP)] or associated with other pathologic
processes, including follicular inflammation, atrophy,
scarring, and alopecia [keratosis pilaris atrophicans
(KPA)]. These are reaction patterns that occur alone or
as part of a wide variety of syndromes.
Erythromelanosis follicularis faciei et colli (EEFC) is a

condition probably related to KP.11 The suffix colli
Chapter 87 :: Keratosis Pilaris and Other Inflammatory Follicular Keratotic Syndromes
Mainly involves cheeks and extensor arms

and thighs.
affected and gradual improvement is seen in most

cases by later childhood or adolescence. In the other
pattern, the onset is in teenage years, and the extensor
arms and legs are predominantly involved. It usually
improves by the mid-20s. However, in both patterns,
the condition may be persistent into later adult life.5
The histopathologic pattern in skin biopsy specimens
is nonspecific, simply showing the follicular orifice
distended by a keratin plug.
Treatment is usually with various keratolytics, from
simple urea, lactic acid, or salicylic acid preparations to
topical retinoids and tazarotene.6,7 These preparations
may aggravate associated erythema, limiting their value.
15
KERATOSIS PILARIS
Typical KP is a common condition of keratotic follicular plugging with varying degrees of surrounding erythema. Sometimes, the erythema is so striking
that it is the main complaint. The clinical expression
of KP varies from subtle to conspicuous, which, along
with possible racial differences, may explain the great
range of reported prevalences, from 1% to 42%.14 It
involves most commonly the extensor aspects of the
upper arms (Fig. 87-1) and thighs as well as the face
but may rarely be more extensive, extending to the
distal limbs and the trunk. There seem to be two patterns. In early childhood, the face and arms are mainly
Figure 87-1 Keratosis pilaris in a characteristic distribution on upper outer arm in a patient with ichthyosis
vulgaris.
973
15
refers to the neck. EEFC It is seen primarily in adolescents and young adults, most commonly in males.
Well-demarcated erythema, hyperpigmentation, and
follicular papules involve the preauricular and maxillary areas, usually in a symmetric distribution, with
spread in some cases to the temples and sides of the
neck and trunk. Atrophy is not a feature. Histopathology is nonspecific, demonstrating a variable degree
of follicular hyperkeratosis, dilation of upper dermal
vessels, some perivascular inflammatory infiltrate, and
hyperpigmentation of the basal layer. There are few
reports of EEFC in the literature, however it may be
underreported.
Section 15
KERATOSIS PILARIS RUBRA
Although erythema is often present in typical KP, it

is usually mild and limited to the perifollicular skin.
When perifollicular erythema is more noticeable, the
disorder has been called keratosis pilaris rubra (KPR)
or less commonly keratosis follicularis rubra.12 These
findings are usually limited to the cheeks, forehead,
and neck (Fig. 87-2). Features that differentiate EFFC
from KPR are a lack of reported involvement on the
torso and the presence of hyperpigmentation. However the hyperpigmentation noted in EFFC may, at
least in part, be related to skin pigmentation type, with
darker skin types showing more evidence of hyperpigmentation. Thus it is likely that KPR and EFFC are
variants of the same clinical spectrum.
KERATOSIS PILARIS ATROPHICANS

KERATOSIS PILARIS ATROPHICANS
AT A GLANCE
A group of rare follicular keratosis
conditions with variable degrees of
inflammation, and secondary atrophic
scarring/and or alopecia.
Ulerythema ophryogenes (Keratosis pilaris
rubra atrophicans faciei) predominantly
affects eyebrow area, causing scarring
alopecia; occurs with Noonan,
cardiofaciocutaneous and other syndromes.
Atrophoderma vermiculatum
predominantly involves cheeks and leads to
a striking honeycomb-like atrophy; mosaic
forms described.
Keratosis follicularis spinulosa decalvans
predominantly involves scalp, leading
to severe cicatricial alopecia; associated
features include plantar keratoderma and
photophobia.
The general term keratosis pilaris atrophicans is a group

of rare genodermatoses in which the clinical hallmarks is follicular keratosis with variable degrees of
inflammation, and secondary atrophic scarring and/
or alopecia.1315 Three distinct clinical entities that fall
under the umbrella of keratosis pilaris atrophicans
include ulerythema ophryogenes [UO or keratosis
pilaris atrophicans faciei (KPAF)], atrophoderma vermiculatum, and keratosis follicularis spinulosa decalvans (KFSD).
ULERYTHEMA OPHRYOGENES
(KERATOSIS PILARIS RUBRA
ATROPHICANS FACIEI)
974
Figure 87-2 Keratosis pilaris rubra with dramatic perifollicular erythema on the cheeks.
The prefix ophryo- refers to the eyebrow. UO is a form

of KPA affecting particularly and initially the eyebrow
areas, in some cases extending later to the cheeks and
forehead.13 Scalp and eyelash hair is normal. The onset
is within months of birth, with erythema and small
keratotic follicular papules involving the lateral onethird of the eyebrows. It may slowly progress through
childhood to involve more of the eyebrows and sometimes beyond, leading to alopecia (Fig. 87-3). Progression usually ceases after puberty but the sequelae are
permanent. The condition is frequently associated
with standard KP that may involve the arms and legs
or may be more generalized. The term keratosis pilaris
rubra atrophicans faciei is used interchangeably with
UO, however some prefer this diagnosis for patients
in whom the initial erythema starts on the cheeks as
opposed to the eyebrows.
15
Figure 87-3 A. Ulerythema ophryogenes involving eyebrow area with scarring alopecia. B. Ulerythema ophryogenes
involving the upper face in a patient with Noonan syndrome.
Most cases have followed an autosomal dominant
inheritance pattern, with incomplete penetrance.13
Response to topical corticosteroids, topical retinoids,
and keratolytics has been poor. There is one report of
a good response to several months therapy with oral
isotretinoin, with lessening of the horny plugs and
the erythema.16 The improvement was maintained for
some months after therapy had ceased. Some improvement in erythema was reported with the pulsed tunable dye laser at 585 nm, but the follicular plugging
was unchanged.17
SYNDROMES ASSOCIATED WITH ULERYTHEMA OPHRYOGENES. UO has been reported
in association with isolated woolly hair,18,19 Noonan

syndrome,19,20 cardiofaciocutaneous (CFC) syndrome,21,22 RubensteinTaybi syndrome,23 Cornelia
de Lange syndrome,24 and 18p deletion.25,26 CFC and
Noonan syndrome have overlapping clinical features,
and both have mutations in genes of the Ras pathways.27,28 In CFC, mutations have been described in
BRAF, KRAS, MEK1, and MEK2 genes.27 Whereas in
Noonan syndrome, there is primarily mutations of
PTPN11, but also KRAS and SOS1 genes.29,30
Follicular keratosis in Noonan syndrome, if present, is
usually limited to the face (Fig. 87-3B) and resembles UO
with loss of eyebrow hairs.19,20 In CFC syndrome, follicular keratosis is often much more extensive, and there may
be striking alopecia involving the scalp.22 The remaining
scalp hair in CFC syndrome is brittle and curly.
Involvement of the forehead, arm, and leg, as well as

the typical cheek area, has been described.14 However, in
general, it is rare for the condition to involve the limbs,
and eyebrow involvement does not occur. Standard KP
of the extensor aspects of arms and legs is a common
associated finding.31 Unlike the other KPA disorders
in which the onset is in infancy, AV usually starts in
childhood, between 5 and 12 years old, although later
onset has been described14; the course is usually one of
inexorable worsening. The condition is often sporadic
but, in some cases, appears to be inherited as an autosomal dominant trait.33 Several more or less linear unilateral cases have been described,34 suggesting a possible
mosaic form of the condition.35 However, it is possible
that at least some of these cases may represent examples
of nevus comedonicus.35
Histopathologic evaluation demonstrates atrophic pilosebaceous units with mild perifollicular and
ATROPHODERMA VERMICULATUM
(FOLLICULITIS ULERYTHEMATOSA
RETICULATA)
AV is a form of KPA in which the cheeks are predominantly involved, with follicular plugs and pit-like
depressions up to 1.5 mm in diameter and a background
of erythema. Alopecia and follicular papules are not features of the condition,22,31 but sparse open and closed
comedones and milia may be found.32 The depressions
merge into each other, producing a worm-eaten,
honeycombed, or reticular appearance (Fig. 87-4).
Figure 87-4 Atrophoderma vermiculatum demonstrating honeycomb atrophy on the cheek of an adolescent
girl.
975
15
TABLE 87-1
Syndromes with Follicular Atrophoderma as a Feature
Section 15
Condition
Inheritance
Main Features
Comments
Bazex syndrome (Bazex

DupreChristol syndrome)41
X-linked dominant
Hypotrichosis, pili torti,

hypohidrosis, milia,
development of basal cell
carcinomas in adolescence.
Rombo syndrome38
Autosomal dominant
Hypotrichosis, especially of
eyelashes, peripheral cyanosis,
basal cell carcinomas, and
trichoepitheliomas.
X-linked dominant
chondrodysplasia punctata
(ConradiHnermann
syndrome)39
X-linked dominant, lethal in

males
Congenital Blaschkodistributed red scaly lesions

that resolve in months,
replaced by follicular
atrophoderma. Cataracts,
shortening of limbs, frontal
bossing, saddle nose, low-set
ears.
Mutation in emopamil binding

protein gene, relevant in
cholesterol biosynthesis
Congenital ichthyosis, follicular

atrophoderma, hypotrichosis,
and hypohidrosis42,43
Probably autosomal recessive
Congenital, diffuse ichthyosis,

hypohidrosis, hypotrichosis.
Woolly hair in one pedigree.
Only described in two families

so far
Hereditary perioral pigmented

follicular atrophoderma
associated with milia and
epidermoid cysts40
Autosomal dominant
Epidermoid cysts and milia.
Follicular atrophoderma
limited to face, especially
periorally
Nevus comedonicus44
Somatic mutation
Blaschko-distributed
comedo-like plugs in dilated
follicular orifices. Cribriform
atrophy follows extrusion of
comedones.
Due to somatic mutation

of fibroblast growth factor
receptor 2, identical to
that, which, if present in
the germline, causes Apert
syndrome
perivascular inflammation. The follicular orifices are

dilated and filled with keratin plugs. Numerous dermal horn cysts may be found. There is perifollicular
fibrosis and a decrease in elastic fibers in the dermis.31,36
Therapy is uniformly unsuccessful and has included
topical steroids, topical retinoids, cryotherapy, and
derm-abrasion. Favorable results have also been
described with carbon dioxide laser in a case in which
atrophy was prominent, and pulsed dye laser in a case
with a marked erythematous component.32 Oral isotretinoin suppressed the inflammation in one patient.37
SYNDROMES ASSOCIATED WITH FOLLICULAR ATROPHODERMA. Follicular atrophoderma
occurs as a feature of several rare syndromes3843 and

in nevus comedonicus (Table 87-1).44 As such, these
conditions may come into the differential diagnosis of
atrophoderma vermiculatum.
KERATOSIS FOLLICULARIS SPINULOSA

DECALVANS
976
The term KFSD was first used by Siemens in 1926 who

described a scarring follicular condition in 20 members
of a large family.45 The condition begins in infancy with
noninflammatory, flesh-colored, spiny lesions affecting hair-bearing areas, especially the scalp (Fig. 87-5)
and later eyebrows, eyelashes, and the dorsal of the
hands and fingers. Sometimes, more proximal limbs
and even the trunk become involved.4547 An associated plantar keratoderma may occur, especially over
the heels.15 By puberty, many of the follicular spines
have disappeared and are replaced by atrophy. Scarring alopecia of scalp (see Fig. 87-5), eyebrows, and
eyelashes becomes apparent in childhood and progresses till puberty. It is often patchy and is rarely total.
Facial lanugo hair is absent, and axillary and pubic
hair is often thinned.
Photophobia is seen in many patients, and punctate
corneal epithelial defects have been seen in some.47 It is
unclear whether there is a primary epithelial defect or
whether the corneal changes occur as a result of irritation from distorted remnant lashes and keratotic plugs
in eyelash follicles. There are rare reports of other ophthalmologic abnormalities, including cataract and retinal detachment.48
Biopsy specimens show follicular based hyperkeratosis, perifollicular and dermal inflammation, fibrosis,
and distorted follicles at different stages of the condition.46 Family studies suggest an X-linked dominant
inheritance pattern,45,4749 with men often more severely
OTHER SYNDROMES WITH

FOLLICULAR KERATOSIS AS A
SIGNIFICANT FEATURE
15
Apart from the conditions described in the preceding

sections in association with UO, there are other conditions that have follicular keratosis as a significant feature (Table 87-2).
MONILETHRIX
affected than women. A mutation in the gene encoding

spermidine/spermine N(1)-acetyltransferase (SSAT)
has been noted in these patients and has been localized
to Xp22.13-p22.2.50 However clinical heterogeneity is
likely as there have been identification of pedigrees
unlinked to this region as well as rare instances of male
to male transmission suggesting an autosomal dominant form.51,52 In the differential diagnosis of KFSD is
ichthyosis follicularis with alopecia and photophobia
(IFAP) syndrome [see Section Ichthyosis Follicularis,
Alopecia (Atrichia), and Photophobia Syndrome].53
However, features in KFSD not shared by IFAP are
involvement of the fingers, late atrophy, and scarring
of involved follicles, and the development in some
patients of a redbrown telangiectatic pigmentation of
cheeks and brows.
In general, treatment of KFSD is unsatisfactory;
however, there are isolated reports of improvement in
photophobia with oral vitamin A,47 as well as conflicting reports on the results of dapsone,51,54 and oral retinoids.46,55,56
FOLLICULITIS SPINULOSA DECALVANS

A variant of KFSD has been called folliculitis spinulosa
decalvans (acknowledging that this name may lead to
confusion with the separate entity of folliculitis decalvans).15,57 This variant is characterized by persistent
pustule formation, especially on the scalp. Unlike the
typical variant of KFSD, there is more severe inflammation, and it is progressive, rather than stable or remitting after puberty. In addition, the inheritance appears
to be autosomal dominant rather than X-linked recessive. Treatment response to isotretinoin has been
unsuccessful.57
KERATOSIS PILARIS AND HEREDITARY

KOILONYCHIA
A family has been described with koilonychia and widespread KP, involving all areas of trunk and limbs. Affected
family members also showed eyebrow involvement with
alopecia, simulating UO/KPAF.68 The inheritance pattern
appeared to be autosomal dominant. Unlike previous
cases, there was no monilethrix in this pedigree.
KERATITIS, ICHTHYOSIS, AND

DEAFNESS SYNDROME
(See Chapter 49)
Figure 87-5 Keratosis follicularis spinulosa decalvans

with severe scarring alopecia of scalp. (Photograph used
with permission from Dr. Peter Hogan.)
(See Chapter 88)

Monilethrix is an autosomal dominant condition
producing a beaded appearance of the hair.58 Mutations in the human basic hair trichocyte keratins K81,
K83, and K86 (formerly hHb1, hHb3, and hHb6, respectively) have been reported.5961 However, the failure to
demonstrate these mutations in one family suggests the
possibility of genetic heterogeneity.62 A striking follicular keratosis is associated in some pedigrees and may
involve the scalp (Fig. 87-6), face, and limbs. Nail onychodystrophy or koilonychia are also variably reported.
Genotype/phenotype correlation is not obvious in
reported cases in which mutations have been identified.63,64 The clinical phenotype of autosomal recessive
hypotrichosis resembles that of monilethrix. In these
patients, there is a defect of the desmoglein 4 gene, which
belongs to the desmosomal cadherin superfamily and
is also expressed in the cortex of the hair follicle.6567
TABLE 87-2
Syndromes That May Feature Follicular Keratosis

Monilethrix
Keratosis pilaris and hereditary koilonychia
Hereditary mucoepithelial dysplasia
Ichthyosis follicularis, alopecia, and photophobia syndrome
Keratitis, ichthyosis, and deafness syndrome
Cardiofaciocutaneous syndrome
Noonan syndrome
RubensteinTaybi syndrome
Cornelia de Lange syndrome
18p deletion
977
15
ICHTHYOSIS FOLLICULARIS, ALOPECIA

(ATRICHIA), AND PHOTOPHOBIA
SYNDROME
Section 15
978
Figure 87-6 Striking follicular keratosis of the scalp in a

patient with monilethrix.
Widespread spiny follicular keratosis is a striking
feature of keratitis, ichthyosis, and deafness syndrome,
a connexin/gap-junction disorder. This autosomal
dominant disorder is also characterized by alopecia of
scalp, body, eyebrow, and eyelash hair, vascularizing
keratitis, and a profound sensorineural hearing loss.69
HEREDITARY MUCOEPITHELIAL
DYSPLASIA
The characteristic features of hereditary mucoepithelial
dysplasia (HMD) are follicular keratosis, nonscarring
alopecia with some coarse abnormal hairs remaining,
fiery-red palatal and gingival mucosae, photophobia
with demonstrable keratitis and corneal vascularization,
and psoriasiform hyperkeratotic lesions in the perineal
area and often also on the extensor limbs.7072 The condition occurs in both sexes, and family studies suggest
both autosomal dominant and autosomal recessive patterns of inheritance may be possible. Light microscopic
evaluation of skin and mucosae shows dyskeratotic cells
in the spinous layer, vacuolated basal cells, and lack of
epithelial maturation.70,72 Electron microscopy shows
paucity of desmosomes, cytoplasmic vacuolization, and
presence of multilaminar bands and wheat sheaf-like
collections of filamentous fibers in the cytoplasm, resembling gap-junction material, and suggesting a disorder of
desmosomal or gap junction proteins.72 However, subsequent studies of several characteristic cases in one pedigree found normal expression of gap junction proteins
(connexins 26, 32, and 43), desmosomal proteins (desmogleins 1 and 2, plakoglobin, desmoplakins I and II,
and plakophilin 1), adherens junction proteins (-catenin
and E-cadherin), and cytoskeleton proteins (keratins,
-tubulin, vimentin, and actin).70 Genetic analysis in the
studied family excluded the desmosomal cadherins in
chromosome 18q12 as candidate genes and ruled out a
mutation in connexin 26.70
The association of ichthyosis follicularis, alopecia,

and photophobia was first reported as a syndrome
by McLeod in 1909,73 and for many years additional
reported cases of what came to be designated IFAP
syndrome occurred in males. Affected individuals demonstrate widespread, flesh-colored, spiny, follicular
projections with minimal, if any, inflammation (except
for inflammatory palmoplantar keratoderma with
advancing age), severe alopecia, often total atrichia
involving eyebrows and lashes as well as scalp hair, and
severe photophobia, often with demonstrable corneal
vascularization.53,7476 The condition was postulated
to be inherited as an X-linked recessive trait, which is
supported by the report of the mother and sister of a
male patient with classical features of IFAP syndrome
having linear lesions of hyperkeratosis, hypohidrosis,
and atrophy and a patchy scalp alopecia, distributed
along Blaschkos lines.77 Recently, the gene defect has
been mapped to Xp22.11-p22.13 and a missense mutation of the gene, MBTPS2, which codes for an intramembrane zinc metalloprotease, has been identified.78
This gene is essential for cholesterol homeostasis and
endoplasmic reticulum stress response.
Patients may have only cutaneous features, but
neurologic and skeletal anomalies and recurrent infections have occasionally been described.44,7982 Atypical
cases have included females with generalized involvement and transmission from mother to daughter83,8486;
psoriasiform patches,80,85,86 particularly involving the
perineal area; and hypotrichosis rather than complete
atrichia.86 Some patients with psoriasiform plaques
lack the typical spiny follicular projections80,81 and
may represent a different entity,76 or even a variant of
HMD.86 In support of the latter is the ultrastructural
finding of reduced numbers of desmosomes in one
patient with IFAP and psoriatic lesions, analogous
to what is seen in HMD.85 Patients with documented
mutations in MBTPS2, have reportedly had spiny
follicular projections during infancy, and the later
progressive development of psoriasiform plaques.
Treatment of IFAP is usually unsatisfactory, but there
are reports of temporary flattening of the follicular keratotic papules and plaques and regrowth of eyelashes
with oral acitretin.87,88
KEY REFERENCES
12. Marqueling AL et al: Keratosis pilaris rubra: A common
but underrecognized condition. Arch Dermatol 142:16111616, 2006
13. Callaway SR, Lesher JL Jr: Keratosis pilaris atrophicans:
Case series and review. Pediatr Dermatol 21:14-17, 2004
15. Oranje AP, van Osch LD, Oosterwijk JC: Keratosis pilaris
atrophicans. One heterogeneous disease or a symptom in
different clinical entities? Arch Dermatol 130:500-502, 1994
52. Castori M et al: Clinical and genetic heterogeneity in

keratosis follicularis spinulosa decalvans. Eur J Med Genet
52:53-58, 2009
70. Boralevi F et al: Hereditary mucoepithelial dysplasia: Clinical, ultrastructural and genetic study of eight patients and
literature review. Br J Dermatol 153:310-318, 2005
78. Oeffner F et al: IFAP syndrome is caused by deficiency in

MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response.
Am J Hum Genet 84:459-467, 2009
APPROACH TO THE PATIENT WITH HAIR

GROWTH DISORDERS AT A GLANCE
Exclude or confirm common hair growth

disorders based on clinical assessment and
diagnostic tools (see Table 88-1).
Find the right treatment for confirmed diagnosis.
Dispel misconceptions on treatment options
and results, and educate patient.
INTRODUCTION
The importance of human hair in view of social communication and sexual attraction is enormous. Thus,
diseases that lead to hair loss (alopecia), structural hair
shaft defects or excessive hair growth on the body are
often accompanied by diminished sense of personal
well-being and self-esteem, leading to depressive
moods and withdrawal from social interims.
In this chapter, we discuss the biologic basis and
clinical presentation of hair growth disorders, give
definitions (eTable 88-0.1 in online edition), explain key
management principles, and provide practical advice
for diagnosis, therapy and patient management.
Two frequently applied terms of alopecia and effluvium need to be characterized. While effluvium typifies the process of hair shedding, alopecia characterizes
the final result of this. Both terms are nonspecific; they
do not give etiological information of the underlying
hair loss (see eTable 88-0.1 in online edition).
Disorders that result in alopecia can be grouped
into diffuse, patterned and focal hair loss as well as
into scarring (synonym: cicatricial) and nonscarring
forms. Scarring forms are characterized by permanent
destruction of hair follicular stem cell structure result-
Hair Growth Disorders
Classify hair disorder based on patients

history and clinical pattern (see eTable 88-0.2
in online edition).
::
Take patient with hair growth disorders

serious and provide emotional support.
ing in loss of hair producing capabilities. In contrast, in

nonscarring alopecia the hair follicle is not ultimately
destroyed and subsequent hair regrowth follows periods of hair shedding. In both, scarring and non scarring
alopecia, distribution of hair loss can occur in a diffuse
pattern over the whole scalp or be circumscribed, affecting only a few, more or less demarcated areas. Alopecia
can also be due to improper or missing follicle development. These rare inherited hair abnormalities can be
focal (e.g., aplasia cutis congenita, see Chapter 107) or
diffuse (e.g., ectodermal dysplasia, see Chapter 142).
Hair growth disorders caused by structural hair shaft
defects can be acquired or inherited. While acquired hair
shaft defect are accompanied by increased hair breakage
and are usually due to hair grooming practices, inherited hair shaft defects can be grouped into disorders
with or without increased hair breakage. Acquired hair
shaft disorders are reversible when trigger factors are
stopped. Inherited hair shaft disorders cannot be cured,
but tend to improve as the patient ages.
Chapter 88
Chapter 88 :: Hair Growth Disorders

:: Nina Otberg & Jerry Shapiro
15
PRINCIPLES OF HAIR
FOLLICLE BIOLOGY
(See Chapter 86)
TABLE 88-1
Diagnostic Proceduresa
Essential procedures
Hair pull test to assess scalp hair cycling
Hair shaft microscopy
Dermatoscope
Biopsy (mandatory if scarring alopecia is suspected)
Additional useful tests
Trichogram (hair pluck test)
Hair shedding count
Potassium hydroxide stain (for suspected fungal
infection)
Laboratory tests
Most commonly performed for hair loss: complete
blood cell count, ferritin or iron/total iron binding
capacity, thyroid-stimulating hormone, and thyroxine
a
See online Table 88-1.1 for additional diagnostic procedures.

Data from Olsen EA: Current and novel methods for assessing efficacy
of hair growth promoters in pattern hair loss. J Am Acad Dermatol
48:253, 2003.
979
15
DIAGNOSTIC TECHNIQUES FOR

EVALUATING HAIR GROWTH
DISORDERS
HISTORY
Section 15
A thorough patient history is critical for the development of an initial differential diagnosis and for the
relationship with the patient. The patient should be
asked about the duration and pattern of the hair problem. Was the problem present at birth, did it evolve
gradually over time starting at a certain age or was
there a rapid onset? A hair problem that is present at
birth leads more to a genetic disorder; certain conditions are more common in children, such as tinea capitis, alopecia areata, or trichotillomania. For example,
a rapid onset of hirsutism can lead to the diagnosis
of an androgen-secreting tumor. A gradual thinning
of fronto-parietal scalp hair fits more to the diagnosis
of androgenetic alopecia (AGA) (see eTable 88-0.2 in
online edition). Patients with hair loss should be asked
if the hair is shedding or thinning and if the hair is coming out by the root or if it is breaking off. A patient
history includes the family history as well as questions
about current and past medication, pregnancy, menses, menopause, thyroid function, diet, past and present health, surgeries, accidents, physical or emotional
stress events and hair care practices.
GLOBAL ASSESSMENT AND IMAGING

The global examination of the scalp should first of
all assess the overall pattern of the hair problem. It is
important to determine density and distribution and if
the hair loss is focal or global. Furthermore, the presence of scaling, erythema, erosions, crust or pustules
and the presences or absence of follicular ostia should
be noted. The clinical examination should also involve
the nails, since some disorders, for example alopecia
areata, lichen planopilaris (LPP), or ectodermal dysplasia can also affect finger and toe nails. Excessive
body hair is oftentimes shaved or epilated. The extent
of unwanted terminal hair growth can be evaluated by
a patient self-assessment with the help of images (see
Section Hirsutism).
PULL TEST
980
The pull test is a useful ancillary, qualitative test for

the assessment of the ongoing activity of hair loss. The
examiner grasps approximately 5060 hairs and tugs
at them from proximal to distal end. Removal of six
hairs indicates a positive pull test and active shedding.
However, the test can be considered positive if three
hairs can be pulled out in several different areas of
the scalp. The proximal ends can be examined against
a white (for dark hair) or black (for light hair) background. A blunt tip indicates hair breakage; a tapered
tip can indicate regrowth or miniaturized hairs. The
proximal end of the hair shafts may also be examined

with a light microscope to determine, if the hairs break
off (blunt ends) or came out as club hairs (telogen hair).
BIOPSY
A scalp biopsy is necessary, particularly when confirming the diagnosis of scarring alopecia. A scalp biopsy
should also be considered for the differential diagnosis
of TE, diffuse alopecia areata and AGA. The following
recommendations were developed at the consensus
meeting on cicatricial alopecia in February 2001: one
4-mm punch biopsy including subcutaneous tissue
should be taken from a clinically active area, processed
for horizontal sections and stained with hematoxylin
and eosin. Elastin (acid alcoholic orcein), mucin, and
periodic acid-Schiff (PAS) stains may provide additional information. A second 4-mm punch biopsy from
a clinically active disease affected area should be cut
vertically into two equal pieces. One-half provides tissue for transversely cut routine histological sections;
the other half can be used for direct immunofluorescence (DIF) studies.1,27 Usually only one biopsy from
the affected area is necessary for the diagnosis of a
nonscarring alopecia; the samples are preferably processed with horizontal sections.
TRICHOGRAM
This technique is a simple method of quantifying hair
loss by comparing the proportion of anagen to catagen
and telogen hairs. For accurate measurement, patients
should avoid washing their hair 34 days prior the
test. Also perms, dyes, or straightening of hair can alter
results and have to be avoided at least 6 weeks prior. A
group of about 2550 hairs should be grasped with a
needle holder close to the scalp and plucked sharply in
the direction of the hair. The proximal ends of the hair
shafts are place on a glass slide in a drop of water and
covered with a cover slip. Alternatively, a solution of 1%
dimethylcinnamaldehyde in 0.5 N hydrochloric acid
can be used, which stains the anagen hairs red due to
the presence of protein bound citrulline in the inner root
sheath. The roots are than examined by light microscopy with 100-fold magnification. Ten to twenty percent
of telogen hair can be regarded as normal (the percentage of anagen hairs is slightly higher in women and
children compared to men); a telogen count over 35% is
highly suspicious for a TE. By repeating the trichogram
over a time period, a hair loss condition can be followed
and treatment results can be measured28 (Fig. 88-1).
Investigation of plucked hairs for spores allows
establishing the diagnosis of tinea capitis. In this case
the hair should be mounted in 5% potassium hydroxide and gently heated.
ANDROGENETIC ALOPECIA
AGA or pattern hair loss is by far the most common
type of hair loss in men and women. Male pattern hair
15
Chapter 88
::
Figure 88-1 A. Telogen club hairs have a cornified, depigmented, rounded-up bulb without an attached root sheath.
B. Loose anagen hair obtained by hair pull: Ruffled cuticle and no attached root sheath. Anagen hairs are recognized clinically by their pigmented, somewhat distorted, malleable bulb. Anagen hairs should not normally be found in a hair pull
in patients with alopecia areata. C. Comparison with a normal anagen hair obtained by hair pluck. D. A newly growing
anagen hair has a tapered distal tip rather than the blunt distal end of hairs that have been cut or trimmed or ends that are
intrinsically broken. (From Ralf Paus, Elise A. Olsen, Andrew G. Messenger: Fitzpatricks Dermatology in General Medicine.
7th ed. Copyright The McGraw-Hill Companies, Inc. All rights reserved, with permission.)
ANDROGENETIC ALOPECIA (AGA)

AT A GLANCE
Most common form of human hair loss.
Presents as a nonscarring hair loss
condition under the influence of androgens
(dihydrotestosterone, DHT); androgen
susceptibility of the follicles plays an
important role.
Clinical characteristics include a reduction
of terminal hair density on the scalp that
follows a typical pattern in both genders,
with a conversion of terminal to vellus-like
hairs and an increase of telogen hair (in an
episode of active shedding).
Classification with gender-specific features
(NorwoodHamilton classification for men
and Ludwig classification in women) with
clinical overlap.
FDA approved therapeutic options are:
topical minoxidil 2% (women) and 5%
(men), oral finasteride 1 mg daily (men),
hair restoration surgery, and low laser light.
loss (MPHL) (also known as male AGA, male balding)

is an androgen-dependent, genetically determined
trait. Female pattern hair loss (FPHL) (or female androgenetic alopecia) is believed to be the same entity.
However, the requirement of androgens is less clearcut than in men and the distribution of hair loss is generally different.35,36 In both, men and women, AGA is
characterized by a progressive decline in the duration
of anagen, an increase in the duration of telogen and
miniaturization of scalp hair follicles.
EPIDEMIOLOGY
MEN
Estimates of the prevalence of AGA vary widely. Most
men will develop some degree of recession of the hairline during their lifetime. A progression to at least type
III (see Fig. 88-2) is seen in around 50% of men and
women beyond 40 years of age.3740,41 The risk of male
pattern baldness depends on the family history in the
father, the mother, or the maternal grandfather.42,43 Men
whose father had hair loss were twice as likely to have
hair loss as men whose father showed no hair loss.
Ethnic variation in the incidence of AGA has been
reported. AGA seems to be four times less frequent
in men of African ancestry,44 around three times less
frequent in Korean men45 and approximately 1.5 times
981
15
Section 15
Figure 88-2 Patient with male pattern hair loss, Norwood

Hamilton class III.
less frequent in men originating form China, Japan or

Thailand.46,47
WOMEN
FPHL is less common than MPHL but shows a similar
age-related increase in frequency and severity. However, the condition can start as early as the prepubertal
period both in men and women (Fig. 88-3). Around
40% of Caucasian women have developed some degree
of FPHL at age 70.35,48 FPHL seems to be less frequent
in Asian woman.45
The underlying causes of patterned hair loss have yet

to be determined. In men, MPHL appears to result from
a combination of androgen hyperactivity, a genetic
predisposition to hair loss-related sensitivity to androgen action as well as an androgen-independent genetic
predisposition. For females, the condition known as
female pattern hair loss (FPHL) may have a more complex etiology. However, androgen action combined
with genetic sensitivity to those actions seems to play
a dominant role in most cases, and indeed these factors
may be present generally in FPHL.
In AGA, large, pigmented hairs, called terminal
hairs, are gradually replaced by fine (nearly invisible)
colorless vellus hairs.1,39 This transformation follows a
progressive course with each hair cycle in the following manner. Scalp hair develops in three phases40,49:
(1) a growth phase, or anagen, of approximately 26
years; (2) a short (23 weeks) phase, catagen, which
actually represents the termination of anagen; and (3)
transition to the telogen phase. A telogen hair does not
grow and is shed from the follicle after about 12 weeks.
The transition to catagen results in decreased levels of
anagen-maintaining cytokines within the hair follicle.
MPHL and FPHL exhibit a progressive decrease in
anagen duration with each cycle, producing shorter,
thinner hairs.38 Finally, the interval between late telogen hair shedding (exogen) and new hair growth with
initiation of anagen increases, resulting in more follicles without hair and an apparent reduction in scalp
hair density.37
CLINICAL FINDINGS
982
Figure 88-3 Patient with female pattern hair loss, Ludwig

typ II.
The identification of AGA is usually not difficult if the

alopecia occurs in a classical clinical pattern. In 1951,
Hamilton produced the first grading scale for MPHL.
The Hamilton scale ranges from type I to VIII. Whereas
type I represents the prepubertal scalp with terminal
hair growth on the forehead and all over the scalp,
type II and III show gradual frontal mostly M-shaped
recession of the hairline, type IV, V and VI show additional gradual thinning in the vertex area, type VII
and VIII show a confluence of the balding areas and
leave hair only around the back and the sides of the
head.50,90 In 1975 Norwood modified the classification, and included variations on the middle grades III
a, IV a and V a, that show a more prominent gradual
receding of the middle portion of the frontal hairline
and type III vertex which is characterized by a loss of
hair mainly in the tonsure area and a frontotemporal
recession which never exceeds that of type III.91 (Fig.
88-4). In 1977, Ludwig introduced a classification for
pattern of AGA in women, characterized by a diffuse
loss of hair on the crown and persistence of the frontal hairline.92 In 1994, Olsen noted that women with
AGA did not necessarily present with diffuse hair loss
over the entire top but rather may have increasing hair
loss towards the front, called frontal accentuation or
Christmas tree pattern (Fig. 88-5). Women can also
Hamilton-Norwood classification of pattern hair loss in men
IV
II
IVa
IIa
IIIa
VII
III
Va
III vertex
VI
Chapter 88
15
::
Figure 88-4 HamiltonNorwood classification of pattern hair loss in men. (From Olsen EA: Female pattern hair loss. J Am
Acad Dermatol 45:S70, 2001.)
983
15
Pattern hair loss in women
Box 88-1 Androgenetic Alopecia

Telogen effluvium
Diffuse Alopecia areata
Trichotillomania
Secondary syphilis
Male pattern
(Hamilton)
Diffuse
(Ludwig)
Frontal accentuation
(Olsen)
Section 15
In women, a laboratory test for ferritin and thyrotrophin-stimulating hormone (TSH) are recommended to rule out sources for and underlying TE. An
extensive laboratory workup for androgens is not recommended for a routine visit. Women with irregular
periods and/or other signs of androgen excess should
be at least checked for free and total testosterone as
well as DHEA-S. The best time for the blood work is in
the morning of one of the days of her menstrual cycle.
She also must be off the pill for at least one cycle.
RISK FACTOR AND ASSOCIATION

WITH OTHER DISEASES
An increased risk of coronary heart disease and insulin
resistance has been correlated for early vertex balding,
especially in young men with hypertension, obesity, and
dyslipidemia.9395 Early vertex balding has also been
correlated with an increased risk of prostate cancer.96,97
B
Figure 88-5 Pattern hair loss in women. A. Different phenotypic expressions. B. Characteristic frontal accentuation
(widened hair part). (From Wolff K, Goldsmith LA, Katz SI,
Gichrest BA, Paller AS: Fitzpatricks Dermatology in General
Medicine. 7th ed. Copyright The McGraw-Hill Companies, Inc. All rights reserved, with permission.)
984
show a male pattern of distribution, as well as men can

show a more female pattern.1
A thorough scalp exam together with the patient history usually allows a definitive diagnosis.
Standardized global scalp photography, especially
of the part area, is very helpful as a qualitative assessment of the progression of the hair loss and as therapy
control. A pull test and a trichogram can give information on the ongoing activity of the condition. Videodermoscopy and phototrichogram techniques can be used
for therapy control.
The diagnosis can be more difficult if the hair loss
is more diffuse over the entire scalp or if it occurs
together with other hair loss conditions such as TE,
diffuse alopecia areata or mild forms of cicatricial alopecias. A scalp biopsy allows a definitive diagnosis,
since it provides information on histological features,
the number of terminal and vellus hair per area and
the number of anagen and telogen hair.
(Box 88-1)
TREATMENT
AGA is a progressive condition with a decrease in hair
density of approximately 6% of hair fiber per year.40
However, increased shedding can occur periodically
and the extent of hair loss depends on the genetic predisposition. Currently two pharmaceutical treatments
are approved for the therapy of AGA in men: oral finasteride and topical minoxidil.
MINOXIDIL
Minoxidil is a biologic response modifier, which has
been shown to halt AGA in many patients and regrow
hair to a certain extent. Minoxidil, a piperidinopyrimidine derivative, was noted to cause hypertrichosis when administered orally as an antihypertensive.
It is now used as a 2% and a 5% topical treatment in a
lotion or foam preparation.
The mechanism of action is not fully understood. A
direct effect on the hair follicle cells may be responsible
for the effects of minoxidil. It has been shown to have a
mitogenic effect on epidermal cells leading to prolonged
survival time and induced increased proliferation
Finasteride is a synthetic azo-steroid that has been used

for the treatment of AGA in men since 1997. It is a potent
and highly sensitive selective 5-reductase type-2
inhibitor.59 It binds irreversibly to the 5-reductase isoenzyme 2 and inhibits the conversion of testosterone
to DHT. Finasteride has a pharmacological half-life of
around 8 hours. The administration of 1 mg finasteride daily reduces the concentration of DHT in scalp
skin by 64%, serum DHT is reduced by 68%.59 The
15
::
FINASTERIDE
dose response curve is nonlinear and therefore higher

doses do not lead to significantly increased suppression of DHT or greater clinical benefits.103 In placebocontrolled studies, a significant hair count increase
in men with vertex alopecia or frontal AGA could be
shown after 6 and 12 months.104,105 Finasteride stabilizes
hair loss in 80% of patients with vertex hair loss and 70%
of patients with frontal hair loss. The chance of mild
to moderate regrowth is 61% on the vertex and 37%
on the frontal scalp.106 After 24 months of continuous
use, 66% of the patients experienced a certain amount
of hair regrowth in the vertex area (approximately
10%25% of the hair the patient lost previously).107
Most of the patient showed no further hair loss and
only a few patients continued to lose hair. Continued
use beyond 2 years does not promote continued hair
regrowth. Instead the hair density stabilizes with the
retention of the newly acquired hair.107 If successful,
the treatment should be continued indefinitely because
the balding process continues once treatment ceases.38
Finasteride was found to be well tolerated with side
effects occurring in fewer than 2% of patients. The side
effects included decreased libido in 1.8% of the recipients versus 1.3% in the placebo group, erectile dysfunction in 1.3% of the recipients versus 0.7% in the placebo
group and decreased ejaculate volume in 0.8% of the
recipients versus 0.4% in the placebo group.108,109 Finasteride 1 mg daily does not affect spermatogenesis or
semen production in men aged 1941 years of age.110
The effect on prostate volume and serum prostate specific antigen (PSA) in younger men was small and reversible after discontinuation of the drug.110 Finasteride can
decrease PSA levels by 50% in older men.111 Therefore a
baseline PSA should be taken in men over 40 and the
family doctor should be advised to double the PSA value
while patients are taking finasteride.106 Long term side
effects of 1 mg finasteride daily are yet unknown. A placebo controlled study over 7 years carried out in 9,060
men 55 years of age or older, taking 5mg finasteride
per day or placebo, showed that finasteride prevents or
delays the appearance of prostate cancer, but a slightly
higher risk of high-grade prostate cancer.
Finasteride is not approved for the use in women and
its efficacy in FPHL is still controversial. A multicenter
double-blind, placebo-controlled, randomized study
of finasteride 1 mg/day in postmenopausal women
with FPHL showed no differences in anagen:telogen
ratio and the terminal hair:miniaturized hair ratio.
However, Camacho et al reported hair regrowth using
finasteride 2.5 mg/day in 41 women with FPHL and
SAHA (seborrhea, acne, hirsutism, and alopecia).39,49
Chapter 88
of hair follicles in vitro.98100 A possible mechanism of

action involves a change in calcium homeostasis of cells,
as minoxidil is converted to minoxidil sulfate, a potassium channel agonist. Increased potassium channel permeability leads to impaired entry of calcium into cells,
thus decreasing epidermal growth factors and enhancing hair growth.101
Several clinical trial have shows the efficacy of topical
minoxidil. An increase in hair counts probably reflects
reversal of miniaturized hairs to thicker, more highly
visible terminal hairs. Although studies have been performed on the vertex scalp, the drug also works on the
frontal scalp, especially if hairs have not completely
miniaturized to vellus-like hairs. Moderate to dense
regrowth could be seen in up 30%45% of patients.41
Some patients experience an increased shedding in the
first 46 weeks of application. This positive sign seems
to indicate anagen induction with earlier molting
of telogen hairs from the follicles. The patient should
be educated and prepared for this possible side effect
to improve compliance. Observed side effects include
contact dermatitis in 6.5% of patients and facial hypertrichosis in 3%5% of women.102 Most patients do not
have a true contact allergy to minoxidil but an irritation from propylene glycol. The 2% lotion with less
propylene glycol, other vehicles with butylene glycol
or the foam may then be used. To discriminate, which
component causes the dermatitis, a patch test or testing the product on the volar forearm (repeated open
application test) may be helpful.
Only minimal amounts of minoxidil are systemically
absorbed and serum levels are too low to have hemodynamic effects in normotensive or hypertensive patients.
Nevertheless, less than one in thousand patients may
experience tachycardia and decreased blood pressure.
Patients with hypotension or heart problems should be
cautious and use the medication with approval from
their cardiologist. The cardiac effects suggested in earlier studies could not definitely be linked to minoxidil
and may be due to increased incidence of coronary
artery disease in subsets of men with AGA.93
Topical minoxidil solution is used twice daily (1ml
or 25 drops bid). It is also available in a 5% foam. If the
hair has been shampooed, the hair and scalp should be
at least towel-dry. The lotion or foam should stay on
the scalp for at least 4 hours before the next shampoo.
The patient should be informed that this is a lifelong
treatment. It takes 46 months before the medication
starts working and that the maximum effect can be
expected after 1 year.
DUTASTERIDE
Dutasteride is an inhibitor of type I and II 5-reductase.
It is approved at a dose of 0.5 mg daily for the treatment of symptomatic benign prostatic hyperplasia.
Some studies have shown great efficacy in the treatment of MPHL and FPHL.112115 However, dutasteride
is not FDA approved for use in androgenetic alopecia.
More studies are necessary for the evaluation of the
safety profile of this drug.
985
15
CYPROTERONE ACETATE
Section 15
The antiandrogen cyproterone acetate (CPA) is a synthetic derivative of 17-hydroxyprogesterone. It acts as an

AR antagonist with weak progestational and glucocorticoid activity.62 It also inhibits the steroidogenic enzyme
21-hydroxylase, reducing the production of aldosterone
and to a lesser extent 3--hydroxysteroid dehydrogenase, both of which are needed to synthesize cortisol.
CPA is available in Europe, Canada and South America.
It is usually combined with ethinyl estradiol as a birth
control pill. CPA is not approved by the FDA for the
treatment of AGA. For the treatment of FPHL a regimen
with 100 mg CPA daily on days 515 of the menstrual
cycle and 50 g of ethinyl estradiol on days 525 or
50 mg CPA daily on days 110 of the cycle and 35 g of
ethinyl estradiol on days 121 have been suggested.116
In a randomized 12 months clinical trial in 66 women,
33 women with FPHL used topical minoxidil 2%
plus combined oral contraceptive whereas 33 women
received CPA 52 mg daily plus ethinyl estradiol 35 g
for 20 days of the cycle. The later combination result in
greater hair density in women with hyperandrogenism.117 Side effects from CPA are irregular menstrual
cycles, weight gain, breast tenderness, loss of libido,
depression, nausea. Since CPA is an antiandrogen, its
use in men is obsolete, unless a gender change is desired.
SPIRONOLACTONE
Spironolactone is a synthetic 17-lactone drug, which is
a renal competitive aldosterone antagonist with a mild
antiandrogenic effect by blocking the AR and preventing its interaction with DHT. The maximum androgen
suppression is reached after 412 months; dosages of
200 mg daily are required. Spironolactone may have a
preventative effect in FPHL and may reduce shedding
in individuals without hyperandrogenism.118 However,
Spironolactone is not approved by the FDA for the treatment of FPHL and, sd sn antiandrogen, should not be
used in men. The main side effect is menstrual irregularities, which may be mitigated by decreasing the dose
to 5075 mg/day and adding oral contraceptives or
after 23 months of therapy. Spironolactone is contraindicated in patients with renal insufficiency, hyperkalemia, pregnancy, abnormal uterine bleeding, and women
with genetic predisposition of breast cancer.116,118
17a- AND 17b-ESTRADIOL
986
In Europe topical 17- or 17-estradiol are commercially available for the treatment of FPHL. Studies
showed an increased in anagen and decreased telogen
rates after topical treatment compared with placebo
treatment.119 The underlying pathways of 17-estradiol
induced hair regrowth are unknown. Niiyama et
al showed that 17-estradiol is able to diminish the
amount of DHT formed by human hair follicles after
incubation with testosterone while increasing the
concentration of weaker steroids.119,120 Recently, it has
been shown that hair follicles in women with FPHL

express more aromatase activity as compared to male
hair follicles. Under the influence of 17-estradiol, an
increased conversion of testosterone to 17-estradiol
and androstenedione to estrone takes place in hair follicles derived from the occiput, which might explain
the beneficial effects of estrogen treatment in FPHL.
Woman who were taking aromatase inhibitors were
shown to develop FPHL more rapidly.121 Another theory about the effectiveness of estradiol is the systemic
induction of SHBG and therefore the reduction of free,
bioavailable testosterone.63 Since estradiol is absorbed
through the scalp skin, systemic side effects must be
considered, and it cannot be used in men.
LOW-LEVEL LIGHT THERAPY

Laser sources have become very popular in medical
and nonmedical areas. Manufacturers and suppliers
often guarantee hair regrowth and various devices are
available without prescription. The only FDA approved
low-fluence laser light device is the Hair Max Laser
Comb (Lexington international, LLC, Boca Raton, FL,
United States of America) (FDA approval as a medical device). Paradoxical hair growth has occurred in
patients undergoing laser hair removal when relatively low energy fluences were used. The mechanism
of action of this phenomenon is unknown. One theory suggests an increase in blood flow in the dermal
papilla.122124 Low-level laser light sources appear to be
safe to use in the treatment of hair loss. More studies
are necessary to understand the mechanism of action
and to evaluate the efficacy of these devices.
HAIR RESTORATION SURGERY

Hair restoration is the most successful and permanent treatment for AGA in suitable candidates. It
includes hair transplantation (HT) and, in skillful
hands, scalp-reduction surgery. Suitable candidates
for HT are those with reasonable expectations, a donor
supply that is adequate to cosmetically improve the
recipient area coverage and those without contraindications for surgery. The most dramatic change in cosmetic appearance is achieved in patients with stages
HamiltonNorwood VI and VII, and in patients with
anterior accentuation of balding (subtypes IIIa and
IVa, Christmas tree pattern).
With recent advancements in technique and combination with medical treatment, more patients may
benefit from the surgical option. Larger numbers
of smaller grafts are moved per session, and results
have thus become very natural.125,126 It is possible and
advisable to distribute small grafts in between preexisting hairs and thus account for future hair loss.
Rational use of the donor area with strip harvesting or
FU extraction makes several sessions possible in many
patients if they experience progressive hair loss.
HT is based on the principle of donor dominance
as shown by androgen-independent follicles retaining their properties when they are transplanted into
DIFFUSE HAIR LOSS

GENETIC
HYPOTRICHOSIS SIMPLEX. Hypotrichosis simplex is characterized by progressive global loss of scalp
hair starting during childhood. This autosomal dominant disorder affects both sexes equally; eyebrows and
body hair is unaffected by the condition. The pathogenesis is of hypotrichosis simplex is not fully understood. In two families with hypotrichosis simplex, a
gene defect in the corneodesmosin gene (adhesin protein) was found84,127 (Fig. 88-8).
REDUCED OR ABSENT HAIR GROWTH
ASSOCIATED WITH ECTODERMAL
DYSPLASIA
A failure in normal follicle development in utero can
results in a reduction or absence of hair follicles. These
developmental disorders are often associated with
Norwood-Hamilton
stage Va, VI, VII
Oral finasterid or/and

topical minoxidil
solution and/or
low fluence laser
light for 1 year
Hair transplantation
scalp reduction
and/or
Finesterid
Topical minoxidil
Low fluence laser light
Hair piece
Improvement or
stabilization
YES
Continue
medical
therapy
indefinitely
NO
Hair
transplantation
scalp reduction
Figure 88-6 An algorithmic approach on the treatment of

male pattern hair loss.
ectodermal defects. These hereditary syndromes, most
frequently show abnormalities of bones, central nervous system, teeth or eyes (see Chapter 142). The most
common ectodermal dysplasia, hypohidrotic ectodermal dysplasia, which is characterized by sparse hair,
Scalp prostheses are practical for patients who are not

candidates for hair restoration surgery, women with
extensive hair loss and/or patients without satisfying improvement after using medical therapy. Wigs
and hairpieces can provide excellent cosmetic results,
especially when they are custom made. It is usually
easier to overcome the reluctance to wear a scalp prosthesis if the hair piece blends in nicely with the preexisting hair and is comfortable to wear. Women tend to
be less reluctant to wear a wig or hairpiece, especially
if the patient is exposing her natural hairline (Figs.
88-6 and 88-7).
Norwood-Hamilton
stage III-V
15
::
WIGS AND HAIRPIECES
Algorithmic approach on the treatment of

male pattern hair loss
Chapter 88
androgen-dependent areas. The donor supply is limited by the area of the strip (size of the safe zone,
scalp elasticity) and the density of donor hair.
HT is an outpatient procedure and may take up to
10 hours, depending on various factors, especially the
number of grafts. Tumescence anesthesia is used for
the donor and recipient areas, sometimes combined
with nerve blocks. The most commonly used technique is strip harvesting. It allows for a relatively fast
removal of large numbers of hairs leaving a fine line as
a scar, which can be minimized with special harvesting
and wound closure techniques. The strip is dissected
into FUs (families of hairs growing together in one
connective tissue sheath) under magnification these
grafts are then carefully and strategically placed in the
balding areas. The recipient side is prepared with small
needles or spears, according to the size of the graft. A
recent technique involves separately harvesting individual FUs using very small blunt punches (follicular
unit extraction (FUE). This procedure is usually more
time consuming but avoid a long scar in the occipital
area. Follicular unit extraction is indicated in patients
who desire to wear a very short hairstyle.
Algorithmic approach on the treatment of

female pattern hair loss
Ludwig stage I-II
Ludwig stage III
Topical minoxidil
solution for 1 year
Endocrine work up
Improvement or
stabilization
Hair piece and/or

Antiandrogens/
finesterid
YES
Continue
topical
minoxidil
indefinitely
NO
Occipital donor
area
YES
Hair transplantation
and/or
Antiandrogens/
finesterid
NO
Hair piece
and/or
Antiandrogens/
finesterid
Figure 88-7 An algorithmic approach on the treatment of

male pattern hair loss.
987
15
Section 15
Figure 88-8 Hypotrichosis simplex in a 35-year-old woman.
abnormal teeth and reduced or absent sweating, is

due to a mutation in the ectodysplasin signaling
pathway.128 This pathway is involved in the early
embryogenic formation of the hair follicle.129131 Ectodermal dysplasias with hair disorders are discussed
in Chapter 142.
ATRICHIA WITH PAPULAR LESIONS

Atrichia with papular lesions is an autosomal dominant hair disorder that presents in infancy. Hair is usually present at birth but alopecia develops within the
first year of life. Several years after the development of
alopecia, papular follicular cysts often appear.132 Mutations either in the hairless gene or the gene encoding
the vitamin D receptor can lead to this phenotype. Hair
follicle formation in utero appears to be normal, but
massive apoptosis in the hair bulb during the first catagen phase leads to a separation of the dermal papilla
from the base of the hair follicle and consequent failure to reenter anagen. The follicular epithelium than
undergoes a cystic change. If universal hair loss occurs
during the first month of life, atrichia with popular
lesions and alopecia areata universalis should be considered as differential diagnosis. If universal alopecia
is seen in the family, gene testing and genetic counseling should be considered.
slowly and can be pulled out without pain. Hair density can appear normal or reduced and some children
may display demarcated areas of incomplete alopecia.
The typical patient with loose anagen hair syndrome is
25 years of age. The condition more frequently affects
girls and hair is most often light blond. The hair loss
tends to get better without any treatment once the
child grows older. Microscopic examination of gently
pulled hair can make the diagnosis; 80%100% of the
hairs are anagen hairs with a ruffled cuticle and no
inner root sheath. However, the hair loss can cycle, and
it may be hard to gather enough hair with a gentle pull,
necessitating collection by the parent at home and later
microscopic evaluation. Loose anagen hair syndrome
can be familial, sporadic or associated with other
developmental defects such as Noonan syndrome or
hypohidrotic ectodermal hyperplasia.133 It is also seen
in association with HIV.134 Hair shaft abnormalities,
alopecia areata and trichotillomania have to be considered in the differential diagnosis. (See Fig. 88-9.)
TELOGEN EFFLUVIUM
EPIDEMIOLOGY
The second most common cause of hair loss in women
after FPHL is TE. The latter presents as a nonpatterned
increase in shedding of terminal hairs, diffusely over
the entire scalp, and can produce an apparent thinning
of hair in severe cases.135 While both genders can experience TE, attitudes toward hair loss result in a greater
proportion of females who complain. TE can copresent with AGA, particularly in early-onset situations,
and this can complicate diagnosis and treatment. TE
differs from AGA in that it is not androgen-sensitive,
SHORT ANAGEN SYNDROME

The term short anagen hair syndrome applies to a
poorly understood clinical presentation of short fine
hair in children.87 The hair fails to grow long due to a
shortened anagen phase. Hair density and hair shafts
seem to be normal. The condition may improve after
puberty. Short anagen hair can be inherited autosomal
dominant or can occur sporadically.
LOOSE ANAGEN SYNDROME

988
Loose anagen syndrome is characterized by an easy

epilation of anagen hair. The hair appears to grow
Figure 88-9 Loose anagen hair syndrome with diffuse

hair loss. (From Olsen EA et al: The presence of loose
anagen hairs obtained by hair pull in the normal population. J Investig Dermatol Symp Proc 4:258, 1999, with
permission.)
does not appear to be inherited and, since it does not

involve a terminal- to vellus-hair transition, does
not decrease matrix cell volumes or hair shaft diameters.136 TE also tends to be related to external causes
and is often reversed when the exogenous stimuli are
removed.
ACUTE TELOGEN EFFLUVIUM

ACUTE TELOGEN EFFLUVIUM
AT A GLANCE
Sudden conversion of large numbers of

actively growing anagen to telogen hair
leads to diffuse hair shedding.
ETIOLOGY AND PATHOGENESIS. The pathophysiology underlying TE is best characterized as a

premature shift of hairs from the anagen (growth)
phase into the catagen (resting) and telogen (terminal) phases. However, there are variants: anagen may
be prolonged, or telogen may instead be shortened or
prolonged. Which type of shift occurs depends on the
stimulus producing the shift, with the main clinical difference being the latency of effluvial onset following
the stimulus.
The hair loss that commonly occurs following
pregnancy is generally seen 2 or 3 months postpartum, although some individuals can exhibit longer
times to onset. While this is classic TE, the mechanism has been shown to involve a delayed transition
from anagen to catagen/telogen, which results in a
simultaneous shedding of large numbers of terminal
hairs.137 This hair does eventually regrow; however,
the returning hair may show changes in texture, color
and curliness, and may not attain its previous length.
As such, pregnancy (parturition or abortion) may in
some cases produce permanent changes in anagen
length.136
Other perturbations can produce TE, usually involving premature termination of the anagen phase. Some
women experience transient TE 23 months after discontinuing or changing oral contraceptive medication;
the delayed onset of TE in these cases distinguishes it
from the anagen effluvium (AE) initiated by certain
drugs (see below). In the 1970s, the popularity of fad
crash diets resulted in many cases TE about 3 months
after initiation of these spartan regimens, depending
on the severity of weight loss. Sudden deprivation of
Reversible once the initiating factor is

eliminated.
CLINICAL FINDINGS. TE is characterized by a

fairly sudden onset of massive shedding. Anagen hairs
are prematurely shifted into telogen hairs and the normal anagen/telogen ratio of 90:10 can switch to 70:10.
Women often present with the bag sign: bringing in
bags with hair that they have collected every day or
over a couple of days (Fig. 88-10). More than 300 telogen hairs can be shed every day. The global examination of the scalp may show a reduction in hair density
especially in the temporal area. The pull test is usually
positive (3 or more hairs can be pulled out on different
parts of the scalp). A trichogram or phototrichogram
can be use to quantify the amount of telogen hair. A
scalp biopsy may be helpful to distinguish the condition from diffuse alopecia areata or AGA.
::
Seen after severe illness, surgery, nutritional

deficiency, iron deficiency, childbirth, in
association with medications and in patients
with thyroid disease.
15
Chapter 88
Nonscarring alopecia.
amino acids and other dietary factors most likely produced the condition, and the hair tended to regrow
following cessation of the diets.136 Surgical procedures,
psychological traumas, and febrile illness have all been
reported to produce TE events.
Drugs are widely reported to produce temporary
hair loss. This is usually, but not necessarily, of the AE
variety, since, depending on the causal agent, the time
course and severity may suggest a diagnosis of TE to be
appropriate. Agents producing TE include cimetidine,
enalapril and captopril, imiquimod, metoprolol and
propranolol,138141 lithium,142 l-dopa143 trimethadione,144
and bromocriptine.145 The hair loss from administration
of etretinate146 and isotretinoin are problems, more of
the AE, as is hair loss that sometimes follows renal dialysis, possibly with hypervitaminosis A.136 Finally, hair
loss occurring following environmental contamination or poisoning, for example with selenium, arsenic,
thallium, mercury, and lead, displays an AE-like rapid
onset, probably involving a cytotoxicity mechanism.
CHRONIC TELOGEN EFFLUVIUM

ETIOLOGY AND PATHOGENESIS. Chronic Telogen Effluvium (CTE) was first proposed in 1996 as a
means of distinguishing the abrupt-onset, short-acting
Figure 88-10 Diffuse thinning in a female patient with

acute telogen effluvium.
989
15
Box 88-2 Causes of Telogen

Effluvium
Endocrine
Childbirth, miscarriage, abortion
Hypo- and hyperthyroidism
Discontinuation of estrogen-containing drugs
Stressful events
Febrile illnesses
Section 15
Catabolic illnesses (e.g., malignancy, consumptive chronic infection)

Major surgery
Major trauma
Acute or chronic psychological stress
Nutritional
Rapid weight loss (e.g., crash dieting)
Caloric or protein deprivation
Chronic iron deficiency
Excessive vitamin A ingestion
Intoxication
Thallium
Mercury
Arsenic
Drugs
Anticoagulants (including heparin)
Blockers (propanolol)
Captopril
Cholesterol-lowering drugs
Colchicine
type TE, usually caused be exogenous triggers or parturition, from a more durable condition (CTE) that may
not be so clearly related to any external event.147
A few conditions have been proposed to be underlying stimuli for CTE. While crash diets have been
pinpointed as potential triggers for acute TE, chronic
malnutrition can analogously lead to CTE. Protein
deficiency is the likely mechanism in this type of balding. It is less clear whether zinc148 or biotin deficiencies are also correlated with chronic diffuse hair loss.
Although controversial, iron deficiency, as evidenced
by decreased serum ferritin and anemia, may be a trigger for CTE.27,149,150,151 Hypothyroidism has also been
associated with CTE (Box 88-2).
990
CLINICAL FINDINGS. CTE can most commonly be

seen in women. Patients report ongoing massive shedding or recurrent episodes of shedding. As a rule of
thumb, any diffuse hair shedding lasting longer than 6
months after any triggering event, or after withdrawal
from suspected causal drugs, should be considered
CTE. The clinical examination can show a normal or
reduced hair density. Regrowth of tapered new anagen hair can usually be found. The pull test may be
moderately positive. A trichogram or phototrichogram
can be used to confirm and quantify the diagnosis. A
scalp biopsy is very helpful for the confirmation of the
diagnosis and to distinguish the condition other forms
Box 88-3 Acute Telogen Effluvium


Androgenetic alopecia
Diffuse Alopecia areata
Trichotillomania
Anagen effluvium
Secondary syphilis
of alopecia. Since other types of hair loss disorders,

chiefly FPHL/MPHL and alopecia areata, may copresent with TE and CTE, clinicians may be advised to
assay serum iron and thyroid hormone concentrations
in order to eliminate iron deficiency and hypothyroidism as treatable causes for the patients baldness.152
DIFFERENTIAL DIAGNOSIS. (Box 88-3)

PROGNOSIS AND CLINICAL COURSE. Both
acute and CTE usually resolve once trigger factors are
eliminated. However, in CTE triggers may be difficult
to identify. Women with TE are often most concerned
about complete baldness. The patient has to be reassured that the condition does not lead to complete
baldness and that the hair likely grows back around
6 months after removal of the initiating trigger. The
patient should understand that the condition is reversible, but that the shedding may persist for a few weeks
or months once the initiation factor is eliminated.
TREATMENT
The removal of the cause is the major goal in the treatment of TE. Iron supplementation is recommended if
the ferritin level is less than 70 ng/mL.150,153 Borderline
hypothyroidism can be difficult to identify. Women,
who complain about hair loss, depression, lack of
energy, mental fatigue, cold intolerance, weight gain
or/and constipation are suspicious for the diagnosis
of hypothyroidism. TSH levels may fluctuate but are
usually elevated, with normal or reduced thyroid hormone levels. If a thyroid dysfunction is suspected, the
patient should be closely followed by an endocrinologist. Topical 2% or 5% minoxidil solution 1 mL twice
daily can be helpful, especially in women with prolonged hair loss with unknown triggers or in patients
with drug related hair loss who are unable to discontinue the initiating medication.
ANAGEN EFFLUVIUM
AE is a result of a disturbance of hair follicle matrix
cells. The anagen phase is interrupted and the hair
falls out 714 days after the initiating event without
entering catagen or telogen. Two different types of
AE can be distinguished: Dystrophic AE and Immediate anagen release. Dystrophic AE can be caused by
Nonscarring hair disorder.

Occurs in both genders equally and can
affect every age group, although incidence at
younger age is higher.
Most common form of hair loss in children.
Clinically presents with well-demarcated
round or oval bald spots on the scalp or
other parts of the body.
5% develop hair loss of their entire scalp hair
(alopecia areata totalis), 1% develop alopecia
areata universalis (loss of total body hair).
Nail changes include pitting or sandpaper
nails.
Thought to be an autoimmune disease with a
possible heredity component.
Usually without associated disorders, but
can coexist with other autoimmune disorders
such as Hashimoto thyroiditis or vitiligo.
ALOPECIA AREATA
EPIDEMIOLOGY. At any given time, approximately
0.2% of the world population is suffering from alopecia areata with an estimated lifetime risk of 1.7%.154,155
CLINICAL FINDINGS. Alopecia areata is characterized by an acute onset. It typically presents with
oval or round, well-circumscribed, bald patches with
a smooth surface in a diffuse distribution (Fig. 88-11).
Alopecia totalis results in the loss of the entire scalp
hair and may occur suddenly or follow partial alopecia (Fig. 88-12). Partial alopecia may be observed in
other areas of the body as well. Loss of total body hair
is called alopecia universalis and may also occur suddenly or follow of long-standing partial alopecia.
Characteristic hallmarks of alopecia areata are black
dots (cadaver hairs, point noir), resulting from hair
that breaks before it reaches the skin surface. Exclamation point hairs, with a blunt distal end and taper
proximally, appear when the broken hairs (black dots)
are pushed out of the follicle. Localization of the initial
patch is most frequently on the scalp, but may occur on
ALOPECIA AREATA AT A GLANCE
ETIOLOGY AND PATHOGENESIS. Alopecia

areata is a chronic, organ-specific autoimmune disease,
mediated by autoreactive CD8+ T-cells, which affects
hair follicles and sometimes nails.156159 Alopecia areata
is thought to be an autoimmune disease with inappropriate immune- response to hair follicle associated
antigens. A collapse of the normal immune privilege of
the anagen hairbulb, probably induced by interferon-,
may play a key role in the pathogenesis of this
disease.156,159 Melanogenesis-associated autoantigens,
which are normally sequestered from immune recognition by a functional hair follicle immune privilege,
may be one key target of autoaggressive inflammation
in alopecia areata.160 There is a high frequency of a positive family history of alopecia areata in affected individuals, ranging from 10% up to 42% of cases,161 and
a much higher incidence of a positive family history
in early onset alopecia areata.162 Many patients report
the experience of major emotional stress prior to the
onset of alopecia. A genome-wide association studies
recently showed several loci linked to alopecia areata
containing genes controlling both innate and acquired
immunity, as well as genes expressed in the hair follicle itself.163
Histologically, alopecia areata is characterized by an
inflammatory infiltrate, comprised mainly of T-cells,
in and around the bulbs of anagen hair follicles
(swam of bees). However, the classic inflammatory
infiltrate may be missing in subacute or chronic forms.
Alopecia areata should be in the differential diagnosis
whenever high percentages of telogen hairs or miniaturized hairs are present, even in the absence of peribulbar inflammation.
15
::
NONSCARRING FOCAL HAIR LOSS
It is a common cause of abrupt-onset hair loss, but

occurs less frequent than androgenic alopecia or TE.
Both sexes are affected equally. Although it may occur
at any age, incidence at younger age is higher. Alopecia areata is the most common form of alopecia seen
in children. The familial occurrence is around 15% but
expression of the disorder is variable among different
family members. 5% of patients suffering from alopecia areata develop hair loss of their entire scalp hair
(alopecia totalis), and 1% of patients develop loss of
total body hair (alopecia universalis) at some point.
Chapter 88
chemotherapy, radiation, toxins or alopecia areata.

Microscopic investigation of the hair bulbs, obtained
from a hair pull test or trichogram, usually shows a
tapered tip with the weakened hair shaft broken
shortly above the bulb (dystrophic hair).1
Drugs used in chemotherapy quickly produce
severe hair loss and even total baldness. A rapid onset
undoubtedly indicates an immediate release from anagen hair. Immediate anagen hair release is characterized
by an easy release of anagen hairs after gentle pulling.
The anagen hair has a broom-shaped, pigmented bulb.
Therapeutic agents that can cause immediate anagen
hair shedding include vincristine, vinblastine, methotrexate, doxorubicin, and fluorouracil.
Normal appearing anagen hair with inner and outer
root sheath can be found to some extent in every AE,
but especially in bullous dermatosis of the scalp with
sub- or intraepidermal blisters.
Once the initiating trigger is removed, the hair usually regrows after around 120 days. Cases of incomplete recovery following multiagent chemotherapy
have been reported.1 Patients should be advised about
scalp prostheses and other forms of head covering.
991
15
Box 88-4 NonScarring Focal Hair

Loss Differential Diagnosis

Section 15
992
Figure 88-11 Patient with patchy alopecia areata.

any hair-bearing part of the body. Patches are usually
without further symptoms, but may show mild itching and erythema in some cases. Alopecia areata can
less commonly present in a diffuse generalized pattern that resembles androgenic alopecia or TE. In the
acute stages, gentle pulling from the periphery of bald
areas will yield more than 10 hairs. Involvement of
nails is common with nail pitting and a sandpaper-like
appearance. The disease has been described in association with a variety of other disorders, such as cataracts,
thyroid disease, vitiligo, atopic dermatitis, psoriasis,
and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), CronkhiteCanada,
and Down syndromes.164,165
Clinical features, such as shape and look of the
patches, presents of exclamation point hair, nail changes
(pitting or sandpaper nails) lead to the diagnosis of alopecia areata. In most patients the physical findings are
Figure 88-12 Patient with alopecia areata totalis showing

some regrowth of fine hair.
Temporal triangular alopecia

Tinea capitis
Early scarring alopecia
Trichotillomania
Secondary syphilis (alopecia areolaris)
Androgenetic alopecia
Telogen effluvium
Anagen effluvium
so characteristic that the diagnosis is obvious. Moreover, positive family history and/or the presence of
associated diseases may give further evidence in cases
of doubt. Scalp biopsy reveals a generalized miniaturization and a marked increase in catagen and telogen
hair follicles. In the acute phase, a peribulbar lymphocytic infiltrate, which has been described as a swarm
of bees may be found. Sometimes mast cell, plasma
cells and eosinophils can also be seen. Laboratory tests
to rule out thyroid dysfunction should be performed.

COMPLICATIONS. A relapsing course and progression of hair loss to severe forms of alopecia totalis or universalis are dreaded complications. Missing
hair on the scalp and face, including nasal hair and eye
lashes/brows can increase the incidence of sunburn
and skin cancer, as well as nasopharyngeal and ophthalmologic inflammation. Although the condition is
not life threatening, changes in appearance frequently
cause a diminished sense of personal well-being and
self-esteem, leading to severe depression and withdrawal from social situations.
PROGNOSIS AND CLINICAL COURSE. The
course of the disease is very variable and characterized
by an irregular relapsing course, with about 25% of
affected individuals having a solitary episode. Spontaneous regrowth of hair is common. Different body
areas appear to regrowth independently. About 60%
of patients have at least a partial regrowth by 1 year,
but this is often followed by repeated episodes of hair
loss. About 40% of the relapses occur within the first
year, but a large percentage of patients may relapse
after 5 years. Hair can regrow white but may change
to the patients natural color over time. Poor prognosis
is linked to involvement of the occiput and/or hairline (called the ophiasis pattern if sweeping around
the periphery of the scalp), a chronic relapsing course,
the presence of nail changes, and onset during childhood.166168 The number of patients progressing to alopecia totalis also higher in patients with hair loss from
the trunk and extremities.
TREATMENT. Very little evidence-based data
is available for the treatment of alopecia areata;
15
Treatment algorithm for alopecia areata

Alopecia areata
age < 10
Minoxidil 5% solution
short contact anthralin or

topical corticosteroid
Age
Scalp prostheses should be

considered in patients with
> 50% scalp involvement
age > 10
< 50%
involvement
Extent of scalp
involvement
Topical immunotherapy
DPCP / SADBE / DNCB
Poor
Response
Good
::
Continue topical
immunotherapy pm
PUVA
Figure 88-13 Treatment algorithm for alopecia areata. (Copyright by Jerry Shapiro, Vera Price and Harvey Lui).
recommendations are mainly based on case series and

clinical experience. At this time all available treatments
for alopecia areata are palliative, only controlling the
ongoing episode of hair loss and not curing the condition itself. However, helpful treatment guidelines have
been published.166168 Fig. 88-13 shows an algorithm
for treating alopecia areata based on age and scalp
involvement.
CONSERVATIVE MANAGEMENT. Alopecia

areata shows a high rate of spontaneous remission,
especially in those patients with a short history and
limited scalp involvement. On the other hand, in alopecia totalis and universalis, treatments have a high
failure rate. After the discussion of possible risks and
benefits of all options, no treatment may be a legitimate option for some patients.
Topical Corticosteroids.
Superpotent (class I)
and potent (class II) topical corticosteroids are widely
used to treat alopecia areata. Evidence of efficacy has
been proven for class I corticosteroids when applied
under occlusion169 and for class II corticosteroids when
used in combination with minoxidil.170
Intralesional
corticosteroid (triamcinolone acetonide or triamcinolone hexacetonide) injection is first line therapy for
adult patients with less than 50% scalp involvement.
Triamcinolone acetonide is used at concentrations
from 2.510 mg/mL. Treatment are repeated every 4
to 6 weeks, and the total amount injected per session
Minoxidil 5% solution
short contact anthralin or

Intralesional Corticosteroids.
Chapter 88
Intraiesional corticosteroids
minoxidil 5% solution
short contact anthralin
> 50%
involvement
varies from 1540 mg.109,166168,171 An initial response is

often seen after 48 weeks. Some patients experience
indentation of the scalp skin in the injection sites due
to a nonpermanent atrophy of the subcutaneous fat.
Permanent skin atrophy can occur if the same skin
area is injected repeatedly over months and years. If
no regrowth can be seen after 4 months of treatment,
other treatment options should be considered. Intralesional corticosteroids injections are usually used on the
scalp, eyebrows and beard area and can be combined
with topical treatment.
Systemic Corticosteroids. Systemic corticosteroids are effective in the treatment of alopecia areata.
However, the regrown hair frequently falls out again
when the treatment is discontinued. The use of systemic corticosteroids is controversial and largely used
on a short-term basis with rapidly advancing hair
loss. They should not be used as routine treatments
because they do not alter the long-term prognosis
and can cause side effects such as striae, acne, obesity, cataracts and hypertension. Dosages vary from
initial 2040 mg prednisone daily tapered down to
5 mg daily in a few weeks or different pulse therapies regiments with short-term high doses of oral
prednisolone (100300 mg) or i.v. methylprednisolone
(250 mg).109,166168
Topical Minoxidil. There is some evidence of clini-
cally acceptable hair regrowth using topical minoxidil

5% solution.172,173 Better results can be achieved when
minoxidil is used in combination with class II topical
993
15
Section 15
994
corticosteroids or anthralin.170 Minoxidil shows little

efficacy in alopecia totalis and universalis.
Anthralin. Anthralin is an irritant that may have a

nonspecific immunomodulating effect and is primarily used in the treatment of psoriasis (Chapter 18).174
Several studies have shown efficacy in the treatment of
alopecia areata with cosmetically acceptable improvement varying from 20% to 25% for patchy alopecia
areata.175,176 Anthralin is used as a 0.2%1.0% cream
or ointment. It is usually applied daily to the affected
scalp areas and left on for 2030 minutes for the first
2 week, and then 45 minutes daily for 2 week, up to a
maximum of 1 hour daily. Some patient may tolerate
overnight therapy.109,175 When therapy is effective, new
hair growth can usually be seen after 23 months of
treatment. Because of its good safety profile, anthralin can be used safely in affected children. Side effects
of anthralin are irritation, scaling, folliculitis and
regional lymphadenopathy. Anthralin is not suitable
for the treatment of eyebrows and beard area. Patients
should be cautious not to get anthralin in the eyes and
to protect the treated skin areas from UV irradiation.
Brown discoloration of the treated skin and brown
staining of clothes and linen may occur. The patient
should be advised to rinse off the anthralin with cool
or luke-warm water, since hot water increases the likelihood of brown stains of tiles and bathtub.
Topical
Immunotherapy. Although not

approved by the FDA, topical immunotherapy seems
to be the most effective therapeutic option with the
best safety profile in the treatment of chronic severe
alopecia areata. The exact mechanism of action is
not fully understood. A decrease in the peribulbar
CD4+/CD8+ lymphocyte ratio and a shift in the position of T-lymphocytes from the perifollicular area to
the interfollicular area and dermis are believed to be
responsible for the immunomodulating effect.177179
The desired effect of the treatment is the creation of a
contact dermatitis. Diphenylcyclopropenone (DPCP)
and squaric acid dibutyl ester (SADBE) are the most
commonly used contact sensitizers. DPCP and SADBE
are compounded in an acetone base and stored in
opaque bottles to protect the solution from photodegradation. Applying a small amount of a 2% solution to
a small scalp or other area (often the arm) one week
prior to treatment initiation sensitizes the patient. The
DPCP or SADBE solution is then applied weekly to
the scalp, starting at a concentration of 0.0001%. The
scalp should not be washed for 48h post treatment and
should be protected from UV radiation. Every week the
concentration is carefully increased until the patient
develops a mild erythema and mild itching. The treatment is continued with this concentration; the highest concentration used is 2%. Success rates vary from
17%75% with the lowest success rates in patients with
alopecia totalis and universalis.20 Side effects include
lymphadenopathy in 100% of patients, severe contact
eczema, discoloration of the skin including vitiliginous
patches and hyperpigmentation on the scalp and other
arts of the body. Greater caution is indicated in patients
with atopic dermatitis and dark skin types.
Photo(chemo)Therapy. Ultraviolet B light

has been reported to be useful in some patients with
alopecia areata.180 Further therapeutic options
include both oral and topical administration of
psoralen followed by UVA irradiation (PUVA-therapy). PUVA may affect T cell function and antigen
presentation, and possibly inhibits the local immunologic attack against the hair follicle by depleting
Langerhans cells.181 Photo(chemo)therapy shows a
very high relapse rate especially after tapering the
treatment. The major concern about long term UV
irradiation of any kind is its promotion of all types
of skin cancer, including melanoma. Therefore phototherapy should only be considered in exceptional
cases.20
Cyclosporine. Systemic cyclosporine at doses of 46
mg/kg/day has been shown to have a beneficial effect

in some patients with alopecia areata.20,182 Side effect
of oral cyclosporine include elevated serum transaminases and cholesterol levels, as well as headaches,
dysesthesia, fatigue, diarrhea, gingival hyperplasia,
flushing and myalgias. Cyclosporine can be combined
with low dose oral prednisone and may be considered
in patients with severe atopic dermatitis and alopecia
areata. However, due to its side effect profile and the
high recurrence rate observed after discontinuation,
cyclosporine seems to be a relatively impractical treatment for alopecia areata.
Camouflage, Wigs, and Hairpieces.
When
alopecia is progressive despite treatment and sometimes during treatment for improved cosmesis, extensive alopecia areata of the scalp can be camouflaged
with wigs. In women with alopecia areata of the eyebrows, permanent makeup may be considered.
The treating physician should provide psychological support. Local and national alopecia areata support
groups (National Alopecia Areata Foundation, www.
naaf.org) can be very helpful for patients and their
relatives.
TEMPORAL TRIANGULAR ALOPECIA

Temporal triangular alopecia (TTA) is a nonscarring,
noninflammatory alopecia that presents with one or
more roughly triangular, oval, or lancet-shaped alopecic patches in the fronto-temporal area.183185 A few
terminal hairs or vellus-like hairs can often be found
in the periphery of the affected area and the scalp is
normal.186190 The lesions are usually asymptomatic
and the hair elsewhere on the scalp is of normal density. The patches are mostly unilateral (80%) but can
occur bitemporally as well (20%)34,185,190 (Fig. 88-14). A
strip of hair of normal density can be seen between the
affected patch and the forehead. Lesions can be present at birth or first appear before school age. TTA has
been reported in Asian and Caucasian patients with no
sexual predilection. TTA seems to be unresponsive to
medical treatment. Hair transplantation or excision is
reasonable therapeutic approaches.191 TTA is often misdiagnosed as alopecia areata.
SYPHILIS
Cicatricial or scarring alopecias comprise a diverse

group of scalp disorders that result in permanent hair
CICATRICIAL ALOPECIA AT A GLANCE

Scarring alopecia occurs in a heterogeneous
group of hair disorders of a wide variety of
causes.
The inflammatory process leads to
permanent destruction of hair follicular stem
cell structure and subsequent replacement
with fibrous tissue.
CICATRICIAL ALOPECIA
PRIMARY CICATRICIAL ALOPECIAS
::
Hair loss is a common symptom of secondary or tertiary syphilis. In its classical form, the hair loss is an
irregular, patchy loss of hair scattered throughout the
scalp, which has been described as moth eaten (Fig.
88-15). Eyebrows may be shed and patchy alopecia
may occur in the beard or other hair-bearing areas
of the body. Syphilitic alopecia can be very difficult
to distinguish from alopecia areata. The presence of
plasma cells, lack of peribulbar eosinophils, and abundant lymphocytes in the isthmus are histological features of syphilitic alopecia. Essential syphilitic alopecia
occurs in the absence of any other cutaneous sign of
secondary syphilis,192 and is characterized by a diffuse
shedding, thereby resembling TE.
15
Chapter 88
Figure 88-14 Temporal triangular alopecia.
loss. The destructive process can occur as a primary or

secondary cicatricial alopecia. Primary cicatricial alopecia refers to a group of idiopathic inflammatory diseases, characterized by a folliculocentric inflammatory
process that ultimately destroys the hair follicle. Secondary cicatricial alopecias can be caused by almost
any cutaneous inflammatory process of the scalp skin
or by physical trauma, which injures the skin and skin
appendages. Regardless of whether a cicatricial alopecia is primary or secondary in nature, all scarring
alopecias are characterized clinically by a loss of follicular ostia and pathologically by a replacement of
hair follicles with fibrous tissue. Cicatricial alopecias
are psychosocially distressing for the affected patient
and medico-surgically challenging for the treating
physician.
The destructive process can occur as a

primary or secondary cicatricial alopecia
In each case, the differential diagnosis
includes alopecia areata, an alternative form
of cicatricial alopecia, temporal triangular
alopecia, trichotillomania, and secondary
syphilis (alopecia areolaris).
Loss of hair ultimately occurs with
permanent alopecia.
No evidence-based treatment is available.
EPIDEMIOLOGY.
cias are rare.
Figure 88-15 Alopecia secondary to syphilis. (From Wolff

K, Goldsmith LA, Katz SI, Gichrest BA, Paller AS: Fitzpatricks
Dermatology in General Medicine. 7th ed. Copyright
The McGraw-Hill Companies, Inc. All rights reserved, with
permission.)
Inflammatory cicatricial alope-
ETIOLOGY AND PATHOGENESIS. The mechanisms causing the follicle stem cell destruction are not
completely understood, and there is no cure to date.
Primary cicatricial alopecias are characterized by an
inflammatory infiltrate affecting the upper, permanent
portion of the follicles referred to as the infundibulum,
and below it, the isthmus of the follicle. The isthmus
is the home of pluripotent hair stem cells, which are
found in the bulge region where the arrector pili muscle attaches to the outer root sheath. Pluripotent hair
follicle stem cells are responsible for the renewal of the
upper part of the hair follicle and sebaceous glands,
995
15
Box 88-5 Forms of Primary

Cicatricial Alopecia
Section 15
Lymphocytic Chronic cutaneous lupus erythematosus (discoid lupus erythematosus, DLE)

Lichen planopilaris (LPP)
Classic LPP
Frontal Fibrosing Alopecia
GrahamLittle syndrome
Classic Pseudopelade of Brocq
(PPB)
Central centrifugal cicatricial
alopecia (CCCA)
Alopecia mucinosa
Neutrophilic Keratosis follicularis spinulosa

decalvans
Folliculitis decalvans
Dissecting cellulites/folliculits
(perifolliculitis abscedens et
suffodiens)
Mixed
Folliculitis (acne) keloidalis

Folliculitis (acne) necrotica
Erosive pustular dermatosis
Source: Olsen EA et al: Summary of North American Hair

Research Society (NAHRS)-sponsored Workshop on Cicatricial
Alopecia, Duke University Medical Center, February 10 and 11,
2001. J Am Acad Dermatol 48:103-110, 2003.
and for the restoration of the lower cyclical component

of the follicles at the onset of a new anagen period.27,193
Damage to the bulge area and the sebaceous gland
with the isthmus, affected either stem cells or sebaceous glands, may result in an incomplete hair cycle
and can be associated with chronic follicular inflammation and foreign body reaction.194 Scarring hair loss
is the consequence.5,195197
A working classification on the basis of pathology
of scalp biopsy was suggested by the North American
Hair Research Society in 200127 (Box 88-5).
996
CLINICAL FINDINGS. Primary cicatricial alopecia usually affects the central and parietal scalp before
progressing to other sites of the scalp. Isolated alopecic
patches showing atrophy and a lack of follicular ostia
with inflammatory changes such as diffuse or perifollicular erythema, follicular hyperkeratosis, pigment
changes, tufting, and pustules provide hints to the
diagnosis.20,198 However, clinically visible inflammatory change might be absent in the affected lesions and
may present histologically as inflammatory infiltrates
in the deep dermis and subcutaneous tissue. Diagnostic tools such as a tenfold magnifying dermatoscope
with and without polarized light can help to identify
the presence or absence of follicular ostia, perifollicular erythema and follicular hyperkeratosis in the
affected areas.
A thorough examination of the entire scalp, a

detailed clinical history, and skin biopsies of an active
lesion are crucial in the correct diagnosis of cicatricial
alopecia. Patient-reported symptoms such as itching
or pain might be used as approximate indicators of
disease activity but can also be completely absent. The
presence of other indirectly related symptoms, such
as sun sensitivity, can also help support a particular
diagnosis [e.g., discoid lupus erythematosus (DLE)].
A scalp biopsy is necessary to confirm the diagnosis
of scarring alopecia, and should be taken as described
in Section Diagnostic Techniques for Evaluating Hair
Growth Disorders under Biopsy.1,27,199,200 Keratoses
follicularis spinulosa decalvans is a form of cicatricial
alopecia associated with follicular plugging that is
more fully described in Chapter 87 as well as online.
LYMPHOCYTIC PRIMARY
CICATRICIAL ALOPECIAS
CHRONIC CUTANEOUS LUPUS ERYTHEMATOSUS (Discoid Lupus Erythematosus). (See also Chapter 155). Discoid lupus
erythematosus (DLE), together with LPP, is the most

common cause of inflammatory cicatricial alopecia.198
Women are more often affected than men and the disease is more common in adults (with first onset typically at the age of 2040 years) than in children.201203
Systemic lupus erythematosus (SLE) will develop in
26%31% of children and approximately 5%10% of adult
patients with DLE.203,204 Patients with DLE are found to
have a higher incidence of concurrent alopecia areata.
Moreover, DLE has also been associated with verruciform
xanthoma and papulonodular dermal mucinosis.205
Clinical Presentation. DLE usually presents

with one or more erythematous, atrophic, and alopecic patches on the scalp (Fig. 88-16). Follicular hyperkeratosis, hyperpigmentation, hypopigmentation and
telangiectasia can be present.194,206 Hyperpigmentation
is frequently found in the center of the lesion. Active
lesions can be sensitive or pruritic, and the patient
might report a worsening after UV exposure.
Pathology.
Characteristic features of early, active

DLE lesions are lymphocyte-mediated interface
Figure 88-16 Discoid lupus erythematosus.
15
dermatitis with vacuolar degeneration of the basal

cell layer and necrotic keratinocytes, a thickening of
the basement membrane and destruction of sebaceous
glands. Elastic fibers are frequently destroyed throughout the reticular dermis.1,195 The lymphocytic infiltrate
is predominantly found in the upper part of the follicle,
but can also be found in deeper parts of the follicle, in
the interfollicular epidermis and around the periadnexal vessels.18,207209 DIF typically shows a linear granular deposition of IgG and C3 at the dermalepidermal
junction. IgM, C1q, and rarely IgA can also be found.
Management and Treatment.
Figure 88-17 Extensive lichen planopilaris.

clinical features with those of DLE are frequently seen.
Patients complain about itching, burning sensations
and sensitivity of the scalp (Fig. 88-17).
FFA is characterized by a frontal, band-like, or circumferential scarring alopecia.195 In some cases a few
hairs are spared in the original frontal hairline. Follicular hyperkeratosis and perifollicular erythema may
be found in a band-like pattern in the frontal hairline.
Alopecia of the eyebrows is also frequently seen in
FFA (Fig. 88-18). GrahamLittle syndrome presents
with lesions of classic LPP on the scalp, nonscarring
alopecia of axillae, pubic area, and eyebrows as well as
keratosis pilaris of the trunk and extremities.
Clinical Presentations of LPP. Classic LPP

typically starts at the crown and vertex area. In classic LPP, the affected areas usually show perifollicular
erythema and follicular hyperkeratosis. The alopecic
areas of LPP are often smaller, irregularly shaped and
interconnected, which can lead to a reticulated clinical
pattern as compared to DLE. However, overlapping
::
LICHEN PLANOPILARIS. LPP is a follicular variant of lichen planus. Together with DLE, this is the
most common cause of primary cicatricial alopecia. LPP
can be divided in classic LPP, frontal fibrosing alopecia
(FFA), and GrahamLittle syndrome. The typical age
of onset of classic LPP is around the fifth decade, and
women are more often affected than men. Extracranial
lichen planus may occur in up to 28% of patients.196,213,214
FFA predominantly affects postmenopausal women.
GrahamLittlePiccardiLassueur Syndrome is a very
rare condition that predominantly affects female adults.
It is characterized by LPP of the scalp, noncicatricial of
the eyebrows, axilla, and groin and keratosis pilaris.
Lichenoid drug eruptions can be triggered by many
drugs and might present as LPP. Some of the most common drugs, causing lichenoid drug eruption are gold,
antimalarials and captopril. Actinic lichenoid drug eruption is confined to sun exposed sites. The most likely drugs
to cause this are quinine, and thiazide diuretics.215217
Chapter 88
Hydroxychloroquine at a dose of 200400 mg daily in adults or

46 mg/kg in children has been shown to be highly
effective. A baseline ophthalmologic examination and
complete blood count is required before the therapy
is started.201,203 Bridge therapy with oral prednisone
(1 mg/kg) tapered over the first 8 weeks of treatment
might be helpful in adult patients with rapidly progressive disease.20,198
In limited or slowly progressive DLE, intralesional
triamcinolone acetonide should be used at a concentration of 10 mg/cc every 46 weeks, alone or in addition
to oral therapy.198 Intralesional triamcinolone acetonide
can be used with or without topical class I or class II corticosteroids. Topical corticosteroids alone have also been
shown to be effective in milder forms of DLE,1,18,20,203
and oral acitretin and isotretinoin have shown some
efficacy.210,211 Immunosuppressive therapies such as
mycophenolate mofetil, methotrexate, or azathioprine
should only be considered if the above therapies fail.
Multimodal aggressive therapy in rapidly progressive
DLE might reverse early alopecic patches and save hair
follicles from the destructive process.212
Pathology. The three subgroups of LPP show similar histopathological features. A lymphocytic infiltrate
and interface dermatitis are predominantly found in
and around the upper permanent part of the hair follicle. Unlike DLE, the vascular plexus is not affected
by inflammation and mucin deposits are absent.195 DIF
typically shows globular cytoid depositions of IgM,
and rarely IgA, IgG or C3, in the dermis around the
infundibulum.218
Figure 88-18 Frontal Fibrosing alopecia.
997
15
Section 15
Management and Treatment. First line treatment for moderately active classic LPP lesions is intralesional triamcinolone acetonide at a concentration
of 10 mg/cc every 46 weeks or in combination with
topical class I or class II corticosteroids.198,211 Literature on the efficacy of oral medication is limited. Oral
cyclosporine, retinoids, antimalarials and griseofulvin194,206,219222 have been shown to have a positive effect
in patients with rapidly progressive LPP. Oral corticosteroids in the first weeks of treatment as bridge therapy might be considered in very active cases. In FFA,
a lower dose of intralesional triamcinolone acetonide
(2.55 mg/cc), or topical application of minoxidil or
tacrolimus can be considered, although no effective
treatment has been reported yet. The treatment of
GrahamLittle syndrome is typically similar to the
management of classic LPP.
CLASSIC PSEUDOPELADE OF BROCQ. PPB is

classified as an idiopathic lymphocytic primary cicatricial alopecia that predominantly affects the scalp. It is
the second most common cause of primary cicatricial
alopecia.196 Women between 30 and 50 years of age are
most frequently affected.
Clinical Presentation. Pseudopelade of Brocq usu-
ally affects the vertex and occipital area of the scalp. It

presents with small flesh-toned alopecic patches with
irregular margins. This pattern has been described as
footprints in the snow.223 PPB can also present as a noninflammatory centrifugally spreading patch of alopecia,
which might be seen as a variant of central centrifugal
cicatricial alopecia in Caucasians. Follicular hyperkeratosis and perifollicular or diffuse erythema is mostly
absent.206 Clinically the features may overlap with LPP.
Pathology. Early PPB lesions typically show a sparse

to moderate lymphocytic infiltrate around the follicular
infundibulum with a complete destruction of the sebaceous glands.176 In later disease stages, hair follicles are
completely replaced by fibrous tracts. Unlike DLE and
LPP, interface dermatitis is usually absent and the elastic fibers are preserved and thickened in PPB.224
Management and Treatment. Intralesional tri-
amcinolone acetonide at a concentration of 10 mg/cc

every 46 weeks in combination with topical corticosteroids is the treatment of first choice. Hydroxychloroquine, oral prednisone, and isotretinoin have shown
some effectiveness in treating PPB.196,206,225,226
CENTRAL CENTRIFUGAL CICATRICIAL ALOPECIA. CCCA is classified as a lymphocytic primary
cicatricial alopecia, primarily affecting women of color.

It remains unclear which of the following contribute
most to its formation: chemical processing, heat, traction or other traumas.1,18 CCCA can rarely be seen in
Caucasians (sometimes called central elliptical pseudopelade) and African-American men. Due to clinical
and histopathological similarities, it has been debated
whether CCCA is a variant of PPB.
998
Clinical Presentation. CCCA presents with a skin
colored patch of scarring alopecia on the crown, gradu-
Figure 88-19 Central centrifugal cicatricial alopecia.

ally progressing centrifugally to the parietal areas. Perifollicular hyperpigmentation and polytrichia might be
present.198 Patients may complain about itching, tenderness and pins and needle sensations227 (Fig. 88-19).
Pathology. Limited studies suggest that histopathological features of CCCA seem to be similar to those of
PPB.18,194
Management and Treatment. Topical cortico-
steroids and tetracycline have shown to be effective in

active progressive cases.18 Since a multifactorial etiology is debated for CCCA, some dermatologists recommend a switch to more natural, less traumatizing,
hair care practices.1,206,228 Wigs and hairpieces can help
camouflage the alopecia and are frequently used by
women with CCCA.
ALOPECIA MUCINOSA. Alopecia mucinosa (AM)

can present as indurated, well-demarcated erythematosus or skin colored patches of scarring or nonscarring
alopecia that can be accompanied by diffuse hair loss229
and alopecia of the eyebrows.230 Grouped follicular papules, follicular cysts and follicular hyperkeratosis may
be present in some cases. Early lesions of AM show
mucin deposition in the outer root sheath and replacement of the entire pilo-sebaceous unit by pools of mucin
in more advanced lesions.195,230 AM strictly speaking
it is not a primary cicatricial alopecia because the hair
follicle is not replaced by a true scar.195 AM can occur
idiopathically or in the setting of cutaneous T-cell lymphoma or mycosis fungoides.231 Cell atypia and monoclonal populations of T-lymphocytes can be present in
the idiopathic form of AM as well as in the latter form.231
Management and Treatment.
A complete
workup is necessary to rule out an underlying malignancy such as mycosis fungoides and Szary syndrome, its advanced endpoint. Oral corticosteroids,
minocycline and isotretinoin have been shown to be
effective. Topical and intralesional corticosteroids,

dapsone, indomethacin and light therapy have also
been used with variable outcomes.232
NEUTROPHILIC PRIMARY
CICATRICIAL ALOPECIA
Pathology. Early lesions are characterized by keratin aggregation in the infundibulum with numerous
intraluminal neutrophils, as well as an intrafollicular
and perifollicular neutrophilic infiltrate.194,195,206 Sebaceous glands are destroyed early. In advanced lesions,
the infiltrate may consist of neutrophils, lymphocytes,
and plasma cells and extend into the dermis.198,206 Hair
shaft granulomas with foreign-body giant cells can frequently be found.194,206 In end-stage lesions, follicular
and interstitial dermal fibrosis as well as hypertrophic
scarring can be observed.206
DISSECTING FOLLICULITIS. Dissecting folliculitis (DF) (or dissecting cellulites or perifolliculitis capitis abscedens et suffodiens of Hoffman) is related to
acne conglobata and hidradenitis suppurativa. These
three diseases have been described as follicular occlusion triad. DF predominantly occurs in young men
between 18 and 40 years of age.198 African-American
men seem to be more commonly affected compared to
Caucasian men. The pathogenesis of DF may include
follicular occlusion, seborrhea, androgens and secondary bacterial overpopulation as well as an abnormal
host response to bacterial antigens.239246
::
Clinical Presentation. FD frequently starts at the

vertex area of the scalp with erythematous alopecic
patches, follicular pustules and follicular hyperkeratosis. Tufted folliculitis is typically found in FD, but can
also occur in other cicatricial inflammatory alopecias.
Tufted folliculitis is characterized by multiple hairs
(515) emerging from one single, dilated follicular
orifice. In older lesions pustules might be absent but
progressive scarring may still continue (Fig. 88-20).
An overlap with acne keloidalis is possible since some
patients with acne keloidalis not only develop cicatricial lesion on the nape of the neck but also develop
progressive cicatricial alopecia that resembles FD in
other areas of the scalp. Patients frequently complain
about pain, itching and/or burning sensations.
15
Chapter 88
FOLLICULITIS DECALVANS. Approximately,

11% of all primary cicatricial alopecia cases are diagnosed with folliculitis decalvans (FD).194,196 FD predominantly occurs in young and middle-aged adults
with a slight preference of the male gender. A bacterial infection involving S. aureus, in combination with
hypersensitivity reaction to superantigens and
defect in host cell-mediated immunity have all been
suspected as possible pathogenetic factors.194,234,235
over many years. Bacterial cultures with the testing of

antibiotic sensitivities are recommended. Eradication
of Staphylococcus aureus with minocycline, erythromycin, cephalosporines, and sulfamethoxazole-trimethoprim has shown some effectiveness. Relapse can
often be observed after the antibiotics are discontinued.20,234,236 If so, the patient might have to stay on low
dose antibiotics for many years. Rifampin in combination with clindamycin has shown good response;
however, this combination shows a higher incidence of
side effects.234,237 Oral fucidic acid alone or in combination with other agents has also shown to be effective
in some patients.238 Oral therapy should be combined
with topical antibiotics such as mupirocin, 1.5%
fusidic acid and 2% erythromycin237,238 and antibacterial cleansers. Intralesional triamcinolone acetonide at
a concentration of 10 mg/cc every 46 weeks might
help to reduce the inflammation and reduces symptoms such as itching, burning, and pain.20,196 Intranasal eradication of S. aureus with topical antibacterial
agents have been described to be useful.206
Clinical Presentation. DF typically presents with
Management and Treatment. Treatment of FD
fluctuating nodules, abscesses, and sinuses, which frequently show spontaneous discharge of pus, as well as
with erythematous, follicular papules and pustules. Initial lesions are mostly found on the vertex and occipital
scalp. Multifocal lesions can form an intercommunicating ridge and sero-purulent exudates can be discharged
when pressure is applied to one region of the scalp (Fig.
88-21). The lesions can be pruritic and tender. Chronic
and relapsing courses result in cicatricial alopecia,
which can show hypertrophic or keloidal scars.246
Figure 88-20 Folliculitis decalvans.
Figure 88-21 Dissecting cellulitis.
in general is difficult and disease activity can be noted
999
15
Pathology. The main histological feature is an intra-
follicular and perifollicular neutrophilic infiltrate with

follicular occlusion in early lesions.195 In more advanced
stages, interconnecting sinus tracts lined by squamous
epithelium, follicular perforation, perifollicular and
deep dermal abscesses are typical findings.195,206,209
Section 15
Management and Treatment. Multimodal

treatment has been reported with successful results,
such as systemic antibiotics (minocycline, tetracycline,
cloxacillin, erythromycin, cephalosporin or clindamycin), intralesional corticosteroids, and oral prednisolone.247,248 The benefits of systemic antibiotics are most
likely due to their antiinflammatory effects rather than
to their antibacterial action. Isotretinoin at a dose of
0.51 mg/kg/d has shown prolonged remission.249,250
Incision and drainage of therapy resisted, painful nodules, marsupialization with curettage of the cyst wall,
complete scalp extirpation with skin grafting have
been reported, but should be an exception for extreme
and therapy refractory cases.250252
MIXED PRIMARY CICATRICIAL
ALOPECIAS
ACNE KELOIDALIS NUCHAE. Acne keloidalis nuchae (AKN) predominantly occurs in AfricanAmerican men age 14 to 25. This idiopathic primary
cicatricial alopecia might be triggered by trauma (shirt
collars) or infection (Demodex or bacteria). Clinically
AKN presents with skin-colored follicular papules,
pustules and plaques as well as keloid-like scarred
lesions in the occipital scalp (Fig. 88-22). Histologically,
acne keloidalis is characterized by an acute inflammation with neutrophilic or lymphocytic infiltration and
chronic granulomatous inflammation around the isthmus and the lower infundibulum. Treatment is usually
difficult and protracted. Monthly intralesional triamcinolone acetonide (1040 mg/mL) alone or combined
with topical 2% clindamycin or oral (tetracyclines)
antibiotics is the treatment of first choice.1,18,194,253,254
Class I or II topical steroids alone or in combination
with topical antibiotics for mild cases of AKN as well
as cryotherapy and laser therapy have shown some
success. Surgical excision of extensive keloidal lesions
may be considered but should be reserved for therapy

refractory, extensive and symptomatic cases.
ACNE NECROTICA (VARIOLIFORMIS). Acne

necrotica varioliformis is a very rare, chronic condition, which predominantly occurs in adults. Frontal
and parietal scalp as well as seborrheic areas of the
face are most commonly affected. Acne necrotica presents with umbilicated, pruritic or painful papules that
undergo central necrosis. The condition leaves varioliform, or smallpox-like scars.255,256 Histology shows
a suppurative, necrotic, infundibular folliculitis with
lymphocytic or mixed inflammatory infiltrate.256 Oral
antibiotics, isotretinoin, intralesional or topical corticosteroids have shown success.257 Excision of larger
scarred areas can be considered.
EROSIVE PUSTULAR DERMATOSIS. Erosive
pustular dermatosis is an uncommon disorder predominantly occurring in elderly women.258,259 The
characteristic lesion is a suppurative, necrotic, erosive papule or plaque.258,260 Histology of early lesions
is nonspecific, but older lesions show an extensive,
chronic mixed inflammatory infiltrate the dermis and
later dermal fibrosis. Treatment include class I or II
topical steroids with or without topical antibiotics, systemic antibiotics, and oral isotretinoin.258,260
(Box 88-6)

Once the hair follicle is destroyed and replaced by
fibrous tissue, there is no hope for hair regrowth. Various medical treatment options may fail and the inflammatory process may continue and leave the patient
with a disfiguring permanent alopecia.
TREATMENT
The main goal in treating primary cicatricial alopecia
is to stop the inflammation and therefore further progression of the disease. If hair loss is already extensive
and/or medical treatment fails, patients should be
advised about camouflage techniques, hairpieces and
wigs. Women with extensive LPP lesion on the crown
and vertex benefit highly from a well designed hair
piece, which can look very natural, particularly if the

1000
Figure 88-22 Acne keloidalis nuchae.
Alopecia areata
Secondary cicatricial alopecia
Trichotillomania
Secondary Syphilis (alopecia areolaris)
frontal hairline is preserved and is usually more comfortable to wear compared to a full wig. Hair restoration surgery including HT and scalp reduction can be
an option for burnt out cicatricial alopecia. No disease
activity should occurs on the scalp for at least 1 year
without therapy. The patient has to be warned about a
possible limited graft survival and disease recurrence,
which seems to be higher in neutrophilic primary.
SECONDARY CICATRICIAL ALOPECIA

PROGNOSIS AND CLINICAL COURSE. Prognosis and clinical course of secondary cicatricial alopecia depend on the underlying disease. Once scar tissue
has formed and the adnexal structures are destroyed
no hair regrowth can be expected.
Minimal or severe injuries to the scalp can result in

alopecia. It usually presents with fine streaks of hair
loss in the injured scalp area, but if the wound borders undergo contusion or destruction, this may result
in irregular and large patches of hair loss. Traumatic
hair loss can occur after scalp surgery, especially after
extensive scalp reduction or large donor strip harvesting in hair restoration surgery, if too much tension is
applied with wound closure. This type of hair loss is
usually reversible but can also be permanent. Traumatic birth induced alopecia is infrequent; causes
include mechanical extractor marks, tears or contusions or resulting infections. Aplasia cutis congenita
should be considered in the differential diagnosis of
cicatricial alopecia at birth.1
TRACTION ALOPECIA
Prolonged traction of the hair may lead to transient or
if continued over a period of time, may lead to follicular atrophy, resulting in cicatricial alopecia. Chronic
traction can be caused by tight ponytails, braids, heavy
dead locks, or extensive use of rollers. Due to ethnic
differences in hair fragility and cultural differences
in hair styling practices, marginal traction alopecia is
more commonly seen in African-American women
due to hair braiding and weaving procedures1 (Fig.
88-23). Patchy traction alopecia in the frontal hairline
or temples is commonly seen in Sikh boys, whose hair
is usually tight up in a topknot.270 Cicatricial alopecia caused by prolonged traction can be treated with
HT, if the patient discontinues the injuring hairstyles
and sufficient donor hair supply is available.
is crucial in the diagnosis of secondary cicatricial alopecia. Diagnosis in early stages can sometimes be made
based on specific clinical and histological features of
the underlying disorder. Follicular orifices are lost
clinically, and histology shows extensive scarring with
fibrosis, loss of elastic fibers and adnexal structures.261
TRAUMATIC INJURIES
::
CLINICAL FINDINGS. A thorough clinical history
15
Chapter 88
ETIOLOGY AND PATHOGENESIS. In secondary

cicatricial alopecias, permanent hair loss is caused by
various other scalp conditions not related to the hair
follicle. In these conditions, the primary event develops outside the FU and this leads to incidental destruction of the follicle. Possible causes are congenital
defects, trauma, inflammatory conditions, infections,
neoplasms, and rarely drugs (eBox 88-6.1 in online edition). Permanent, chronic traction alopecia and scars
from surgery can be considered secondary scarring
alopecias as well.261
scalp. Traumatic alopecias are usually of three types: (1)

acute trauma, (2) prolonged traction, and (3) pressure.
TREATMENT. Treatment is specific in active conditions, while in localized end-stage lesions, specific medical treatment is no longer efficient and hair restoration
surgery techniques become the mainstay of therapy.
TRAUMATIC HAIR LOSS

An acute or chronic mechanical insult to the scalp hair
may lead to reversible or irreversible alopecia of the
Box 88-7 Differential

Diagnosis Box

Primary cicatricial alopecia

Alopecia areata
Trichotillomania
Secondary Syphilis (alopecia areolaris)
Figure 88-23 Traction alopecia. (From Wolff K, Goldsmith

LA, Katz SI, Gichrest BA, Paller AS: Fitzpatricks Dermatology in General Medicine. 7th ed. Copyright The McGrawHill Companies, Inc. All rights reserved, with permission.)
1001
15
Section 15
1002
TRICHOTILLOMANIA
Trichotillomania (Greek: tricho = hair, tillo = pull,
mania = excessive excitement) is a form of traumatic
alopecia caused by an irresistible compulsion to pull
out or twist or break of ones own hair. Trichotillomania is relatively common with an estimated incidence
of 1 million Americans.1 Two forms of trichotillomania can be distinguished: (1) infantile trichotillomania or (2) early onset trichotillomania, which starts
in early childhood is typically of short duration and
may resolve spontaneously or with simple interventions.271,272 Childhood trichotillomania may be seen
analogous to other habitual infantile behaviors such
as thumb sucking. Boys are more frequently affected.
Trichotillomania, which starts around or after puberty,
shows a more chronic course and is usually a sign of
a more severe underlying psychopathology. It is classified as an impulse control disorder.273275 Women are
far more often affected than men. The clinical presentation is usually quite distinctive with a single or multiple asymmetrical, occasionally geometrically shaped
areas of hair loss on the scalp or other areas of the
body (Fig. 88-24). The areas are not smoothly devoid
of hairs, as seen in alopecia areata but display short
or bristly anagen hair. Telogen hair in the involved
area is usually plugged out easily; anagen hair may be
plucked out, twisted and broken at various lengths.
Regrowing anagen hair needs to reach a certain length
before it can be plugged out again. Alopecia areata
and tinea capitis should be considered as differential
diagnosis. Where doubt remains, a scalp biopsy can be
diagnostic, showing a characteristic increase in catagen hair, trichomalacia and pigment casts within the
follicular canal secondary to traumatic hair removal.
Most important in the therapy of trichotillomania is
the education of patient and/or parents and in late
onset trichotillomania the treatment of the underlying psychopathology. Especially if patients deny the
self-inflicting nature of their hair loss, a referral to a
psychiatrist or psychologist is usually refused and
treatment becomes difficult.
Figure 88-24 Trichotillomania.
PRESSURE ALOPECIA
Pressure alopecia can occur after a patient was unconscious and completely immobile for a certain length of
time. Hair loss is presumably due to ischemia caused by
the pressure of the body weight to a certain scalp area.
The ischemic injury may lead to permanent hair loss.
HAIR SHAFT ABNORMALITIES

Hair shaft abnormalities are structural defects of the
hair shaft. They can be inherited or acquired. Inherited hair shaft abnormalities can be associated with
increased hair breakage or can lead to unruliness of the
scalp hair.
HAIR SHAFT ABNORMALITIES WITH

INCREASED HAIR BREAKAGE
TRICHORRHEXIS NODOSA. Trichorrhexis
nodosa can be inherited or acquired. Affected hair
shafts develop a breach in the cuticle with separation
and fraying of the exposed cortical fibers, which leads
to a node-like swelling.142 The fibers then fracture and
the shaft breaks with the resultant appearance of a
splayed paint brush or fan-like array (Fig. 88-25). Congenital trichorrhexis nodosa can be present at birth or
may develop in the first months of life. In rare cases,
Trichorrhexis nodosa can be associated with teeth and
nail defects or hyperkeratosis1 and with metabolic disorders such as argininosuccinic aciduria (see Chapter
131), Menkes syndrome, and trichothiodystrophy.
Acquired trichorrhexis nodosa is much more common. Hair breakage may either occur in the proximal
or distal hair shaft. Proximal trichorrhexis nodosa is
more commonly seen in African-American women
usually after repetitive chemical or hot-comb straightening. Distal trichorrhexis nodosa is mostly secondary
Figure 88-25 Trichorrhexis nodosa. (From Wolff K, Goldsmith LA, Katz SI, Gichrest BA, Paller AS: Fitzpatricks
permission.)
to excessive brushing, teasing or chemical treatment

such as bleaching or permanent waves. Patients with
trichorrhexis nodosa should be advised to avoid any
harsh chemical or physical hair styling practice. Proximal trichorrhexis nodosa may take month to year to
resolve even if the initiating hair care is avoided.
15
A
TRICHOSCHISIS AND TRICHOTHIODYSTROPHY. Trichoschisis is characterized by a clean
In pili torti, the affected hair shafts are flattened and

twisted on their axis, usually through an angle of
180, with a range of 90360 (Fig. 88-26). The twisting occurs in multiple irregular intervals along an
otherwise straight hair shaft. Pili torti do not signify
a particular abnormality but can be seen in many different syndromes and in the presence of other hair
shaft disorders.277 The way of inheritance in pili torti is
mostly autosomal dominate, but can also be autosomal
recessive or sporadic. Clinically, the patients may present with patchy alopecia with coarse stubble or longer broken hairs. Hair fragility usually improves after
puberty.
Pili torti occurs in combination with trichorrhexis
nodosa, trichoclasis, and trichoptilosis in Menkes
kinky hair syndrome, also called steely hair syndrome or trichopoliodystrophy. Menkes syndrome
is an X-linked recessive multisystem disease, which
begins in infancy. It is associated with depigmented
hairs, hypopigmentation of the skin, metal retardation,
neurologic impairment secondary to degeneration of
cerebral, cerebellar, as well as bone and connective
Figure 88-26 Pili torti. A. Irregularly spaced 180 twists

in hair shaft. (From Whiting DA: Hair shaft defects. In Disorders of Hair Growth: Diagnosis and Treatment, edited by
EA Olsen. New York, McGraw-Hill, 2003, with permission.)
B. Brittle broken hair typical of congenital pili torti.
PILI TORTI AND MENKES SYNDROME
::
TRICHOCLASIS. Trichoclasis is the common greenstick fracture of the hair shaft. It is characterized by a
transverse fracture of the shaft, which is splinted partly
or completely by intact cuticle. Cuticle, cortex and sulfur content are normal. Trichoclasis does not indicate
any specific underlying disease. It can occur in normal
hair or may be associated with pili torti.1
Chapter 88
transverse fracture of the hair shaft in an area of a focal

absence of the cuticle. It is usually, but not specifically,
a marker for sulfur-deficient hair in trichothiodystrophy, in which the scalp hair, eyelashes and eyebrows
are short and brittle (see Chapter 139). The hair cysteine content is less than one-half normal, primarily
from a major reduction and altered composition of the
ultrahigh-sulfur matrix proteins.276 Microscopic examination with polarized light characteristically shows a
tiger tail pattern with altering light and dark bands,
secondary to alterations in the sulfur content1 (eFig.
88-25.1 in online edition). Various structural abnormalities can be detected by confocal and scanning
electron microscopy. These complex alterations make
hair shafts in trichothiodystrophy excessively prone to
breakage and weathering.1 Sulfur and amino acid analysis of the hair is diagnostic. Hair shaft abnormalities
in trichothiodystrophy identify a group of autosomal
recessive disorders that are associated with neuroectodermal abnormalities (eTable 88-1.2 in online edition).
tissue degeneration. The clinical features result from

a defective copper transport and an accumulation of
intracellular copper, which results in a functional deficiency of copper-dependent enzymes. Most patients
die by the age of 3 years. In Menkes syndrome, copper
uptake is normal, therefore copper supplementation
is ineffective, but copper-histidin given immediately
postpartum may prevent or ameliorate the severe neurodegeneration. Low serum concentrations and ceruloplasmin levels are diagnostic.1
TRICHORRHEXIS INVAGINATA
(BABOO HAIR) AND NETHERTON
SYNDROME
Trichorrhexis invaginata is a diagnostic marker for
Netherton syndrome, although it also may occur
sporadically and in association with other hair shaft
abnormalities. Netherton syndrome is an autosomal
recessive inherited disorder, characterized by a triad of
atopic diathesis, ichthyosiform skin changes and trichorrhexis invaginata (see Chapter 49). The primary hair
defect appears to be abnormal keratinization of the
hair shaft in the keratogenous zone, allowing intussusception of the fully keratinized and hard distal shaft
into the incompletely keratinized and soft proximal
portion of the shaft.278 This leads to the typical balland-socket deformity (Fig. 88-27). Once the hair fractures, it shows a typical golf tee-shaped the distal end.
Affected short, brittle hairs can be distributes over
the scalp, which may result in sampling errors. Retinoids and phototherapy may be considered as therapy,
1003
15
Section 15
Figure 88-27 Trichorrhexis invaginata (light micrograph

400). (From Whiting DA: Hair shaft defects. In: Disorders of
Hair Growth: Diagnosis and Treatment, edited by EA Olsen.
New York, McGraw-Hill, 2003, with permission.)
although the condition frequently improves, as the

patient gets older.
MONILETHRIX
Monilethrix present with extremely short, brittle, fragile, beaded hairs emerging from a hyperkeratotic follicular orifice. Monilethrix hair shafts show elliptical
nodes, 0.71 mm apart, with intervening, tapered constrictions that are nonmedullated (Fig. 88-28). These
internodes are the predetermined breaking points and
often present with longitudinal ridges. Most cases of
monilethrix are of autosomal dominant inheritance,
with variable expression. In rare cases it is autosomal recessive. It is caused by one of the three genes
encoding type II hair keratin (KHb1 or KRT81, KHb3
or KRT83, and KHb6 or KRT86). In the case of autosomal recessive inheritance, the underling gene encodes
desmoglein 4 (DSG4). In mildest cases monilethrix is
localized to the occiput or the nape of the neck. The
hair shaft defect may occur alone or in association with
keratosis pilaris, nail and teeth abnormalities, syndactyly, cataracts and physical retardation. Retinoids and
topical minoxidil may improve the condition, although
monilethrix frequently improves spontaneously with
age.1,279,280
LOCALIZED AUTOSOMAL RECESSIVE

HYPOTRICHOSIS. This rare autosomal recessive
disorder present with localized sparse broken hair

involving scalp and eyebrows. The gene defect lies in a
1004
Figure 88-28 Monilethrix. Typical beaded appearance of

hair as seen under light microscopy (40). (From Wolff K,
Goldsmith LA, Katz SI, Gichrest BA, Paller AS: Fitzpatricks
permission.)
Figure 88-29 Uncombable hair syndrome.

mutation in the gene for desmoglein 4 (DSG4). Unlike
Monilethrix, the hair does not present with beading.281
HAIR SHAFT ABNORMALITIES ASSOCIATED WITH UNRULY HAIR

Uncombable Hair Syndrome. Uncombable hair
syndrome, also known as spun glass hair or pili trianguli et canaliculi is an inherited autosomal dominant
trait or a sporadic structural hair abnormality.282 This
unique syndrome is characterized by rigid hair shafts
with a triangular or kidney bean-shaped cross section,
but irregular forms, such as flattened, heart-shaped and
longitudinal grooves may be present. Clinically, the hair
is dry, coarse, usually blond to light brown, and with a
spangled appearance. The scalp hair is frizzy, unruly,
kinky and unmanageable from infancy, grows in multiple directions and cannot be combed flat (Fig. 88-29).
Male and female individuals are equally affected. It
first occurs more often during early childhood, but it
can develop as late as age 12 years. Microscopic analysis of hair samples under polarized light shows a
homogeneous band on one edge caused by the shadow
thrown as light passes over the pili canaliculi.283 There
is no definitive therapy, but uncombable hair syndrome
may improve over time without treatment.284
Wooly Hair. Wooly hair is a rare congenital struc-
tural anomaly of scalp hair. It is marked by an extreme

kinkiness of the hair in Caucasians. Wooly hair can be
present at birth or appear in the first months of life.
The curls, which have an average diameter of only 0.5
cm, lie closely together and usually make the hair difficult to comb. In addition, the hairs may be more fragile
than usual. Hair growth rate is usually normal but the
anagen phase may be truncated, with the result that the
hairs do not grow to be long. The hair shaft exhibits an
elliptical cross section, an axial rotation and a kinked
formation. A circumscribed occurrence of wooly hair
in the form of a wooly hair nevus285 is distinguished
from the forms that affect the entire scalp. The latter
forms are: autosomal dominant wooly hair (hereditary wooly hair) and, the much rarer form, autosomal
recessive hereditary wooly hair (familial wooly hair).286
Autosomal recessive hereditary wooly hair can be syndromic and accompanied by palmoplantar hyperkeratosis and heart anomalies (Fig. 88-30). No treatment
is currently available. Harsh physical and chemical
HIRSUTISM
15
Hirsutism is defined as excessive growth of terminal

hair in a male distribution in women.292 Hirsutism
is indicated by a hirsutism score of 8 or more on the
FerrimanGallwey scale (Fig. 88-31).61 It must be distinguished from hypertrichosis, generalized excessive
hair growth that may be hereditary or result from certain medications in men and women. Hypertrichosis
is distributed in a generalized, nonsexual pattern and
is not caused by excess androgen (although hyperandrogenism may aggravate it).
Defined as terminal body hair growth in

women in a male distribution
MARIEUNNA HYPOTRICHOSIS. MarieUnna

hypotrichosis is of autosomal dominant inheritance
and is characterized by sparse or absent hair at birth
and variable coarse, wiry hair growth during childhood, affecting scalp and eyebrows. Once the child
grows older, scalp hair is lost in a pattern, resembling AGA with scattered thick hair in the balding
areas. Body hair is sparse or absent. Male and female
individuals are equally affected. Light and electron
microscopic examination shows irregular twisting,
longitudinal ridging and cuticle peeling. Diffuse follicular hyperkeratosis and facial milia-like lesions
may be present. MarieUnna hypotrichosis results
from mutations in the upstream untranslated open
reading frame region of the hairless gene,287 which
maps to chromosome 8p21.288 There is no known
treatment.
HAIR SHAFT ABNORMALITIES
UNASSOCIATED WITH BREAKAGE OR
UNRULINESS
Pili Annulati. Pili annulati or ringed hairs occur as
an autosomal dominant or sporadic hair shaft abnormality without increased hair breakage. Pili annulati
can be present at birth or develop during infancy. It is
characterized by altering light and dark bands, which
are secondary to air-filled cavities in the cortex.289
The ringed appearance is clinically only detectable
in blond or light brown hair. The gene locus for pili
annulati maps to chromosome 12q24.290,291 No treatment is necessary, although hair care practices should
be gentle.
Women with mild to moderate hirsutism

and regular menstrual cycles are most
likely diagnosed with idiopathic hirsutism;
hormone testing is not necessary
Hormone testing is necessary in women with
moderate to severe hirsutism and all women
with hirsutism and irregular menstrual
cycles or sign of virilization
cosmetic treatments should be avoided. Wooly hair is

most pronounced during childhood; the manifestation
often becomes less severe in adulthood.
Women with a FerrimanGallwey score 8 or

higher are considered hirsute
::
Figure 88-30 Sporadic recessive wooly hair. (From Wolff

K, Goldsmith LA, Katz SI, Gichrest BA, Paller AS: Fitzpatricks
permission.)
Chapter 88
HIRSUTISM AT A GLANCE
Therapy should always consist of direct hair

removal with or without medical therapy
EPIDEMIOLOGY
Approximately 5% of women of childbearing age are
suffering from mild to severe hirsutism (Ferriman
Gallwey score 8 or higher).

Prior to puberty, body hair is vellus (small, straight, and
fair), and the sebaceous glands are small. In response
to the increased levels of androgens at puberty, vellus follicles in specific areas develop into terminal
hair follicles (larger, curlier, and darker). The growth
of terminal body hair (sexual hair) is entirely dependent on the presence of androgens, especially testosterone.292 Higher androgen levels are required for the
growth of beard hair than for pubic and axillary hair.
In other areas of the body (for example, the forehead
and cheeks), the increased androgen levels dramatically increase the size of the sebaceous glands while
the hair remains vellus.
Hirsutism results from an interaction between the
androgen level and the sensitivity of the hair follicle
to androgens. Some women have hirsutism without
evidence of androgen excess (idiopathic hirsutism).
1005
15
Upper lip
1
Chin
Section 15
Chest
Abdomen
Pelvis
Upper arms
Thighs
Upper back
Lower back
Figure 88-31 FerrimanGallwey scale.
1006
LABO RATORY TESTS

If hirsutism is mild (FerrimanGallwey score 815)
and menses are regular with no evidence of risk factors
that would suggest a secondary cause, it is reasonable
not to pursue laboratory evaluation, given the very
high likelihood of idiopathic hirsutism. If hirsutism is
moderate or severe (FerrimanGallwey score over 15),
or there are features to suggest an underlying disorder (Box 88-8), androgen excess must be ruled out. An
onset or progression of hirsutism or evidence of virilization (such as clitoromegaly or increasing muscularity) would raise concern for an androgen-secreting
neoplasm.62,297 Since most androgenic drugs are not
detected by testosterone assays, the history is particularly important. Medications that cause hirsutism
include anabolic or androgenic steroids; thus, whether
the patient is an athlete or has endometriosis or sexual
dysfunction heightens this risk. Valproic acid is unique
in raising plasma testosterone.298 The high frequency
of PCOS as a cause of hirsutism warrants attention to
evidence for anovulation (such as menstrual irregularity), obesity, metabolic syndrome, or insulin resistance
(acanthosis nigricans or a family history of type 2 diabetes mellitus). If risk factors like menstrual irregularity are present, even normal degrees of focal hirsutism
are usually associated with androgen excess.299 Other
disorders to be considered include various endocrinopathies. Cushing syndrome is suggested by the
development of truncal obesity, moon facies, buffalo
hump, purple striae, or proximal muscle weakness;
virilizing congenital adrenal hyperplasia or PCOS by a
Hughes CL: Hirsutism. In: Disorders of Hair Growth: Diagnosis and

Treatment, edited by EA Olsen. New York, McGraw-Hill, 1994,
p. 344, Table 14-2.
Clinical diagnosis and scoring can be difficult since

most women with hirsutism will practice various hair
removal techniques. Therefore, it is useful to let the
patient rate her degree of hair growth is different skin
areas according to the FerrimanGallwey score (upper
lip, chin and checks, chest, abdomen, pubic area and
lower abdomen, arms, legs, upper back and lower
back, and buttocks) with the help of images.
Androgen-secreting tumors
Adrenal
Adenoma
Adenocarcinoma (rare)
Ectopic adrenocorticotropic hormone-secreting
tumor (rare)
Ovarian
Gonadal stromal tumor
Thecoma
Lipoid tumor
Functional androgen excess
Adrenal enzyme deficiencies (congenital adrenal
hyperplasia)
Early onset 21-hydroxylase deficiency
Late-onset 21-hydropxylase deficiency
11-hydroxylase deficiency
3-ol dehydrogenase deficiency
Cushing syndrome
Polycystic ovarian disease
With or without adrenal contribution
Hyperthecosis
Idiopathic hirsutism
Medication/drug use
::
CLINICAL FINDINGS AND DIAGNOSIS
Box 88-8 Hirsutism
15
Chapter 88
Most women with a twofold or greater elevation of

androgen levels have some degree of hirsutism, but
in others these levels are associated with a hirsutism
equivalent (acne vulgaris, seborrhea, pattern alopecia, hidradenitis suppurativa, or hyperhidrosis).292
Androgen excess relates to an increase in bioactive free testosterone plasma levels. Total testosterone
includes the albumin bound and SHBG (sex hormone
binding globulin) bound testosterone. Hirsute women
commonly have a relatively low level of SHBG and
therefore more bioactive testosterone.62,293,294 Thus,
the free testosterone level may be elevated when the
total testosterone level is normal. SHBG levels are suppressed by the hyperinsulinemia of insulin-resistance
and by androgen excess itself.62,295 The level of SHBG
is also low in persons with hypothyroidism; rarely, it is
congenitally absent.296
history of the premature development of pubic hair or

acne; hyperprolactinemia by the presence of galactorrhea; and acromegaly by coarsening of the facial features or hand or foot enlargement.292
SPECIAL TESTS
Once androgen excess is confirmed, further tests
should be considered such as pregnancy test (if the
patient has amenorrhea), pelvic ultrasonography (if
an ovarian neoplasm or PCOS is suspected) and measurement of dehydroepiandrosterone sulfate and early
morning 17-hydroxyprogesterone (if congenital adrenal hyperplasia or adrenal neoplasm is suspected),
and a prolactin level. It may include measurement of
thyroid function, adrenocortical function, and IGF-I.
Further workup typically begins with dexamethasone suppression testing to determine the source of
androgen. If androgen excess is not suppressible by
dexamethasone, the presence of Cushings syndrome,
neoplasm, and PCOS must be considered. If androgen
excess is dexamethasone-suppressible, an adrenocorticotropic hormone (ACTH) test for congenital adrenal
hyperplasia is indicated. If an undetected neoplasm is
suggested, further imaging studies may be warranted,
such as abdominal computed tomography for adrenal
neoplasm.300
1007
15

Hirsutism tends to get more severe as the patient gets
older. Underlying disorders associated with hyperandrogenemia as mentioned earlier have to be ruled
out.
TREATMENT
Section 15
The main treatment goals are to remove the existing

terminal hair and to prevent further vellus-to-terminal
hair transformation. Direct hair removal should be considered for all women with hirsutism. In patients with
moderate to severe hirsutism and women with androgen access additional medical therapy is necessary.
Direct hair removal can be achieved with nonpermanent
techniques such as shaving, depilatories (lasts 12 hours
to a few days), waxing, threading and sugaring (lasts up
to 4 weeks), or permanent hair removal techniques such
as electrolysis (for white and blond hair) and photoepilation (intense pulsed light or laser). Several sessions of
photoepilation at intervals of 46 weeks are necessary
to achieve a satisfying result, since only anagen hair follicles with dark bulb areas can be destroyed by the light
source. Topical eflornithine has been shown to slow
down the hair cycle and can be used in combination
with every hair removal technique.
The first line medical therapy is oral contraceptives,
eventually in combination with antiandrogens. Glucocorticoids can be considered for women with hirsutism due to nonclassic congenital adrenal hyperplasia
who have a suboptimal response to oral contraceptives and/or antiandrogens, cannot tolerate them, or
are seeking ovulation induction. GnRH agonists in
women with severe forms of hyperandrogenemia,
such as ovarian hyperthecosis, who have a suboptimal
response to oral contraceptives and antiandrogens.
HYPERTRICHOSIS
Hypertrichosis is defined as an androgen-independent
generalized, increased growth of hair on the body. The
hair can be terminal or lanugo. Hypertrichosis can be
acquired or inherited. Congenital hypertrichosis lanuginosa is characterized by a generalized overgrowth of
silvery blonde to gray lanugo hair at birth or in early
childhood. This rare condtion is thought to be of autosomal dominant inheritance with variable expressivity. Most patients display anomalous dental eruptions.
Lanugo hair may persist, increase or decrease with
age.301,302 Autosomal dominant Ambras syndrome or
1008
Hypertrichosis universalis congenita is characterized

by much longer thicker hair distributed over the entire
body with accentuation over the face ears and shoulders. Ambras syndrome can be associated with facial
dysmorphism and dental anomalies.303305 An X-linked
dominant congenital generalized Hypertrichosis has
been described in a five-generation family with an
accentuation on the face and upper body.302,306 Patients
with autosomal dominant or recessive gingival fibromatosis frequently display hypertrichosis, mostly on
the face, eyebrows limbs and upper back, which may
be associated with seizures and oligophrenia. Hypertrichosis may show a delayed onset until puberty
although gingival fibromatosis usually appear with
the emergence of the primary teeth1 (eBox 88-8.1 in
online edition).
ACKNOWLEDGMENT
Thanks to Dr. Elise Olsen, an active investigator of hair
diseases, and author of this chapter in three previous
editions for her contributions to hair research and to
this text.
KEY REFERENCES
27. Olsen EA et al: Summary of North American Hair
Research Society (NAHRS)-sponsored Workshop on
Cicatricial Alopecia, Duke University Medical Center. J
34. Tosti A, Gray J: Assessment of hair and scalp disorders. J
Investig Dermatol Symp Proc 12:23-27, 2007
43. Otberg N, Finner AM, Shapiro J: Androgenetic alopecia.
Endocrinol Metab Clin North Am 36:379-398, 2007
62. Zouboulis CC et al: Sexual hormones in human skin.
Horm Metab Res 39:85-95, 2007
102. Shapiro J, Price VH: Hair regrowth. Therapeutic agents.
Dermatol Clin 16:341-356, 1998
109. Price VH: Treatment of hair loss. N Engl J Med 341:964973, 1999
115. Rogers NE, Avram MR: Medical treatments for male and
female pattern hair loss. J Am Acad Dermatol 59:547-566,
2008
166. Alkhalifah A et al: Alopecia areata update: Part I. Clinical picture, histopathology, and pathogenesis. J Am Acad
Dermatol 62:177-188, 2010
167. Alkhalifah A et al: Alopecia areata update: Part II. Treatment. J Am Acad Dermatol 62:191-202, 2010
199. Otberg N et al: Diagnosis and management of primary
cicatricial alopecia: Part I. Skinmed 7:19-26, 2008
200. Wu WY et al: Diagnosis and management of primary
cicatricial alopecia: Part II. Skinmed 7:78-83, 2008
Chapter 89 :: Biology of Nails and Nail Disorders

:: Antonella Tosti & Bianca Maria Piraccini
BIOLOGY OF NAILS
Biology of Nails and Nail Disorders
(See Fig. 89-1A)

The nail plate is a fully keratinized structure that
is continuously produced throughout life (see Fig.
89-1B). It results from maturation and keratinization of
the nail matrix epithelium and is firmly attached to the
nail bed, which partially contributes to its formation.
Proximally and laterally the nail plate is surrounded
by the nail folds, which cover its proximal third and
lateral margins. At the tip of the digit, the nail plate
separates from the underlying tissues at the hyponychium. The nail plate is rectangular, translucent, and
transparent. It is curved in both the longitudinal and
transverse axes, especially in the toes. The nail plate
surface is smooth but frequently shows mild longitudinal ridges that increase with aging (Fig. 89-2). The
pattern of these ridges can be used for forensic identification. The bottom of the nail plate shows longitudinal ridges that correspond to the rete ridges of the nail
::
NAIL PLATE
Chapter 89
The nail apparatus consists of a horny dead product,

the nail plate, and four specialized epithelia: (1) the
proximal nail fold, (2) the nail matrix, (3) the nail bed,
and (4) the hyponychium (Fig. 89-1A). The nail apparatus develops during the 9th embryonic week from
the epidermis of the dorsal tip of the digit as a rectangular area, the nail fold that is delineated by a continuous groove.1 The proximal border of the nail fold
extends downward and proximally into the dermis to
form the nail matrix primordium. By the 15th week the
nail matrix is completely developed and starts to produce the nail plate, which will continue to grow until
death. The nail apparatus lies immediately above the
periosteum of the distal phalanx. The intimate anatomic relationship between the nail and the bone is
responsible for the common occurrence of bone alterations in nail disorders and vice versa. The shape of the
distal phalangeal bone also determines the shape and
the transverse curvature of the nail.
Fingernails usually present a longitudinal major axis
and toenails a transverse major axis. The ratio between
length and width is important for the aesthetic appearance of the nails. The size of the nails varies in the different digits. The biggest nail is that of the first toe, which
covers approximately 50% of the dorsum of the digit.
Nails have numerous functions. Fingernails not only
contribute to the pleasing appearance of the hands, but
are very important in protecting the distal phalanges
and enhancing tactile discrimination and the capacity
to pick up small objects. They are also widely used for
scratching and grooming and are an efficient natural
weapon. Toenails protect the distal toes and contribute
to pedal biomechanics.
bed. The nail plate is homogeneously pink, except for

its free edge, which is white. The pink color of the nail
plate is due to the nail bed blood vessels.
The proximal part of the fingernails, especially of
the thumbs, shows a whitish, opaque, half-moonshaped area, the lunula that is the visible portion of
the nail matrix. In this area the nail plate attachment to
the underlying epithelium is loose. More than 90% of
fingernails show a thin distal transverse white band,
the onychocorneal band, better defined as the isthmus,
which marks the most distal portion of firm attachment
of the nail plate to the nail bed.2,3 This area represents
an important anatomic barrier against environmental
hazards, and its disruption produces nail plate detachment with onycholysis. The onychocorneal band is
separated from the nail plate white free edge by a 1.0
1.5-mm pink band called the onychodermal band.
In transverse sections, the nail plate consists of three
portions: (1) dorsal nail plate, (2) intermediate nail
plate, and (3) ventral nail plate.4 The dorsal and the
intermediate portions of the nail plate are produced by
the nail matrix, whereas its ventral portion is produced
by the nail bed. Above the lunula the nail plate is thinner and consists only of the dorsal and intermediate
portions. There is a natural line of cleavage between
the dorsal and the intermediate nail plate.
The nail plate progressively thickens from its emergence to its distal margin. The mean toenail thickness
at the distal margin is 1.65 0.43 mm in men and 1.38
0.20 mm in women. Fingernails are thinner; the mean
thickness is 0.6 mm in men and 0.5 mm in women.
There is an increase in nail thickness with age, particularly in the first two decades. Nail thickness depends
on the length of the nail matrix and nail bed.5 Thinning
of the nails is usually a sign of nail matrix disorders,
whereas nail thickening is most commonly a consequence of nail bed disorders.
15
PROXIMAL NAIL FOLD

(See Fig. 89-1A)
The proximal nail fold is a skin fold that consists of a
dorsal and a ventral portion. The dorsal portion is anatomically similar to the skin of the dorsum of the digit
but thinner and devoid of pilosebaceous units. The
ventral portion, which cannot be seen from the exterior
and proximally continues with the germinative matrix,
covers approximately one-fourth of the nail plate. It
closely adheres to the nail plate surface and keratinizes
with a granular layer. The limit between the proximal
nail fold and the nail matrix can be histologically established at the site of disappearance of the granular layer.
The horny layer of the proximal nail fold forms the
cuticle, which is firmly attached to the superficial nail
plate and prevents the separation of the plate from the
nail fold. The integrity of the cuticle is essential for
maintaining the homeostasis of this region.
1009
15
Normal nail
Proximal nail fold

Nail matrix
Lunula region
Cuticle
Nail bed
Nail plate
Hyponychium
Section 15
Ventral proximal nail folds:

suprabasal K1, K10, K16, K6
basal pattern of LH6
Matrix tip:
K7, K8, K17, K18
Nail bed:
suprabasal K16, K17
Panepidermal: K6, K14, LH6

C46 antibody to K7/K1
Digit pulp:
K6, K16
Basal pattern of LH6
Panepidermal,
K14
Suprabasal, K1,
K10, Ha-1
Small clusters of
cells in some cases
K17
Normal expression
of K1, K10, K14, LH6
in digit pulp
Figure 89-1 A. Diagrammatic drawing of a normal nail. B. Keratin gene expression at different locations within the nail.
(From De Berker D et al: Keratin expression in the normal nail unit: Markers of regional differentiation. Br J Dermatol 142:89,
2000, with permission.)
The dermis of the proximal nail fold contains numerous capillaries that run parallel to the surface of the
skin and may easily be observed in vivo by capillary
microscopy. This permits the observation of both the
arterial and the venous limbs of the capillaries, which
are arranged in parallel rows and appear as fine regular loops with a small space between the afferent and
efferent limbs. The morphology of proximal nail fold
capillaries is typically altered in connective tissue
diseases.68
NAIL MATRIX
1010
Figure 89-2 Longitudinal ridging of the nail plate surface.

This is commonly observed in the elderly.
(See Fig. 89-1A)

The nail matrix is a specialized epithelial structure
that lies above the mid portion of the distal phalanx.
erhans cells are more numerous in the proximal than

in the distal nail matrix. As in normal epidermis,
Langerhans cells are predominantly found in the
suprabasal layers. However, they may occasionally
be seen within the basal layer of the nail matrix epithelium.
MERKEL CELLS. The presence of Merkel cells in the

nail matrix has been demonstrated. Their density is
possibly influenced by age, with these cells being more
numerous in fetus than in adult nails.18
NAIL BED
(See Fig. 89-1A)
The nail bed extends from the distal margin of the
lunula to the isthmus and is completely visible through
the nail plate. The nail bed epithelium is so adherent to
the nail plate that it remains attached to the undersurface of the nail when the latter is avulsed.
The nail bed epithelium is thin and consists of two
to five cell layers. Its rete ridges, which are longitudinally oriented, interdigitate with the underlying dermal ridges in a tongue-and-groove-like fashion. The
nail bed epithelium is a specialized epithelial structure
with a horny layer that interlocks to of the inferior border of the nail plate and is responsible for the strong
attachment between the two tissues. Nail bed horny
layer forms the ventral nail plate, which corresponds
to approximately one-fifth of the terminal nail thickness and mass.19 In pathologic sections, the ventral nail
plate is easily distinguishable because of its light eosinophilic appearance. Nail bed keratinization is not associated with the formation of a granular layer. This may
appear, however, when the nail bed becomes exposed
after nail avulsion.1
The nail isthmus is a thin transverse distal band that
represents a transitional zone between the nail bed
and the hyponychium and exhibits a unique pattern
of keratinization, the onycholemmal keratinization,
with pale, nucleated keratinocytes. The cornified layer
of the nail isthmus closely adheres to the undulating
inferior surface of the nail plate preventing onycholysis; the two grow forward together.3 Keratin expression
in the nail bed differs form that of the nail matrix since
keratins K6, K16, and K6hf are only expressed in the
nail bed.20 The isthmus differs from nail bed because of
a strong suprabasal expression of K10. Transition from
isthmus to hyponychium is marked by the disappearance of expression of K6hf and K6/16, and return to
expression of K5/17.
MELANOCYTES. (See Chapter 72). Nail matrix

melanocytes are usually quiescent and therefore not
detectable in pathologic sections. However, they possess the key enzymes that are necessary for melanin
production, and may become activated by a large
number of physiologic and pathologic conditions.15
Nail matrix melanocyte activation produces diffuse
or banded nail pigmentation and is more common in
blacks and Japanese than in Caucasians. DOPA-negative (inactive) melanocytes are sparsely present in the
nail matrix and in the nail bed.16 DOPA-positive, activable melanocytes are especially seen in the distal nail
matrix, where they are frequently arranged in small
clusters among the suprabasal layers of the nail matrix
epithelium.17
15
::
NAIL MATRIX KERATINOCYTES. (See Fig. 89-1B).

The nail matrix cells are able to synthesize both soft
or skin-type and hard or hair-type keratins.1012
Evaluation of keratin expression in the different constituents of the nail apparatus showed that the nail
matrix is the sole site of expression of hard keratin
proteins, particularly Ha1 keratin.13 Data indicate that
fibroblasts derived from the nail matrix may induce
hard keratin expression in nonnail-matrix keratinocytes.14
LANGERHANS CELLS. (See Chapter 10). Lang-
Chapter 89
After elevation of the proximal nail fold, the matrix

appears as a distally convex crescent with its lateral
horns extending proximally and laterally.
In longitudinal sections the matrix has a wedgeshaped appearance and consists of a proximal (dorsal)
and a distal (ventral) portion. Nail matrix keratinocytes divide in the basal cell layer and keratinize in the
absence of a granular zone. The site of keratinization
(keratogenous zone) of nail matrix onychocytes can
be clearly distinguished in histological sections as an
eosinophilic area where cells show fragmentation of
their nuclei and condensation of their cytoplasm.1 In
this area, nuclear fragments are destroyed by deoxyribonuclease and ribonuclease enzymes. In some
conditions nuclear fragments may persist within the
intermediate nail plate, producing leukonychia spots.
However, these frequently disappear before reaching
the nail-free edge, due to the persistence of active DNA
and RNA lytic enzymes within the horny nail plate.
Maturation and differentiation of nail matrix keratinocytes do not follow a vertical axis, as in the epidermis, but occur along a diagonal axis that is distally
oriented. For this reason, keratinization of the proximal nail matrix cells produces the dorsal nail plate and
keratinization of the distal nail matrix cells produces
the intermediate nail plate.
In some fingers the distal matrix is not completely
covered by the proximal nail fold but is visible through
the nail plate as a white half-moon-shaped area, the
lunula. The white color of the lunula results from two
main anatomic factors: (1) the keratogenous zone of
the distal matrix contains nuclear fragments that cause
light diffraction, (2) nail-matrix capillaries are less visible than nail bed capillaries because of the relative
thickness of the nail-matrix epithelium.9
HYPONYCHIUM
The hyponychium marks the anatomic area between
the nail bed and the distal groove, where the nail
plate detaches from the dorsal digit (see Fig. 89-1A).
Its anatomic structure is similar to that of plantar
and volar skin, and keratinization occurs through the
formation of a granular layer. The horny layer of the
1011
15
hyponychium partially accumulates under the nail

plate free margin. The hyponychium is normally covered by the distal nail plate, but it may become visible
in nail biters. The architecture of the capillary network
of the hyponychium dermis consists in regular capillary loops arranged perpendicularly to the skin, visible
as red dots with dermoscopy.
BASEMENT MEMBRANE ZONE
Section 15
The antigenic structure of the basement membrane

zone of the nail is identical to that of the epidermis,
and there are no differences in the antigenic composition of the basement membrane zone in the different
portions of the nail apparatus.21 This may explain the
involvement of the nails in conditions characterized
by mutations of basement membrane-associated genes
as well as in autoimmune skin diseases involving the
basement membrane zone antigens.22
DERMIS
(See Fig. 89-1A)
The nail apparatus is devoid of subcutaneous tissue,
and its dermis does not contain pilosebaceous units.
The arrangement of the rete ridges varies in the different portions of the nail apparatus. The dermis beneath
the proximal nail matrix consists of condensed connective tissue that forms a tendon-like structure connecting the matrix to the periosteum of the proximal
phalangeal bone (posterior ligament). A small amount
of subdermal fat tissue is present close to the periosteum of the base of the phalanx.23 The close connection between the lateral horns and the periosteum is
possibly responsible for the nail plates lateral convexity. The rete ridges of the dermis underneath the
nail matrix are characteristically long and root-like in
shape. The dermis under the distal matrix consists of a
loose network of connective tissue containing numerous blood vessels and rare glomus bodies.
The dermis of the nail bed has a unique arrangement
with longitudinal grooves and ridges that run from the
lunula to the hyponychium.1 The longitudinal orientation of the capillary vessels within the nail bed grooves
explains the linear pattern of nail bed hemorrhages
(splinter hemorrhages). The nail bed dermis contains
abundant connective tissue networks with connective
tissue bundles radiating to the phalangeal periosteum.
It contains numerous glomus bodies.
BLOOD AND NERVE SUPPLY
1012
The nail apparatus has an abundant blood supply provided by the lateral digital arteries. These run along
the sides of the digits and produce both branches
that supply the matrix and the proximal nail fold and
arches that supply the matrix and the nail bed. The nail
matrix, therefore, has two different sources of blood
supply. The nail bed is richly supplied (1020 cm2) by
encapsulated neurovascular structures containing one
to four arteriovenous anastomoses and nerve endings. These glomus bodies are arteriovenous shunts
involved in the regulation of the blood supply to the
digits related to thermoregulation. The cutaneous sensory nerves, which originate from the dorsal branches
of the paired digital nerves, run parallel to the digital
vessels.
CHEMICAL PROPERTIES
(See Fig. 89-1B)
The nail plate, like hair, consists mainly of low-sulfur
filamentous proteins (keratins) embedded in an amorphous matrix composed of high-sulfur proteins rich in
cysteine. Other nail constituents include water, lipids,
and trace elements. Nail keratins consist of 80%90%
hard hair-type keratins and 10%20% soft skin-type
keratins. Hard keratins have been identified as the
acidic 44K/46K and basic 56K/60K keratins. Soft keratins have been identified as the 50K/58K and 48K/56K
keratin pairs.24 Keratin filaments have a transverse
orientation that is parallel to the nail surface. This
explains why the nail plate is more susceptible to transverse fractures than to longitudinal fractures. Specific
keratins are expressed only in some compartments of
the nail unit; for instance, K6a and K6b, K16, and K17
are not expressed in the nail matrix.13,25,26 Mutations
of the genes encoding for these keratins are associated with nail thickening due to nail bed hyperproliferation, as is seen in pachyonychia congenita (PC).27,28
Nail keratin content and composition, measured as the
quantity of carbon (C), nitrogen (N), and sulfur (S) in
the fingernails, vary between sexes and in relation to
the aging process. Sulfur content is higher in female
than in male nails and the opposite is for nitrogen.
Carbon content is equal in the two sexes. The carbon
content increases with aging, possibly due to loss of
inorganic material, and the nitrogen content decreases,
while the sulfur content remains stable.29
Under normal conditions, the water content of the
nail plate is 18%, and most of the water is in the intermediate nail plate.30 The average water content of the
nail plate is significantly lower in winter than in summer.31) and varies significantly in time, due to the high
porosity of the nail plate, which allows it to be rapidly hydrated and dehydrated. Dehydration is faster
when the nails are kept long. When the water content
decreases below 18%, the nail becomes brittle; when
it increases above 30%, it becomes opaque and soft.32
The nail contains less than 5% lipids, mainly cholesterol; the nail plate lipid content is under hormonal
control and decreases after menopause.33 The nail plate
also contains traces of several inorganic elements, particularly iron, zinc, and calcium. However, these do
not contribute to nail hardness.
PHYSICAL PROPERTIES
The nail plate is hard, strong, and flexible. The hardness and strength of the nail plate are due to its high
content of hard keratins and cysteine-rich high-sulfur
(See Table 89-1)
BEAUS LINES AND ONYCHOMADESIS

(NAIL SHEDDING)
Beaus lines result from a temporary arrest of proximal nail matrix proliferation and appear as transverse
grooves, often deeper in the central nail plate, that
move distally with nail growth. Onychomadesis also
results from a temporary arrest in nail matrix activity,
The nail plate grows continuously in a proximal to distal manner throughout life. The nail plate is pushed
out by two factors: (1) matrix keratinocytes proliferation and differentiation which makes a new plate,
(2) the nail bed which moves slowly, parallel to the
direction of the nail growth, toward the inferior border
of the nail plate.3
Fingernails grow two times faster than toenails, with
a mean growth rate in adults of 3.5 mm/month for fingernails and 1.5 mm/month for toenails. The 5th fingernail growth rate is significantly slower than other
fingernails and the growth rate of the great toenail significantly faster than other toenails.38
Complete replacement of a fingernail requires 100
180 days (6 months). When the nail plate is extracted, it
is approximately 40 days before the new fingernail first
emerges from the proximal nail fold. After a further
120 days it will reach the fingertip.39 The total regeneration time for a toenail is 1218 months. As a consequence of the slow nail growth rate, diseases of the nail
matrix only become evident a considerable time after
their onset and require a long time to disappear after
treatment.
Nail growth rate varies among different individuals and among the different digits of the same individual. It depends on the turnover rate of the nail
matrix cells and is influenced by several physiologic
and pathologic conditions. Nail growth rate is slow at
birth, increases slightly during childhood, and usually
reaches its maximum between the second and the third
decades of life. It sharply decreases after the age of 50
years.39
Conditions that have been associated with a slow
growth rate include systemic illness, malnutrition,
peripheral vascular or neurologic diseases, and treat-
NAIL SIGNS AS A FUNCTION OF

THE SITE OF PATHOLOGY1,32
15
::
NAIL GROWTH
ment with antimitotic drugs. Nails affected by onychomycosis frequently exhibit a slow growth rate.
An arrest of nail growth is a typical feature of yellow
nail syndrome. Conditions that have been associated
with accelerated nail growth include pregnancy, finger
trauma, psoriasis, and treatment with oral retinoids or
itraconazole. Accelerated nail growth may cause longitudinal ridging of the nail plate (nail beading).
Due to their slow growth rate, the nails may provide information on pathologic conditions that have
occurred up to several months before the time of observation. Drugs, chemicals, and biologic substances
accumulate in nails, where they can be detected and
measured. Advantages of analyzing nail samples
include the ease and noninvasiveness of their collection, the small sample size required for analysis, and
the ease of storage at room temperature. The nail of the
big toe is the best site for investigation because of its
size (big toenail length of an adult: 20 mm) and slow
growth rate (about 2 mm/month) permitting to obtain
data on exposure to drugs and chemicals over a period
of 10 months.40
Chapter 89
proteins, whereas its flexibility depends on its water

content and increases with nail plate hydration.34,35
The double curvature of the nail plate along its longitudinal and transverse axes enhances nail plate resistance to mechanical stress.36
The physical properties of the nail also depend on
the arrangement and adhesion of onychocytes in the
different portions of the nail plate, as well as on the orientation of the keratin filaments within the nail plate
onychocytes.36 At the ultrastructural level, the corneocytes of the dorsal nail plate are flat, with their shorter
diameter perpendicular to the nail plate surface.
The average sizes of these cells are 34 m in length,
64 m in width, and 2.2 m in height.37 Cell adhesion
is strong. This portion of the nail is responsible for nail
plate hardness and sharpness. The onychocytes of the
intermediate nail plate show multiple interdigitations
of their cell membranes. The average dimensions of
these cells are 40 m in length, 53 m in width, and
5.5 m in height. Cell adhesion is provided by desmosomes. This part of the nail plate is responsible for nail
pliability and elasticity. The ventral nail plate is thin
and consists of soft keratins. It provides adhesion to
the underlying nail bed.
TABLE 89-1
Relation Between Resultant Clinical Manifestations

and Location of Pathologic Change
Proximal Matrix
Beaus Lines
Pitting
Longitudinal striations
Longitudinal fissures
Longitudinal grooves
Trachyonychia
Distal matrix
True leukonychia
Proximal and distal

matrix
Koilonychia
Onychomadesis
Nail bed
Longitudinal erythronychia
Onycholysis
Splinter hemorrhages
Apparent leukonychia
Nail bed and

hyponychium
Subungual hyperkeratosis
Proximal nail fold
Paronychia
Periungual erythema
1013
15
Box 89-1 Causes of Beaus Lines

and Onychomadesis
Section 15
Trauma
Manicure
Onychotillomania
Dermatologic diseases
Eczema
Erythroderma
Paronychia
Systemic conditions
Use of certain drugs
High fever
Viral illness (hand-foot-and-mouth disease;
measles)
Diarrhea
Kawasaki syndrome
Peripheral ischemia
and the proximal nail plate is detached from the proximal nail fold by a whole-thickness sulcus. Causes of
onychomadesis are the same as those for Beaus lines
but are more severe (Box 89-1). Multiple Beaus lines
or onychomadesis in the same nail indicates repetitive insults. Measuring the distance of the groove from
the proximal nail fold can date the time of the insult
leading to Beaus lines. Local trauma, such as from
manicures or onychotillomania, or related to local
cutaneous disease, particularly dermatitis, periungual erythema, and paronychia, are causes of Beaus
lines. Beaus lines or onychomadesis at the same levels in several nails suggest a systemic cause (Fig. 89-3).
Most common among these are drugs (especially chemotherapy), high fever, viral illness,41,42 surgery, and
peripheral ischemia. Onychomadesis in children often
relates to recent coxsackievirus infection (hand-footmouth disease).41,43
Figure 89-3 Beaus lines of several nails after systemic

illness. Note involvement of all the nails at the same level.
and fissures. Onychorrhexis is a sign of severe nail fragility and typical of lichen planus (see Chapter 26).
LONGITUDINAL GROOVES
Longitudinal grooves are usually single and appear
as a longitudinal depression of the nail plate (12 mm
large) due to compression of the nail matrix by tumors
of the proximal nail fold.
TRACHYONYCHIA
Trachyonychia results from multiple foci of defective
keratinization of the proximal nail matrix. The nails are
rough due to excessive longitudinal ridging.
TRUE LEUKONYCHIA
True leukonychia results from defective keratinization
of the distal matrix with persistence of parakeratotic
PITTING
Pits result from small areas of abnormal keratinization
of the proximal nail matrix that produce foci of parakeratotic cells in the superficial nail plate. They appear
as small punctate depressions of the superficial nail
plate, which progress distally and often become more
evident with nail growth. Deep and irregularly distributed pits are seen in psoriasis (Fig. 89-4) and atopic
dermatitis; geometric and superficial pits are typical of
alopecia areata (see Chapters 14, 18, and 88).
ONYCHORRHEXIS (LONGITUDINAL
STRIATIONS AND FISSURING)
1014
Onychorrhexis results from diffuse defective keratinization of the proximal nail matrix. The nail plate is usually thinned and presents multiple longitudinal ridges
Figure 89-4 Pitting: small punctate depressions of the superficial nail plate. In psoriasis, pits are irregularly distributed and
often associated with onycholysis and splinter hemorrhages.
Box 89-2 Causes of Longitudinal

Melanonychia
Figure 89-5 Punctate leukonychia due to microtraumas

in a child.
MELANONYCHIA44
Melanonychia describes a brown to black color of the
nail due to the presence of melanin in the nail plate. It
can be caused by activation or proliferation (benign or
malignant) of nail matrix melanocytes. The pigmentation may involve the whole nail (total melanonychia)
or may be banded, as in transverse melanonychia
(rare) or in the most common longitudinal melanonychia (LM). LM may appear as a single band involving one digit, or as multiple bands affecting several
digits, which are usually due to melanocyte activation, as is seen in dark-skinned individuals, pregnant
women, inflammatory nail disorders, individuals with
LaugierHunziker syndrome, and those taking certain
medications (Box 89-2). LM has also been described in
individuals with a variety of systemic disorders, particularly human immunodeficiency virus infection and
Addison syndrome. In LaugierHunziker syndrome,
melanonychia begins during adolescence, affects several digits, and is associated with the presence of lip
and/or genital pigmented macules45,46 (see Chapter
78). Melanonychia due to melanocyte activation may
in some cases involve a single digit, as in patients with
onychotillomania, with frictional melanonychia of the
4th or 5th toenails (Fig. 89-6), with inflammatory nail
diseases, such as psoriasis or lichen planus, or with
nail tumors, such as Bowens disease. A single band
of melanonychia deserves a careful evaluation, since
it may be a sign of a nail matrix nevus or melanoma
(see Chapters 122 and 124). LM of a single nail often
deserves biopsy.
Longitudinal erythronychia reflects a nail bed disorder

and appears as a pinkred longitudinal band of various width extending from the proximal nail to the distal edge. A single band of longitudinal erythronychia
is most commonly caused by an onychopapilloma or
by another benign or malignant subungual tumor (Fig.
89-7). Multiple bands of longitudinal erythronychia
are seen in lichen planus. In Dariers disease bands of
longitudinal erythronychia alternate with white longitudinal bands and V-shaped indentations of the nailfree margin (see Chapter 51).
ONYCHOLYSIS
Onycholysis is detachment of the nail plate from the
nail bed and can be caused by traumatic, inflammatory, infectious, or neoplastic nail bed disorders. See
Section Onycholysis under Environmental Nail
Disorders.
In koilonychia the nail plate is thin and spoon shaped.

Koilonychia is physiologic in the toenails of children.
In adults it can be a sign of iron deficiency or occupational damage to the nail plate.
LONGITUDINAL ERYTHRONYCHIA47
::
KOILONYCHIA
Race
Acquired immunodeficiency syndrome
Inflammatory nail disorders
Addison disease
Pregnancy
LaugierHunziker syndrome
Trauma
Chapter 89
cells in the ventral nail plate. The superficial nail plate

is structurally normal, but the nail presents opaque
white patches or striae, which often disappear before
reaching the distal edge of the nail. Punctate leukonychia is due to microtrauma and is typically seen
in the fingernails of children (Fig. 89-5). Striate leukonychia of fingernails is a consequence of aggressive
manicure. Total or subtotal leukonychia is rare and
usually hereditary.
15
SPLINTER HEMORRHAGES
Splinter hemorrhages appear as red to black small thin
longitudinal lines under the nail plate. They are more
commonly located in the distal nail plate and represent
Figure 89-6 Frictional melanonychia of the 4th and 5th

toenails.
1015
15
SUBUNGUAL HYPERKERATOSIS
Subungual hyperkeratosis is due to inflammatory disorders that cause an abnormal keratinization of the
distal nail bed and hyponychium with accumulation
of scales under the distal nail plate. The most common
causes include psoriasis, onychomycosis, trauma, contact and atopic dermatitis (see Chapters 13, 14, and 18).
PARONYCHIA
Section 15
Paronychia is inflammation of the proximal nail fold

and presents as painful periungual erythema, sometimes with associated purulence. Acute paronychia is
usually caused by infection (see Section Infectious
Nail Disorders). Chronic paronychia is most commonly due to mechanical or chemical factors. If the
periungual area is fluctuant or shows purulence, it
should be drained to avoid matrix damage. Topical
and/or systemic antibiotics should be administered if
bacterial infection is suspected.
NAIL PIGMENTATION
Figure 89-7 Longitudinal erythronychia. The nail plate

shows a narrow longitudinal pale pink band that ends
with a dark red steak corresponding to a splinter hemorrhage. This clinical feature is typical of onychopapilloma.
rupture of the longitudinally oriented nail bed capillaries (Fig. 89-8). Causes include trauma and inflammatory nail disorders, such as psoriasis.
APPARENT LEUKONYCHIA
In apparent leukonychia the nails are pale white due to
nail bed discoloration that fades with pressure.
Nail pigmentation is most commonly due to exogenous staining of the nail plate. In this case the proximal margin of the pigmentation follows the shape of
the proximal nail fold. Exogenous nail pigmentation
is most commonly due to occupational exposures or
nail cosmetics. Nail pigmentation due to endogenous
causes is rare. The proximal margin of the pigmentation follows the shape of the lunula. Possible causes
include drugs, argyria, hemochromatosis, alkaptonuria, and Wilson disease.
HEREDITARY AND CONGENITAL

NAIL DISORDERS48
(See Table 89-2)
ECTODERMAL DYSPLASIAS
(See Chapter 142)
Nail changes may be associated with hypotrichosis,
hypodontia, and hypohidrosis. Most commonly the
nails are short, thickened, and hypoplastic.
1016
Figure 89-8 Multiple distal splinter hemorrhages in a

manual worker with mild nail psoriasis.
(See Chapter 62)

Nail abnormalities are a common feature in most subtypes of epidermolysis bullosa (EB) and have recently
been included among the criteria for scoring EB severity.49
Trauma undoubtedly contributes to the development of
nail dystrophy and for this reason the great toenails are
more often severely affected. Pachyonychia of the toenails
be the first or the only symptom of dominant dystrophic
EB (DDEB) in some families (eFig. 89-8.1 in online edition).
Junctional and dermolytic EB may produce anonychia.50
15
TABLE 89-2
Hereditary and Congenital Nail Disorders
Partial or total anonychia

Pachyonychia
Subungual/periungual
hemorrhagic blisters
Periungual erosions with
granulation tissue
Pachyonychia congenita
Onychogryphosis
Severe thickening
Yellowbrown discoloration
Iso-Kikuchi syndrome
Micronychia/anonychia
Hemionychogryphosis
Nail patella syndrome
Hypoplasia/aplasia
Triangular lunulae
Congenital malalignment
of the hallux
Lateral deviation of the nail

plate
Lateral/distal embedding
of nail
Nail thickening
Yellowbrown discoloration
Transverse ridging
PACHYONYCHIA CONGENITA
(See Chapter 50)
PC is an autosomal dominant genodermatosis characterized by painful keratoderma, nail thickening, oral
leukokeratosis, and epidermal cysts. The severity of PC
can vary greatly among patients and the most problematic aspect of PC, the painful palmoplantar keratoderma (PPK), have vary in extent from focal to a severe,
diffuse PPK.51 The International Pachyonychia Congenita Research Registry (IPCRR) has compared the PC
phenotype with genotype in hundreds of individuals,
and have found issues with the classical division into
PC1 (Jadassohn-Lewandowski type) and PC2 (JacksonLawler). A new molecular classification has been proposed, in which subtypes of PC refer to the mutated
keratin gene.52 Mutations in KRT6A account for almost
50% of known cases, while 24% have mutations are in
KRT16, 23% in KRT17, and 3% in KRT6B.53 In contrast
to the old classification, in which PC1 was thought to
result from mutations in KRT6a or 16, and PC2 from
mutations in KRT6b or 17, the clinical features of the
former subtypes overlap. For example, cysts (a feature
of PC2 and not PC1) most commonly occur in individuals with either a KRT17 mutation or KRT6a mutation.
Nail abnormalities are a constant feature and
develop during infancy to early childhood, although
a late-onset variety of PC has been described.54 In typical cases the 20 nails are thickened, very difficult to
trim, darkened, and with an increased transverse curvature. Nail thickening is a consequence of nail bed
hyperkeratosis and is more evident on the distal half
of the nails, which have an upward angling. Recent
evidence indicates that PC may also present with very
Figure 89-9 Nail patella syndrome: nail hypoplasia of the

1st and 2nd fingers.
subtle nail changes and that there is not a good correlation between mutations detected at molecular level
and clinical phenotype. Severity may even vary among
family members with the same gene mutation.55,56
NAIL PATELLA SYNDROME

Nail abnormalities in nail patella syndrome may
involve all fingernails or may be limited to the thumbs,
which are always the most severely affected digits (Fig.
89-9). Nail hypoplasia is usually more marked in the
medial portion of the nail. The shape of the lunula is
typically triangular.48
::
Atrophy/Thickening
Chapter 89
Ectodermal Dysplasias
CONGENITAL MALALIGNMENT
OF THE HALLUX
Congenital malalignment of the hallux is the most common cause of ingrowing (ingrown) nails and is usually
diagnosed when the child starts to walk. The great toenail shows a lateral deviation that produces embedding
of the lateral side of the nail plate (Fig. 89-10). The digit
is painful and the toenail often shows Beaus lines and
Figure 89-10 Congenital malalignment of the big toenail

associated with mild disto-lateral ingrowing on the medial
side.
1017
15
TABLE 89-3
Infectious Nail Disorders

Bacterial
Streptococcus pyogenes
Viral
Herpes simplex
Warts
Fungal
Dermatophytes
Section 15
Nondermatophytes
Candida sp.
Acute paronychia
Acute paronychia
Acute paronychia
Onycholysis
Periungual vesicles
Periungual/subungual papules
DSO
PSO
WSO
PSO + periungual inflammation
Deep WSO
TO + paronychia
DSO = distal subungual onychomycosis; PSO = proximal subungual

onychomycosis; WSO = white superficial onychomycosis; TO = total
onychomycosis.
onycholysis. Congenital malalignment may be unilateral or bilateral. Spontaneous improvement may occur,
and most children do not have symptoms by the age of
2 years.57 Inflammation due to lateral ingrowing can
be managed by daily massaging of the lateral nail fold
with creams containing steroids, antibiotics, and urea.
Surgical treatment may be necessary if nail symptoms
are severe and do not subside with growth.58,59
INFECTIOUS NAIL DISORDERS

(See Table 89-3)
ACUTE PARONYCHIA
Acute paronychia is most commonly due to Staphylococcus aureus infection and typically affects a childs
fingernail. Predisposing factors include nail biting or
sucking and occupational traumas. The proximal nail
fold is painful, erythematous, and swollen. Pus may
be discharged after pressure (see Chapter 176). The
differential diagnosis includes herpes simplex virus

infection (see Chapter 193) and Hallopeaus acrodermatitis (see Chapter 21), both of which have a typical
relapsing course. Suspicion of Herpes simplex-virus
infection should arise when the pain intensity is disproportionate to the clinical symptoms and the disease
is recurrent. The treatment of choice depends on the
extent of the infection. If diagnosed early, acute paronychia without obvious abscess can be treated nonsurgically, often with topical antibiotics alone. If an
abscess has developed, incision and drainage must be
performed. Oral antibiotics with Gram-positive coverage against S. aureus, such as cephalexin, amoxicillin
with clavulanic acid, and clindamycin, are effective.
GREEN NAILS
Bacteria are not capable of attacking a healthy nail
plate. The Gram-negative bacterium Pseudomonas aeruginosa may colonize the dorsal or ventral nail plate
under propitious conditions, such as chronic paronychia or onycholysis. The presence of Pseudomonas is
revealed by characteristic greenblack nail pigmentation due to pyocyanin staining. Topical application of
a few drops of diluted bleach or chlorhexidine solution
two or three times a day clears the pigmentation in a
few weeks. Administration of systemic antibiotics is
unnecessary.
ONYCHOMYCOSIS60,61
For a detailed description of the onychomycoses, see
Chapter 188. Onychomycosis is a common toenail disease, and its prevalence increases with age.
Clinical features depend on type of nail invasion
(Table 89-4). The possibility of mold onychomycosis should be suspected when proximal subungual
onychomycosis (PSO) is associated with periungual
inflammation, or when white superficial onychomycosis is severe and involves the entire nail plate (Fig.
89-11). Nondermatophytic onychomycoses are becoming more frequent worldwide and represent a clinical
problem, because they usually respond poorly to systemic treatment.
TABLE 89-4
Clinical Presentations of Onychomycosis (See Chapter 188)

Distal subungual onychomycosisa
Trichophyton rubrum,
Trichophyton interdigitale
Onycholysis associated with subungual hyperkeratosis,

patchy or linear yellow discoloration
Proximal subungual onychomycosis
T. rubrumb
Fusarium sp.
Aspergillus sp.
Scopulariopsis sp.
Proximal leukonychia with normal nail plate surface
Trichophyton interdigitalea
Multiple superficial areas of friable opaque

leukonychia
White superficial onychomycosis
Fusarium sp.
Aspergillus sp.
a
1018
Associated with tinea pedis.

Possible marker of human immunodeficiency virus infection.
Associated with periungual inflammation and purulent

discharge
Involvement more diffuse and deeper
ONYCHOMYCOSIS AT A GLANCE
Fifteen percent of the general population and 40%
of individuals older than 60 years are affected.
Clinical presentation reflects the route of nail
invasion.
Dermatophytes account for 85% of cases,
nondermatophyte fungi for 15%.
Toenails are involved in most cases; tinea

pedis is usually associated.
The cure rate for toenail onychomycosis is
approximately 80% with the use of systemic
antifungals, but recurrences are frequent (up
to 20%). Mold infections respond poorly to
systemic treatment.
ENVIRONMENTAL NAIL
DISORDERS
NAIL FRAGILITY62
(Box 89-3)
With nail fragility, the nails are brittle and show distal
lamellar splitting (onychoschizia) (Fig. 89-12). Several
fingernails are usually affected. The nail plate margin is
irregular due to distal splitting. Idiopathic nail fragility
Figure 89-11 White superficial onychomycosis due to Fusarium sp. Note diffuse and deep nail invasion.
usually affects middle-aged women who are exposed

to water and chemicals that dehydrate the nail plate.
Aging also is associated with increased nail fragility.
The risk of nail fragility from trauma is increased by
manicures, onychotillomania, and certain occupations,
especially those that involve frequent exposure to water
and chemicals. Fragile nails can be a feature of several
dermatologic disorders, such as lichen planus, alopecia areata, psoriasis, and onychomycosis. In addition,
nutritional deficiency, peripheral neuropathies, peripheral vascular disease, and use of certain medications
increase the risk of nail fragility. Management includes
protection of the hands by the use of cotton gloves
under rubber gloves and frequent application of topical
moisturizers.61 Oral biotin, 5 mg/day, can be helpful.63
Candida sp. is the causative agents only in

immunosuppressed individuals.
::
Mold fungal infection should be suspected

when PSO is associated with acute periungual
inflammation or when white superficial
onychomycosis involves most of the nail plate.
Idiopathic
Aging
Exposure to water and chemicals
Traumatic
Occupational injury
Manicure
Onychotillomania
Dermatologic diseases
Lichen planus
Alopecia areata
Psoriasis
Onychomycosis
Systemic conditions
Peripheral vascular diseases
Peripheral neuropathies
Nutritional deficiencies
Chapter 89
Infection with human immunodeficiency

virus should be suspected with proximal
subungual onychomycosis (PSO) due to
Trichophyton rubrum.
Box 89-3 Causes of Nail Fragility
15
CHRONIC PARONYCHIA6466
Chronic paronychia is an inflammatory disorder that
almost exclusively involves the fingernails of adult
women. Mechanical or chemical traumas damage the
cuticle and permit penetration of irritant and allergenic environmental substances under the proximal
Figure 89-12 Onychoschizia lamellina: lamellar exfoliation of the distal nail plate.
1019
15
CHRONIC PARONYCHIA AT A GLANCE

Occurs most commonly in food handlers and
housecleaners.
Associated with mechanical or chemical
cuticle damage.
Characterized by eczematous inflammation
of the proximal nail fold and matrix.
Secondary colonization by bacteria and
yeasts usually occurs.
Section 15
First, second, and third digits of the

dominant hand are most often affected.
Management includes protective measures,

topical and/or systemic steroids, and topical
antimicrobials.
Box 89-4 Onycholysis

Primary
Idiopathic
Fingernails: women (mechanical/chemical damage)
Trauma
Fingernails: occupational injury
Toenails: podiatric abnormalities, improper shoes
Secondary
Vesiculobullous disorders
Contact dermatitis
Pompholyx
Herpes simplex
Nail bed hyperkeratosis
Onychomycosis
Psoriasis
Nail bed tumors
Drugs (often hemorrhagic)
Systemic antifungals are not effective.
nail fold, causing an inflammatory reaction of the nail

folds and matrix. Secondary colonization with Candida sp. and/or bacteria occurs in most cases, causing
self-limited episodes of painful acute inflammation
(see Chapter 189). Chronic paronychia most commonly affects the first, second, and third fingers of the
dominant hand. Clinically, the proximal and lateral
nail folds show mild erythema and swelling, and the
cuticle is absent. The nail plate may show superficial
abnormalities and green discoloration due to Pseudomonas invasion. Hand protection from the environmental hazards is mandatory for remission of chronic
paronychia, which can be considered cured only when
the cuticle has regrowth. Systemic antifungals are not
effective. Chronic paronychia should be treated as
contact dermatitis, with topical steroids or tacrolimus
associated with topical antiseptics to prevent secondary microbial colonization.
Idiopathic onycholysis usually affects the fingernails

of women and is a consequence of mechanical and
chemical damage of the nail bed isthmus (Box 89-4).
The detached nail plate is white due to the presence
of air and frequently presents areas of greenbrown
discoloration due to bacterial colonization (Fig. 89-13).
The use of sharp tools to clean the nail plate free margin produces roller coaster onycholysis (manicure onycholysis). Traumatic onycholysis of the fingernails is
usually occupational and is more commonly observed
in butchers, slaughterhouse workers, chicken processing workers, and workers lifting heavy bags. Traumatic
onycholysis of the toenails most frequently affects the
big toe, often bilaterally. It is usually a consequence
of anatomic abnormalities (overlapping of the second toe on the first toe) or poorly fitting shoes. Subungual hematoma is frequently associated. Secondary
onycholysis is seen in several dermatologic disorders. When only one nail is affected, it is important
IDIOPATHIC ONYCHOLYSIS65
IDIOPATHIC ONYCHOLYSIS
AT A GLANCE
Occurs in homemakers and those in certain
occupations.
Caused by mechanical or chemical damage.
Follows asymptomatic and slowly
progressive nail plate detachment.
1020
Management includes taking protective

measures, trimming the onycholytic nail
plate, and applying topical antiseptics.
Figure 89-13 Idiopathic onycholysis: note areas of green

discoloration of the onycholytic space due to Pseudomonas colonization.
to explore the nail bed after cutting the onycholytic

nail to rule out a nail tumor. Patients with idiopathic
onycholysis should be instructed to keep the nail dry,
trim the onycholytic nail plate, and wear cotton gloves
under rubber gloves. Application of topical 4% thymol
in chloroform solution on the exposed nail bed can
accelerate cure.
NAIL TUMORS67
SUBUNGUAL EXOSTOSIS.68 Subungual exosto-
sis appears as a subungual hard nodule that detaches

and lifts the nail plate. The toenails of young adults
are usually affected, and a history of trauma is not
unusual. Radiography confirms the diagnosis.
MYXOID CYST.69 Myxoid cyst appears as a nodule
NAIL MATRIX NEVI.71,72 Nail matrix nevi produce a
band of LM and usually appear in childhood. The color

and width of the band are variable, and modification
of the pigmentation (fading or darkening) with time is
common (eFigs. 89-13.1 and 89-13.2 in online edition).
Pigmentation of the periungual tissues (Hutchinsons
sing) is commonly associated with congenital nevi.
Clinical management of nail matrix nevi in children is
often problematic as lesions frequently show signs (Box
89-5) that are indicative for nail melanoma in adults.73,74
Excision of the lesions that show rapid increase in size
is probably the best option, to exclude the possibility of
a melanoma, which is rare but can occur.
MALIGNANT TUMORS
SQUAMOUS CELL CARCINOMA. (See Chapter
114). In situ squamous cell carcinoma (Bowens disease)
usually manifests in fingernails, with a lesion that clinically, closely resembles a wart. Associated melanonychia
or paronychia may be a diagnostic clue (Fig. 89-14).
FIBROMA/FIBROKERATOMA. Fibroma/fibrokeratoma appears as a nodular or filiform growth that

often has a keratotic surface. Most fibromas originate
in the proximal nail fold and extend to the nail plate
surface, where the tumor presents as a longitudinal
furrow or groove. Subungual lesions are uncommon.
Tuberous sclerosis should be considered, especially if
multiple lesions are present (see Chapter 140).
Periungual pigmentation
Adult age
Change in color/width of the band
Hyperpigmented lines within the band
Proximal portion of the band wider than distal
Thumb, index finger, or toe involvement
Blurred margins
::
BENIGN TUMORS
Chapter 89
Tumors of the nail usually affect one digit and are associated with symptoms that depend on tumor localization: nail plate furrows or grooves are due to tumors in
the proximal nail fold, while onycholysis or subungual
nodule are a consequence of nail bed tumor. The nail
plate may be altered both in its shape and thickness
and in color.
Box 89-5 Clinical Signs That

Require Histologic Evaluation of
Longitudinal Melanonychia
15
of the proximal nail fold associated with a longitudinal groove in the correspondent nail plate. Because
the cyst often drains spontaneously, the shape of the
groove is irregular. Myxoid cysts usually affect the
fingernails of middle-aged women and are associated
with osteoarthritis of the interphalangeal joints.
GLOMUS TUMOR. Glomus tumor may hardly be

seen, appearing as a small red patch under the nail
plate and usually affecting the hand. The minimal
clinical appearance is disproportionate to the intense
pain, which is usually accentuated by cold and radiates to the limb. Due to the small size of the tumor,
preoperative assessment with MRI or high-variable
frequency ultrasound is advisable to improve the out
come of surgery.
ONYCHOMATRICOMA.70
Onychomatricoma is
a rare benign fibroepithelial tumor that originates
from the nail matrix and produces typical clinical
features: the whole or part of the nail is thickened,
overcurved, with a yellowwhite discoloration and
multiple longitudinal tunnels (hollows) that end in
the distal nail producing a beehive appearance of the
free margin.
Figure 89-14 Bowens disease. Verrucous lesion of the

nail bed, associated with onycholysis and melanonychia.
1021
15
Section 15
Figure 89-15 Subungual squamous cell carcinoma: ulcerated subungual nodule.
Human papillomavirus (HPV) 56 has been detected in

tumoral cells of cases of Bowens diseases associated
with LM, indicating that the virus may be involved in the
carcinogenesis of these cases.75 Squamous cell carcinoma
presents as a slowly growing subungual nodule that
eventually ulcerates (Fig. 89-15) or a warty periungual
growth. The underlying bone is commonly involved.
It is more common in the fingernails and after the fifth
decade of life, and the diagnosis is often delayed, since
the tumor simulates other benign nail lesions and is frequently not recognized until it ulcerates.76 Oncogenic
HPV may be isolated from fingernail lesions. Surgical
excision with Mohs surgery is the best treatment for
squamous cell carcinoma without bone involvement.
MELANOMA.7779 (See Chapter 124)

MELANOMA AT A GLANCE
Involvement of nails is rare (0.7%3.5% of
melanomas).
Thumb or hallux is most often affected.
Longitudinal melanonychia and Hutchinson
sign are classic.
Lesion is amelanotic in 25% of cases.
Only 15% of patients survive 5 years or longer.
1022
Nail melanoma is an uncommon form of acral melanoma that arises within the nail matrix or bed. The
incidence for acral melanomas is similar worldwide,
but the proportion is higher in dark-skinned individuals. It represents about 2% of cutaneous melanomas
in Caucasians, and up to 25% in Africans and 10% in
Japanese. Nail melanoma most commonly affects the
thumb or great toe of middle-aged or elderly patients
and is usually an acral lentiginous melanoma. Melanoma of the nail matrix presents as a band of LM,
usually dark in color and with irregular border. Periungual brownblack pigmentation (Hutchinson nail
Figure 89-16 Nail melanoma: note Hutchinsons sign of

the hyponychium.
sign) indicates superficial spreading of the tumor and
is a diagnostic clue (Fig. 89-16). Although dermoscopy
is increasingly utilized in the evaluation of nail pigmentation, the experience in this field is still limited
and there are no data showing that dermoscopy is
superior to clinical evaluation in early detection of nail
melanoma. Recent evidence indicate that dermoscopy
should not be considered a substitute for pathology in
the differential diagnosis of doubtful cases of LM and
an excisional biopsy is recommended in all cases of LM
showing suspicious features (Box 89-5).74
Up to 33% of subungual melanomas are amelanotic,
and they are often misdiagnosed as pyogenic granuloma or squamous cell carcinoma, because the tumor
appears as a nail bed growth that first detaches the nail
plate and then destroys the epithelium with erosion and
bleeding. The low survival rate of patients with nail
melanoma is related mainly to the delay in diagnosis.
NAIL PSORIASIS
(See Chapter 18)
NAIL PSORIASIS AT A GLANCE

Present in up to 50% of patients with skin psoriasis
and up to 83% of those with psoriatic arthritis.
Isolated nail psoriasis is not rare.
Nail matrix and nail bed are most commonly
affected.
Most often precipitated or worsened by trauma.
Most common signs are onycholysis, salmon
patches, subungual hyperkeratosis, and
irregular pitting.
Fingernails and/or toenails may be affected.
Several nails are involved in most cases.
Treatment is often unsatisfactory.
typical of nail psoriasis (eFig. 89-18.1 in online edition).

The capillary density positively correlates with disease
severity and decreases with the response to treatment.83
TREATMENT
Treatment of psoriasis affecting only the nails is often
unsatisfactory and should be limited to patients who
experience functional impairment or severe cosmetic
problems. It is important to instruct patients to avoid
trauma and to refer the patient to a rheumatologist if
digital pain is described.
Systemic treatments for skin and joint psoriasis are generally effective for nail psoriasis (methotrexate, cyclosporine A). Since the advent of biologic therapies for severe
skin and joint psoriasis, their effects on nails symptoms
has been investigated and infliximab 5 mg/kg appears to
be the most effective to date. Statistically significant mean
percent improvement in the Nail Psoriasis Severity Index
(NAPSI) score over placebo was obtained at both week 10
and week 24.84 Phototherapy is not effective.
Intralesional steroids (triamcinolone acetonide 2.5
5.0 mg/mL in saline) are the best treatment for nail
The differential diagnosis of nail psoriasis is summarized in Box 89-6.

Pathology of nail clipping can be helpful for diagnosis
and to rule out onychomycosis.82 When typical symptoms are not present, diagnosis of nail psoriasis may
rely on videodermoscopy of the hyponychium (magnification 40), which shows dilated, tortuous, elongated, and irregularly distributed capillaries, a finding
Figure 89-18 Psoriasis of the toenails producing subungual hyperkeratosis and onycholysis.
::
15
Chapter 89
Up to 50% of patients with psoriasis have concurrent

nail psoriasis, which can occur in the absence of skin
lesions. Up to 30% of patients with skin psoriasis also
have psoriatic arthritis and of these, approximately 80%
have nail disease. It has been recently understood that
the close proximity of the nail unit to the distal phalanx
and the joint has important functional and pathological
consequences.80 The fibers of the extensor tendon of the
digit insert to the periosteum and then are directed to
the nail matrix, which they envelop and link to the bone.
The collateral ligaments of the digit anchor the lateral
sides of the nail to the interphalangeal joint. Thus, any
acute inflammatory process affecting the interphalangeal joint necessarily affects the nail and vice versa.
Psoriasis limited to the nails can be easily diagnosed
when it produces typical signs, usually detectable only
in the fingernails: psoriatic pitting, onycholysis with erythematous border and salmon patches of the nail bed.81
Psoriatic pits are large, deep, and irregular (see Fig. 89-4),
and represent psoriatic involvement of the proximal nail
matrix. Onycholysis is actually the most common manifestation of nail psoriasis and may affect both fingernails
and toenails. In fingernails the presence of an erythematous border along the onycholytic area is diagnostic for
nail psoriasis (Fig. 89-17). In toenails, onycholysis is usually combined with subungual hyperkeratosis and may
closely resemble onychomycosis (Fig. 89-18). Salmon
patches (oil drop sign) appear as yellowred areas of discoloration in the center of the nail or bordering an onycholytic area. Rarely, nail psoriasis may produce severe
nail plate abnormalities such as trachyonychia or crumbling. Other common but rather aspecific signs include
splinter hemorrhages and paronychia.

of Nail Psoriasis
Figure 89-17 Nail psoriasis: onycholysis surrounded by

an erythematous border and salmon patches of the nail
bed.
Onycholysis
Onychomycosis (usually associated with subungual hyperkeratosis): up to 21% of psoriatic nails
have secondary onychomycosis
Idiopathic onycholysis (fingernails): usually seen
with other nail changes
Trauma (toenails): psoriasis usually affects several
nails, not just the great toenails
Pitting
Eczema: often has periungual scaling and Beaus lines
Alopecia areata: different morphology of pits
1023
15
matrix psoriasis limited to a few fingernails, for which

they can be injected in the proximal nail fold every 48
weeks. Acitretin at low dosages (0.20.3 mg/kg/day)
for 4 to 6 months is an effective option in severe nail
psoriasis.85 In nail bed psoriasis, topical treatment with
calcipotriol, combination of calcipotriol and betamethasone, or tazarotene may be effective after removal of
the detached nail plate.8688
PUSTULAR PSORIASIS
Section 15

The diagnosis of Hallopeau acrodermatitis is suggested by a clinical history of relapsing periungual and
subungual pustules with onycholysis (Fig. 89-19). The
patient is most commonly seen when the acute episode
has subsided; at this time the affected digit shows onycholysis with nail bed and periungual erythema and scaling. Low-dose acitretin (0.3 mg/kg/day) may be useful.
LICHEN PLANUS81
(See Chapter 26)
NAIL LICHEN PLANUS AT A GLANCE

Nail lichen planus is seen in approximately
10% of patients with skin lichen planus.
Nail involvement is not associated with oral,
skin, or scalp lesions in most cases.
Nail matrix lichen planus produces nail
thinning, with longitudinal fissuring, dorsal
pterygium, and trachyonychia.
Nail bed lichen planus is frequent, but
clinical signs are not specific (onycholysis
and mild subungual hyperkeratosis).
Several nails are involved in most cases.
Scarring of the nail matrix with dorsal
pterygium is a possible sequela.
Figure 89-19 Hallopeau acrodermatitis continua.

tion and appears as a V-shaped extension of the skin
of the proximal nail fold that adheres to the nail bed.
Idiopathic atrophy of the nails is a rare variety of nail
matrix lichen planus characterized by acute and progressive painless nail destruction leading to diffuse nail
atrophy with and without pterygium. Onycholysis is
quite frequent in both fingernails and toenails. Severe
toenail involvement causes features that resemble yellow nail syndrome, with thickened, yellowbrown toenails. More rarely, nail lichen planus may present with
erosive lesions of the nail bed and periungual tissues.
Other possible clinical presentations include trachyonychia and nail plate thickening.
(Box 89-7)
In patients with brittle nails, the nail abnormalities
are milder. The nails are thin and ridged, but fissuring at multiple sites is not observed. Onychoschizia
is frequently associated. Trauma that produces damage to the matrix in an area wider than 3 mm causes
permanent thinning and fissuring. Only one nail is
Diagnosis should be confirmed by nail

biopsy, and systemic treatment is necessary
to avoid scarring.
1024
Nail lichen planus is not rare, and nail lesions may

occur in the absence of cutaneous or mucosal involvement. Nail localization of lichen planus should be
taken seriously, because it may destroy the nails.
Therefore, it is important to diagnose and treat the disease as soon as possible. Although lichen planus often
affects both the nail matrix and the nail bed, clinical
suspicion should be aroused by nail matrix signs, particularly nail thinning with longitudinal ridging and
fissuring (Fig. 89-20). Dorsal nail pterygium formation
is not common. It results from nail matrix destruc-
Figure 89-20 Nail matrix lichen planus: note longitudinal

ridging and fissuring of the nail plate.
15

of Lichen Planus
Longitudinal fissuring
Brittle nails
Trauma (single fissure)
Systemic amyloidosis
Lichen striatus
Pterygium
Trauma
Bullous diseases
Digital ischemia
Dyskeratosis congenita

Parakeratosis pustulosa is a rather common condition

that occurs only in children. The disease is limited to
one nail in most cases (usually the thumb or index
finger) with a clinical picture that closely resembles
that of psoriasis. Characteristics are distal onycholysis,
fingertip desquamation, and mild subungual hyperkeratosis. Spontaneous regression usually occurs after
puberty.
Nail matrix lichen planus requires oral or intramuscular treatment with systemic steroids, which induce
remission of the disease in 2/3 of the cases (Figs. 89-21
and 89-22). Intralesional (vs. systemic) corticosteroid injections should be considered in patients with
involvement of fewer than three digits. Relapses are
not uncommon, but usually respond to treatment.
PARAKERATOSIS PUSTULOSA
::
TREATMENT
Dorsal pterygium is not reversible and when it is the

sole manifestation, should not be treated. Solitary nail
lichen planus presenting as trachyonychia does not
lead to nail scarring and therefore does not necessarily
require treatment.
Chapter 89
usually affected, and it may show a single fissure.

Nail abnormalities may be the first sign of systemic
amyloidosis, with nail thinning, ridging, and fissuring closely resembling mild nail matrix lichen planus.
In amyloidosis, nail bed hemorrhages are common.
Diagnosis depends on nail biopsy. Lichen striatus may
manifest as nail thinning and fissuring limited to one
or two adjacent digits. Skin changes that course from
the affected nail in a linear configuration are typical.
Inherited (EB) and acquired (e.g., bullous pemphigoid)
bullous diseases can produce pterygium. Skin and
mucosal lesions are usually present. Digital ischemia
is distinguished in that the digit is cold and shows skin
signs of impaired vascular skin supply.
Figure 89-22 Nail matrix lichen planus before and after

treatment with systemic steroids.
TRACHYONYCHIA (TWENTY-NAIL
DYSTROPHY)
TRACHYONYCHIA (TWENTY-NAIL
DYSTROPHY) AT A GLANCE
Idiopathic but likely reflects alopecia areata,
psoriasis, dermatitis, or lichen planus of the
nail. More common in children.
Characterized by nail roughness due to
excessive longitudinal ridging (sandpaper nails).
Several nails are involved in most cases; involvement
of 20 nails is not necessary for diagnosis.
Nail changes often regress spontaneously.
Figure 89-21 Nail matrix lichen planus before and after

treatment with systemic steroids.
Treatment is not required.
1025
15
YELLOW NAIL SYNDROME

YELLOW NAIL SYNDROME
AT A GLANCE
In the typical syndrome, nail changes are
associated with respiratory disorders and
lymphedema.
Arrested nail growth is diagnostic.
Section 15
Figure 89-23 Trachyonychia.
Trachyonychia (twenty-nail dystrophy) is a nail sign

that can be caused by several inflammatory disorders
that produce a mild disturbance of nail matrix keratinization. These include alopecia areata, psoriasis, lichen
planus, and eczema. The nail is rough and opaque
due to excessive longitudinal ridging (Fig. 89-23). The
disease occurs most commonly in children. Trachyonychia does not produce nail scarring, even in cases
due to lichen planus.
DARIER DISEASE1
(See Chapter 51)
The nail abnormalities noted in Darier disease are
diagnostic but are not seen in all patients). Key features are longitudinal erythronychia, longitudinal
leukonychia associated with distal nail plate nicking
(V shaped), and subungual hyperkeratotic papules.
ALOPECIA AREATA
(See Chapter 88)
Nail involvement is seen in approximately 20% of
adults and 50% of children with alopecia areata and
is most common in male patients with severe involvement. Geometric pitting is most typical. Pits are small,
superficial, and regularly distributed in a geometric
pattern along longitudinal and transverse lines. Trachyonychia is quite common in children affected by
alopecia totalis or universalis. Other nail abnormalities
include punctate leukonychia, mottled lunulae, and
acute onycholysis. Nail abnormalities may improve
with systemic steroid treatment or spontaneously; they
respond poorly to application of topical medications.
Nails are overcurved and thickened, the

cuticle is absent, and nail color varies from
pale yellow to green. Onycholysis is often
associated.
Most or all nails are usually involved.
Yellow nail syndrome may or may not be associated

with a systemic disorder and is occasionally familial.88,89 However, it is important to refer patients to a
pneumologist to exclude respiratory tract involvement.
Other conditions that may be associated with yellownail syndrome include rheumatoid arthritis and internal malignancies. The history is the most important
clue to diagnosis, because patients always claim that
their nails have stopped growing (Fig. 89-24).
The nail changes may benefit from treatment with
high oral dosages of vitamin E. Spontaneous improvement is possible. Topical vitamin E and systemic antifungal medications (itraconazole, fluconazole) do not
appear to be effective.8991
NAIL SIGNS OF SYSTEMIC

DISEASES
(Table 89-5)
In systemic diseases, nail manifestations usually
involve most or all nails. The diagnosis is suggested
by clinical history, morphology, and distribution of
ATOPIC DERMATITIS
1026
(See Chapter 14)

Nail abnormalities associated with atopic dermatitis
are nonspecific in most cases. Manifestations are most
commonly Beaus lines, irregular pitting, and chronic
paronychia. Onycholysis and subungual hyperkeratosis are seen in severe cases, especially those triggered
by occupational exposure.
Figure 89-24 Yellow nail syndrome.
TABLE 89-5
Nail Signs of Systemic Disease

See Box 89-1
Koilonychia
Sideropenic anemia
Proximal splinter
hemorrhages
Bacterial endocarditis
Trichinosis
Antiphospholipid syndrome
Altitude sickness
Periungual erythema
Collagen disorders
Infection with human
immunodeficiency virus or
hepatitis C virus
Lichenoid nail changes with

hemorrhages
Systemic amyloidosis
Clubbing
See Box 89-8
Melanonychia
See Boxes 89-2 and 89-5
the nail abnormalities. Beaus lines located at the same

level in all digits or onychomadesis occurring simultaneously in all digits is strongly diagnostic for nail
matrix damage from a systemic cause.
Examination and capillaroscopy of the proximal nail
fold are very important for the diagnosis of connective
tissue diseases. Patients with scleroderma and dermatomyositis show enlarged capillary loops with reduced
capillary density and avascular areas. In systemic lupus,
erythematous, periungual erythema and telangiectasia
are typical; although periungual vessels can be tortuous, the capillary density tends to be normal. Cuticular
hyperkeratosis and hemorrhages are seen in systemic
lupus erythematous and dermatomyositis. Pterygium
inversum unguium is typical of scleroderma; in this
condition the nail plate adheres to the fingertip skin,
which makes nail trimming very painful.
The diagnosis of systemic amyloidosis can be suggested by nail symptoms, which sometimes precedes
skin and mucosal changes. The nails are thinned, longitudinally fissured, and show subungual hemorrhages.
Mild leukonychia is often seen in normal individuals
and therefore does not represent a specific sign of systemic disorders. Clinical patterns include half-and-half
nails (leukonychia affects the proximal half of the nail
bed), Terrys nails (leukonychia affects the entire nail bed
except for its 2-mm distal margin), and Muehrckes lines
(narrow paired transverse bands parallel to the lunula).
Clubbing may or may not be associated with cyanosis (Box 89-8). In clubbing the angle between the proximal nail fold and nail plate is greater than 180 degrees.
The digit has a bulbous appearance, and the nail plate
is enlarged and excessively curved.
Melanonychia can be associated with a variety of
systemic disorders and conditions, particularly human
immunodeficiency virus infection, adrenal disease,
pregnancy, and certain drugs (Box 89-9).
Unilateral.
Associated with cyanosis.
c
Associated with hypertrophic osteopathy.
b
DRUG-INDUCED NAIL
ABNORMALITIES92
A few nail abnormalities are highly likely to have
resulted from administration of medication (see
Box 89-9 Drug-Induced Nail

Changes
Renal disorders
Hepatic disorders
Systemic chemotherapy
Hypoalbuminemia
::
Apparent leukonychia
Half-and-half nails
Terrys nails
Banded nails (Muehrckes
lines)
Cardiovascular disorders
Aortic aneurysma
Congenital/acquired cardiovascular diseaseb
Bronchopulmonary conditionsc
Intrathoracic neoplasms
Chronic intrathoracic suppurative disorders
Gastrointestinal disorders
Inflammatory bowel disease
Gastrointestinal neoplasms
Hepatic disorders
Multiple polyposis
Bacillary dysentery
Amoebic dysentery
Chronic methemoglobinemia
Chapter 89
Beaus lines/onychomadesis
Box 89-8 Causes of Clubbing
15
Chemotherapy
Beaus lines
Onychomadesis
Muehrckes lines
Hemorrhagic onycholysis
Pyogenic granulomas
Melanonychia
Antiretrovirals
Azathioprine
Melanonychia
Indinavir
Pyogenic granuloma
Blockers
Digital ischemia
Bleomycin
Digital ischemia
Psoralen plus ultraviolet A phototherapy
Photo-onycholysis
Melanonychia
Retinoids
Nail fragility
Pyogenic granuloma
Paronychia
1027
15
Section 15
Figure 89-26 Photo-onycholysis: note the presence of

nail bed hemorrhages.
HABIT TIC DEFORMITY

(ONYCHODYSTROPHIA MEDIANA
CANALIFORMIS)
Figure 89-25 Hemorrhagic onycholysis due to taxanes
Box 89-9). Pyogenic granulomas involving several

nails are an occasional side effect of treatment with
retinoids, indinavir, and antiepidermal growth factor receptor chemotherapeutic agents, often leading
to drug discontinuation. Retinoids have also been
associated with nail fragility and paronychia. Taxanes (docetaxel and paclitaxel) frequently induce
painful onycholysis with subungual hemorrhage
and abscess formation (Fig. 89-25). The nail lesions
resemble a subungual infection and are reversible
after drug discontinuation. Both blockers and bleomycin may lead to digital ischemia. Therapy with
psoralen plus ultraviolet A light has been associated
with photo-onycholysis and melanonychia. Photoonycholysis has recently been seen after photodynamic therapy.93 and can rarely follow the intake of
tetracycline derivatives, psoralens, and fluoroquinolones. It may be associated with a photosensitivity
reaction in the skin and typically affects the central
part of the nail plate of one or more fingernails (Fig.
89-26). Onycholysis is painful and often hemorrhagic.94
In habit tic deformity the thumb shows a central longitudinal furrow with multiple transverse parallel lines
(Fig. 89-28). The nail deformity is due to the nervous tic
of pushing back the cuticle and the proximal nail fold
of the thumb with the index finger.
SUBUNGUAL HEMATOMA
Subungual hematoma may be caused by a single acute
trauma or by repeated microtraumas (see Chapter 99).
Nail hematomas last several months because part of the
blood is incorporated into the nail plate. Very dark lesions
require differentiation from melanotic pigmentation.
Dermoscopy shows rounded redblack globules (eFig.
89-28.1 in online edition).74 Acute hematomas require
immediate drainage to avoid matrix compression.
ONYCHOLYSIS
Traumatic onycholysis of the great toenails is frequent
in athletes, in women wearing high-heeled shoes,
TRAUMATIC NAIL DISORDERS

NAIL BITING
1028
Nail biting is common in children and may encourage

spreading of subungual warts (Fig. 89-27). When nail
biting is associated with picking and chewing of the
cuticle and periungual skin, the nail plate often shows
superficial abnormalities and melanonychia due to
melanocyte activation.
Figure 89-27 Subungual warts in a nail biter.
15
Chapter 89
Figure 89-28 Longitudinal furrow of the nail plate due to

habit tic.
Onychogryphosis is common in the elderly and

neglected individuals .The nail is thickened, distorted,
opaque, and yellowbrown, and tends to have an oyster shell appearance.
PINCER NAILS
Pincer nails is a painful abnormality that usually
affects the toenails and may be associated with subungual exostosis. The distal nail plate is overcurved and
compresses the subungual soft tissues (Fig. 89-29).
INGROWING TOENAILS
Ingrowing toenails most commonly affect young
adults with congenital malalignment of the great toenails. Improper nail cutting may lead to embedding
of a nail edge, causing inflammation and granulation
tissue formation. Hyperhidrosis is frequently associated. The aim of treatment for ingrowing toenails is
to extract the nail edge that is ingrowing and prevent
further penetration of nail fragments into the lateral
Figure 89-30 Retronychia: proximal ingrowing of the nail

plate.
folds. To accomplish this, the lateral nail plate can be

lifted by using a cotton pack or by inserting a gutter
splint along the lateral nail margin.95 The width of the
nail plate can also be reduced by surgical or chemical
(phenolization) removal of the lateral nail matrix.96,97
RETRONYCHIA
ONYCHOGRYPHOSIS
::
and in individuals with podiatric abnormalities.

Nail detachment is not associated with nail bed
hyperkeratosis.
Retronychia describes the ingrowth of the proximal

nail plate into the proximal nail fold associated with
multiple generations of nail plate misaligned beneath
the proximal nail.98 It involves 1 or both the first toenails and starts as an onychomadesis (posttraumatic)
not followed by nail shedding. The persistence of the
partially detached plate under the proximal nail fold,
associated with the growth of new nail plates underneath it, results in inflammation with pain and granulation tissue formation (Fig. 89-30). Nail plate avulsion
leads to a slow regrowth of a normal nail.
KEY REFERENCES
Figure 89-29 Pincer nails.
1. Zaias N: The Nail in Health and Disease, 2nd edition. Norwalk, CT, Appleton & Lange, 1990
16. Perrin C et al: Anatomic distribution of melanocytes in
normal nail unit: An immunohistochemical investigation.
Am J Dermatopathol 19:462, 1997
28. McGowan KM, Coulombe PA: Keratin 17 expression in
the hard epithelial context of the hair and nail, and its relevance for the pachyonychia congenita phenotype. J Invest
Dermatol 114:1101, 2000
32. Runne U, Orfanos CE: The human nail. Structure, growth
and pathological changes. Curr Probl Dermatol 9:102, 1981
1029
15
Section 15
1030
38. Yaemsiri S et al: Growth rate of human fingernails and

toenails in healthy American young adults. J Eur Acad
Dermatol Venereol 2009 Sept (epub ahead of print)
40. Daniel CR, Piraccini BM, Tosti A: The nail and hair in forensic science. J Am Acad Dermatol 50:258, 2004
44. Baran R, Kechijian P: Longitudinal melanonychia (melanonychia striata): Diagnosis and management. J Am Acad
Dermatol 21:1165, 1989
47. De Berker DA, Perrin C, Baran R: Localized longitudinal
erythronychia: Diagnostic significance and physical explanation. Arch Dermatol 140:1253, 2004
48. Fistarol SK, Itin PH: Nail changes in genodermatoses. Eur
J Dermatol 12:119, 2002
64. Tosti A, Piraccini BM: Paronychia. In: Contact Urticaria
Syndrome, edited by S Amin, A Lahti, HI Maibach. Boca
Raton, CRC Press, 1997, p. 267
67. Tosti A, Richert B, Pazzaglia M: Tumors of the nail apparatus. In: Nails: Diagnosis, Therapy, Surgery, 3rd edition,
edited by KR Scher, CR Daniel III. Philadelphia, WB Saunders, 2005, p. 195
73. Levit EK et al: The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol 42:269, 2000
74. Tosti A, Piraccini BM, de Farias DC: Dealing with melanonychia. Semin Cutan Med Surg 28:49, 2009
80. McGonagle D, Tan AL, Benjamin M: The nail as a musculoskeletal appendage- implications for an improved
understanding of the link between psoriasis and arthritis.
Dermatology 218:97, 2009
92. Piraccini BM, Iorizzo M: Drug reactions affecting the nail
unit: Diagnosis and management. Dermatol Clin 25:215,
2007
Disorders Due to
the Environment
PA RT
Disorders Due to Ultraviolet Radiation
Chapter 90 :: F
undamentals of Cutaneous
Photobiology and Photoimmunology

:: Irene E. Kochevar, Charles R. Taylor, &
Jean Krutmann
FUNDAMENTALS OF CUTANEOUS PHOTOBIOLOGY
AND PHOTOIMMUNOLOGY AT A GLANCE
When radiation enters the skin, it is scattered
or absorbed. Only light absorbed by molecules
(chromophores) in the skin can cause a
photobiologic response.
Electromagnetic radiation can be
conceptualized either as a wave or as packets of
energy called photons.
An action spectrum indicates which wavelengths
produce a photobiologic response most
effectively and is plotted as the reciprocal of the
minimum effective fluence versus wavelength.
The most erythemogenic wavelengths present
in sunlight are in the ultraviolet B (UVB) range.
Ultraviolet A (UVA) is roughly 1000-fold less
effective than UVB.
Prostaglandins and nitric oxide appear to be the
major mediators for UVB erythema.
When certain drugs and dyes absorb UV/
visible light, inflammation ensues. This is called
photosensitization.
Photosensitivity responses are usually mediated
by reactive oxygen species.
Blocked by sunscreen use, cutaneous vitamin

D production is mediated by wavelengths from
295300 nm. Optimal vitamin D blood levels are
essential for good bone health and increasingly
associated with a myriad of other potential
health benefits.
Ultraviolet radiation is immunosuppressive.
Local and systemic immunosuppressions are
recognized.
Pyrimidine dimers, reactive oxygen species
and urocanic acid initiate UV-induced
immunosuppression.
Interleukin-10 (IL-10), tumor necrosis factor
(TNF)-, platelet-activating factor, plateletactivating factor-like lipids and other molecules
mediate photoimmunosuppression.
The major cellular players in UV
immunosuppression are Langerhans cells,
keratinocytes, macrophages, and T cells.
UV radiation impairs T helper 1-mediated
cellular immune response.
16
Section 16
::
Knowledge of the interaction of sunlight with the skin is

fundamental to understanding the pathogenesis, diagnosis, and treatment of more than 100 cutaneous disorders. Whenever ultraviolet (UV) or visible radiation is
used to diagnose or treat a skin condition, important
principles of photophysics involving absorption and
emission of light underlie the success of the therapy.
Sunscreen recommendations rely on an understanding of solar UV radiation and the ways in which the
causative wavelengths can be minimized. Skin cancer
is an epidemic clinical problem, whose pathophysiology necessitates comprehension of the photophysical,
photochemical, and photobiologic events described in
this chapter.
Almost every ancient civilization worshipped a god
of the sun whose healing powers were believed to be
broad reaching. Even today, sun exposure is widely felt
to induce a sense of well-being. In addition, sunlight is
important for the synthesis of vitamin D3 and the setting of internal clocks. On the negative side, sunlight
causes deleterious acute and chronic inflammatory skin
reactions, skin cancer, and photoaging, and can elicit
adverse reactions to certain drugs (see Chapters 91, 92,
109, 112). Although the sun is a major source of the UV
and visible radiation that interacts with human skin,
UV and/or visible radiation are also emitted from common sources such as fluorescent lights, incandescent
bulbs, photocopy machines, and phototherapy lamps.
Tanning salons are another familiar example. Thus, UV
Generalized steps for ultraviolet (UV) and

visible radiation hitting skin
UV and visible radiation
Tissue optics
Absorption by
chromophores
Excited states
Photoproducts
Biochemical and
cellular changes
Acute and chronic

skin responses
1032
Figure 90-1 Generalized steps from ultraviolet (UV) and

visible radiation hitting the skin to observation of clinical
responses.
and visible radiation are a constant part of the human

environment and play a role in health, disease, and
therapy. Photodermatology is the study of this interaction between human skin and UV and visible radiation.
To understand the responses of skin to UV and visible
radiation, it is essential to be acquainted with the principles governing the interaction of these wavebands
with biomolecules in the skin.
When UV and visible light photons reach the skin
surface the energy of the radiation is transformed into
an observable response as shown schematically in
Figure 90-1. First, the radiation must penetrate to the
appropriate level in the skin where it is absorbed by
molecules in the skin, termed chromophores. Photochemical reactions then convert the chromophores into
new molecules, the photoproducts. These photoproduct molecules stimulate cellular signal transduction
pathways leading to biochemical changes that culminate in cellular effects, such as the proliferation, secretion of cytokines, and apoptosis that are responsible
for the observed acute skin responses.
ULTRAVIOLET AND VISIBLE

RADIATION
UV radiation and visible light are portions of the electromagnetic (EM) spectrum, which includes a wide
range of wavelengths, from high-energy X-rays to
low-energy microwaves and radio waves (Table 90-1;
Fig. 90-2). The UV waveband is of special interest
because dozens of skin disorders are aggravated by
these wavelengths and, many popular therapies, such
as UVB phototherapy (see Chapter 237) and psoralen
and ultraviolet A light (PUVA) photochemotherapy
(see Chapter 238), use sources emitting UV radiation.
Visible light encompasses those wavelengths perceived
as color by the human eye and is also frequently used
in therapies, such as blue-light amino levulinic acid
photodynamic therapy (PDT; see Chapter 238), and is
emitted by several lasers intended to target cutaneous
chromophores (see Chapter 239).
ULTRAVIOLET RADIATION
For medical photobiology, the UV range (200400 nm)
is subdivided into UVA, UVB, and UVC (see Table 90-1
and Fig. 90-2). A division was made at 290 nm because
wavelengths from the sun shorter than 290 nm are
absorbed by ozone in the stratosphere and do not reach
the earths surface at sea level. Wavelengths in the range
of 200 to 290 nm are referred to as UVC or germicidal
radiation. These wavelengths are strongly absorbed by
DNA and therefore can be lethal to viable cells of the
epidermis or to bacteria. UVC lamps emit at 254 nm and
are used for air and water purification. Care must be
taken to avoid exposure of eyes and skin to UVC radiation because of the danger of UV keratitis and mutation.
The range 290 to 320 nm is known as UVB and is
often referred to as mid-UV or sunburn spectrum. It
includes the biologically most active wavelengths
Table 90-1
Electromagnetic Radiation According

to Wavelength
0.110
Vacuum ultraviolet
10200
Ultraviolet C
200290
Ultraviolet B
290320
Ultraviolet A (UVA)
320400
UVA I
340400
UVA II
320340
Visible
400760
Violet
400
Blue
470
Green
530
Yellow
600
Red
700
Near infrared
7601000
Far infrared
1000100,000
Microwaves and radio

waves
>106
reaching the earths surface. The UVB constitutes only

approximately 5% of the UV and 0.5% of total radiation
reaching the earths surface; the exact amount varies
markedly with the time of day, season, cloud conditions, and other factors. Ordinary window glass blocks
UVB. Most sunscreens efficiently reflect or absorb
these wavelengths, and the sun protection factor (SPF)
is primarily based on testing against this waveband.
However, it is important to note that different wavelengths within these subdivisions can elicit greatly
VISIBLE RADIATION
The visible spectrum (400760 nm) is defined by the
wavelengths that are perceived as color by the retina.
Electromagnetic spectrum divided into major wavelength regions

Energy
Gamma
rays
X-rays
Vacuum
UV
10
Ultraviolet
UVC
200
Visible
UVB
Infrared
UVA
Fundamentals of Cutaneous Photobiology and Photoimmunology
X-ray
::
Wavelength Range (nm)
16
Chapter 90
Waveband
varying biologic responses. For example, consider

the response of skin to two wavelengths in the UVB
range, 297 and 313 nm. Radiation at 297 nm is nearly
100 times more erythemogenic than 313-nm radiation1
and more effectively causes DNA damage and photocarcinogenesis.2 An example relevant to phototherapy
is the great efficacy of certain UVB wavelengths for
treatment of full UVB spectrum.3,4 Narrowband UVB
(311 nm) and excimer laser (308 nm) are used to treat
psoriasis because these wavelengths are more effective
than other portions of the UVB spectrum.3,4
Long-wave UV or UVA (320400 nm) is sometimes
referred to as black light because it is not visible to the
human eye but causes certain substances to emit visible fluorescence. Approximately 95% of the UV radiation reaching the earths surface is UVA. As described
for UVB radiation, the response of skin to UVA is not
constant across all wavelengths from 320 to 400 nm.3
In fact, UVA has been divided into UVA I (340400 nm)
and UVA II (320340 nm) because the latter band is
more damaging to unsensitized skin than the longer
wavelengths. Although most sunscreens offer their
greatest protection against UVB wavelengths, those
products said to be broad-spectrum indeed have considerable ability to protect against UVA wavelengths,
although no widely used formal measure equivalent
to the SPF rating yet exists. Generally, the higher the
SPF, for example, 45 or greater, the more likely one is
going to find some UVA protection in that preparation.
Newer sunscreen agents enhance protection against
damaging UVA rays (see Chapter 223). Because of its
predominance in the UV radiation reaching the earths
surface, protection against UVA is quite important for
minimizing adverse cutaneous effects such as photoaging and carcinogenesis.
Radio
waves
Visible
290
760
UVAII
320
UVAI
340
400
Wavelength, nanometers
Figure 90-2 Electromagnetic spectrum divided into major wavelength regions. The lower band emphasizes the ultraviolet (UV) and visible bands that are important for photobiologic responses in human skin.
1033
16
Specific colors are associated with different wavelengths, as shown in Fig. 90-2. Skin responses to visible
light generally require photosensitization. For example, in PDT, dyes absorbing long wavelength visible
light (red) are used (see Chapter 92). Because they take
advantage of the absorption spectra of endogenous
chromophores, intense pulsed visible light sources
such as lasers are used to treat vascular, pigmented
and other lesions without application of a photosensitizing dye (see Chapter 239).
OTHER WAVEBANDS OF
ELECTROMAGNETIC RADIATION
Section 16
::
1034
X-rays and rays occupy the short wavelength (high

energy) end of the EM spectrum, and infrared radiation
(IR) is found at longer wavelengths (lower energy) than
visible radiation (see Table 90-1). X-ray and rays ionize
molecules (remove electrons) indiscriminately and are
known as ionizing radiation, the subject of radiobiology
(see Chapter 240). In radiation therapy of tumors, these
wavelengths kill tumor cells by ionizing water molecules and producing free radicals that damage DNA.
IR has lower energy than visible light. It is subdivided
into IR-A (7601,440 nm), IR-B (1,4403,000 nm), and
IR-C (3,000 nm1 mm). IR-A penetrates into the dermis
and causes skin damage whereas IR-B and IR-C are felt
as heat. Recent studies suggest that IR-A wavelengths
might also be therapeutic.5
PROPERTIES OF
ELECTROMAGNETIC RADIATION
Certain principles are better illustrated by conceptualizing EM radiation as waves, whereas others are better
understood by thinking of it as packets of energy called
photons. These two descriptions are complementary.
When considering EM radiation as a wave, it is
described as oscillating electric and magnetic fields at
right angles to each other and to the direction of propagation. Consequently, it may be described either by its
frequency (number of oscillations per second) or by
its wavelength (distance traveled per oscillation). Frequency and wavelength have an inverse relationship,
which is expressed as: = c/, where = frequency
(number of oscillations per second), c = speed of light
(3 108 m/s), and = wavelength in meters.
EM radiation also may be described as a stream of
discrete packets of energy known as quanta or photons.
The amount of energy in a photon (quantum) is directly
proportional to the frequency of the radiation and
inversely proportional to its wavelength, as expressed
by Plancks law: E = hc/, where E = the energy of the
photon in joules (J), h = Plancks constant (6.626 1034
J/s), c = speed of light, and = wavelength in meters.
This relationship shows that the energy of the photon
increases when the wavelength is shorter and decreases
when the wavelength is longer. For example, a 300-nm
UVB photon has twice the energy of a 600-nm yellow
photon.
SOURCES OF ULTRAVIOLET
AND VISIBLE RADIATION
SUNLIGHT
The shortest wavelength of the solar spectrum reaching the earths surface at sea level is approximately 290
nm, although slightly shorter wavelengths are detected
at high altitudes. Depending on the geographic location and the season, it has been estimated that sunlight
produces between 2 and 6 mW/cm2 of UV radiation
between 290 and 400 nm. Filtering of wavelengths
less than 290 nm by ozone is a very important process
because the shorter UVC wavelengths are highly damaging to animals and plants. Because the transmission
of solar UVC and UVB through the atmosphere varies
exponentially with ozone concentration, small changes
in the ozone layer may result in hazardous increases
in UV irradiance at the earths surface.6 For example,
calculations of the effects of ozone depletion predicted
a doubling of skin cancer incidence by 2,100 ad even if
the Montreal Protocol restrictions on ozone-depleting
substances were followed.7
The UV Index developed by the National Weather
Service and the US Environmental Protection Agency
represents an attempt to quantify the risks attendant
with solar radiation at a given time and place. Among
other factors, the effects of altitude, latitude, season,
and clouds are considered. The scale goes up to 15, and
any UV Index greater than 10 is considered a high-risk
day for possible overexposure in that locale.
ARTIFICIAL SOURCES OF
RADIATION
Skin is exposed to UV and visible radiation from a
wide variety of sources in daily life and from a different set of light sources for therapy and diagnosis.
Specific information should be obtained from the manufacturer before using a new light source.
INCANDESCENT SOURCES. Incandescent light

sources include conventional electric light bulbs, flood
lamps, and some quartz iodide bulbs. In these lamps,
an electric current passing through a metal filament
heats the filament, causing it to emit mostly visible and
IR. Only the occasional patient with solar urticaria,
chronic actinic dermatitis, or some porphyrias is bothered by the output of ordinary incandescent sources.
Tungsten-halogen incandescent lamps, often used as
flood lamps, emit UVA and visible radiation. Some
quartz iodide incandescent lamps produce significant
UVA and some UVB emission.
ARC SOURCES. Arc sources include xenon lamps,
medium- and high-pressure mercury (hot quartz)
lamps, fluorescent lamps, and halide lamps. In arc
lamps, electrons are driven through a gas by a potential difference between two electrodes. The gaseous
16
Emission spectra of some of the fluorescent

lamps used in phototherapy
Relative spectral irradiance
100
80
60
Broadband
UVB
Broadband
UVA
40
20
0
280
300
320
340
360
380
400
380
400
380
400
Wavelength, nm
::
Chapter 90
100
80
Narrowband
UVB
60
Woods
lamp
40
20
0
280
300
320
340
360
Wavelength, nm
100
80
UVA-1 lamps
60
40
20
0
280
300
320
340
360
molecules are ionized and subsequently release EM

radiation. Radiation is emitted preferentially at specific
wavelengths (emission lines) as well as in a continuum,
that is, all wavelengths are emitted rather than just
specific wavelengths. The wavelengths and relative
power at each wavelength depend on the gas used, the
arc temperature, the pressure within the lamp, and the
lamp wall material.
Xenon arc lamps emit both UV and visible radiation
and are now the most common sources used in solar
simulators. Photoprovocation testing for polymorphic
eruption is often done with such sources using filters
to limit the wavelengths. Xenon arcs are also used in
some phototherapy and photobiologic research applications. In a xenon lamp, xenon gas under 2040 atmospheres (atm) of pressure produces intense visible and
UV radiation. At these pressures, the xenon spectrum
becomes a continuum.
The wavelengths emitted by mercury arc lamps are
strongly influenced by the pressure of the gas within the
envelope. Low-pressure mercury germicidal lamps emit
85% of the radiant energy at 254 nm. Because the operating temperature is low, they are also known as cold quartz
lamps. With increasing pressure (1 atm), the primary 254nm emission is absorbed by other mercury atoms within
the lamp and reemitted at longer wavelengths (297, 302,
313, 334, and 365 nm, and visible wavelengths). With
further pressure increases (2100 atm), these spectral
lines broaden and decrease relative to the intensity of
the continuous spectral background. In medical practice, medium- and high-pressure mercury (hot quartz)
lamps are generally used as sources of UVB, although
their spectral power distribution is mainly in the UVA
and visible range.
The commonly used UVB sunlamps (see Chapter
237) and UVA lamps for PUVA therapy (see Chapter
238) are fluorescent lamps. They are, in essence, modified low-pressure mercury arc lamps. The inner surface of the glass tube is coated with a phosphor, which
absorbs the 254-nm radiation and reemits the energy at
longer wavelengths. The chemical composition of the
phosphor determines which wavelengths are reemitted. In general, fluorescent lamps have a relatively
wide, bell-shaped emission spectra, with emission
lines of mercury superimposed, and are referred to as
broadband light sources.
Fluorescent sunlamps (type FS) emit mainly in the
UVB range (Fig. 90-3). They are often referred to as UVB
lamps, even though they emit a portion of UVA radiation, because the therapeutically significant radiation is
in the UVB range (Table 90-2). A fluorescent lamp with
a major emission peak at 311 nm (Philips TL01) was
developed for use in phototherapy (see Fig. 90-3).8,9 This
lamp is an efficient source for psoriasis phototherapy
because, compared to a conventional UVB lamp, the
energy emitted almost entirely overlaps with the action
spectrum for clearance of psoriasis.3 Interestingly, this
lamp has also been successfully used for the treatment
of vitiligo, atopic dermatitis, and polymorphic light
eruption, all of whose action spectra are unknown and
may possibly differ from that for psoriasis.
High-intensity, UVA-emitting fluorescent lamps are
most often used in PUVA therapy of psoriasis, vitiligo,
Wavelength, nm
Figure 90-3 Emission spectra of some of the fluorescent lamps used in phototherapy. A. Broadband ultraviolet B (UVB) fluorescent lamps and UVA (black light)
fluorescent lamps. B. Narrowband (Phillips TL01) fluorescent lamp with a maximum at 311 nm and a fluorescent
lamp with a Woods glass filter. C. UVA I halide lamps
(Sellamed 24,000 bed system). Emission spectra were
measured with a Luzchem model SPR-4001 spectroradiometer.
1035
16
Table 90-2
Approximate Spectral Power Distribution of UVB and UVA Radiation Expressed as Percentage of Total
Emission in the UV Waveband in Common Phototherapy Sources
% UVB
Broadband UVB (Westinghouse Sunlamp)
60
40
80
20
Broadband UVA (Houva Lite; Black Light by Sylvania, Westinghouse, and General
Electric; Sylvania Puva Life Line; Dermalight Metal)
98
UVA Ib (Dermalight UltrA1, Dr. K. Hnle Medizintechnik GmbH)
100
Narrowband UVB (Phillips Fluorescent UVB, TL01, 311 nm)
Section 16
::
1036
% UVA
Woods light (RA Fisher; Spectronics)
100
Halide lampsd (Dermalight Systems, Dr. K. Hnle Medizintechnik GmbH)
100
Most (95% of the UVB emission of the typical narrowband UVB source is centered around 311 nm).
This UVA emission is above 340 nm.
c
The filter used (so-called Woods filter) is glass with nickel oxide phosphor. Consequently, UVB is screened. A moderate amount of visible light is
produced.
d
The actual amount depends on the model purchased and the filters used (glass vs. quartz). Some models allow the operator to change the
filters readily and thus increase the amount of UVB to >50% of the irradiance.
b
and other skin diseases. The most efficient UVA source

for PUVA therapy would maximize the emission of
320- to 360-nm radiation for photoactivation of psoralen molecules, while minimizing the UVB emission.
Table 90-2 shows the percentage of total emission that
is in the 320360-nm range from several UVA-emitting
light sources that are used in phototherapy units.
Woods lamps are small, low-pressure, UVAemitting fluorescent lamps with a UVA-transmitting,
visible-absorbing glass envelope. They are useful in
clinical practice because, after UVA absorption, the fluorescent emission from normal and abnormal components of skin, hair, teeth, and urine may be diagnostic
(e.g., in porphyria, vitiligo, and fungal infection).
Halide lamps emit a high-intensity continuum in
the UVB and especially the UVA range. With appropriate filters, this lamp is used increasingly as a UVB,
as well as a UVA, source for phototherapy (in particular, UVA I therapy) and photochemotherapy. The
metal halide lamp usually consists of a high-pressure
mercury lamp with metal halides as additives.
The continuous range of wavelengths emitted from
halide lamps differentiates them from mediumpressure mercury arc lamps that emit in narrow wavelength ranges. Approximately 20% of the emission
spectrum can be UVA radiation.
LASERS. (See Chapter 239.) Lasers produce intense

beams of monochromatic (single wavelength) radiation. The laser operates by exciting molecules to a
metastable excited state from which photon emission
is stimulated by a subsequent photon incident on the
excited molecule. The emitted photon and the stimulating photon are then each capable of stimulating
emission of yet other excited molecules, eventually
producing an avalanche of photons of the same wavelength, phase, and direction of propagation. Different
lasers emit UV, visible, or infrared wavelengths and
may operate as either continuous or pulsed sources.

RADIATION DOSIMETRY
To treat patients with the appropriate amount and
wavelengths of UV or visible radiation, it is important to become acquainted with how the radiation is
quantified and related to the exposure time. The basic
unit of EM energy is the joule (J). Power is the rate of
energy flow, joules per second (J/s), usually expressed
as watts (W). The rate at which the radiant energy is
delivered to a surface, such as skin, is expressed as the
power delivered per unit area of surface (power/area;
W/cm2). This quantity is called irradiance. The total
radiant energy delivered per unit area of skin surface
over a period of time is called the exposure dose or fluence and is the product of irradiance and time:
Irradiance (w/cm2) time (s) = Exposure dose or fluence (J/cm2)
For most responses to UV and visible radiation, it is
the fluence at particular wavelengths that determines
the magnitude of the response. The irradiance generally does not affect the response using conventional
light sources.
The irradiance delivered by a source as a function
of wavelength is called the spectral irradiance and is
expressed as units of irradiance per nanometer [(W/
cm2)/nm]. A spectroradiometer is used to measure the
spectral irradiance of a light source. When measuring
a light sources irradiance over a given spectral region,
a detector weighted to the wavelengths of interest is
most useful. For example, a broadband radiometric
measurement of wavelengths less than 315 nm provides a rough indication of the erythemally effective
wavelengths emitted by a source of UV radiation.
There is, however, no substitute for knowing the
full spectral irradiance delivered by a source, as determined by a spectroradiometer. For example, in phototesting, only the wavelengths of interest should be
used. To assess endogenous UVA sensitivity, the UVB

portion of a sources emission, if present, must be filtered out so that the more erythemogenic UVB wavelengths do not lead to a falsely lower determination of
erythema threshold in the UVA range.
Approximate penetration of ultraviolet and

visible radiation into skin
250 300 350 400
Stratum
corneum
10-20
Epidermal
reflectance
Dermal
reflectance
Epidermal
absorption
Epidermis
40-150
Dermis
1000-4000
Dermal absorption
Scattering
Figure 90-4 The interaction of ultraviolet and visible radiation with skin. The incident radiation is reflected from
the surface, scattered (circles), and absorbed (black dots) as
it travels through the skin.
Depth, mm
0.4
0.6
0.8
1.0
Figure 90-5 Illustration of the approximate penetration

of ultraviolet and visible radiation into skin. = wavelength.
Scattering includes any process that deflects the path
of optical radiation. For example, skin with scales, as
in psoriasis, scatters more light than does normal skin.
During phototherapy, application of emollients to the
psoriatic plaques helps reduce the scattering of UV
radiation and allows more of the effective wavelengths
to penetrate into the viable tissue.
Melanin, which absorbs relatively uniformly over
the visible wavelengths and is normally present only in
the epidermis, acts largely as a neutral density filter to
diminish remittance from the dermis. The greater overall melanin content in darker skin absorbs more visible
light and therefore causes the skin to appear darker as
there is less light remitted back to the observer. Blood
(hemoglobin) within the dermis absorbs the shorter
(blue) visible wavelengths, diminishing these spectral
regions, and giving a reddish hue to our perception of
the total remittance. Abnormal location and quantity
of these or other pigments account for the appearance
of the skin in pathologic conditions (e.g., melasma
with extra pigment in the epidermis and/or dermis,
vitiligo with an absence of epidermal melanin).
Direct
reflectance
0.2
::
Incident
radiation
700 , nm
Chapter 90
Interaction of ultraviolet and visible radiation

with skin
600
OPTICAL PROPERTIES OF SKIN

When UV and visible radiation strike the skin, part is
remitted (reflected and scattered), part is absorbed by
chromophores in various layers, and part is transmitted inward to successive layers of cells until the energy
of the incident beam has been dissipated (Figs. 90-4
and 90-5). The two major processes limiting the penetration of UV and visible radiation into skin, absorption and scattering, vary with wavelength.10
UV wavelengths less than 320 nm are readily
absorbed by proteins, DNA, and other components of
epidermal cells. Along with scattering, this absorption
accounts for the low penetration of these wavelengths
into skin (see Fig. 90-4). For example, approximately
10% of 300-nm radiation and 50% of 350-nm radiation
reaches the dermalepidermal junction in fair skin.
Between 5% and 10% of incident light is reflected by
the outer surface of the stratum corneum. This surface
or so-called specular reflectance is relatively constant
for all visible wavelengths and accounts for the surface appearance of skin, which is especially glossy if
the surface is smooth, wet, or oily. In contrast, if the
surface is irregular, the light is scattered and the skin
appears dull or rough. Moisturizers applied to the
skin reduce this rough appearance by smoothing out
the many airsurface interface irregularities and making the skin look shinier.
500
16
ABSORPTION OF ULTRAVIOLET
AND VISIBLE RADIATION BY
MOLECULES IN SKIN
When a photon is taken up by a chromophore, it is said
that absorption has occurred. The specific wavelengths
absorbed by each molecule (called an absorption spectrum) are characteristic of the structure of the molecule
(i.e., the arrangement of the nuclei and electrons). Only
radiation that is absorbed by the chromophores can
initiate biologic responses.
The absorption spectrum of a compound is a plot of
the probability of absorption of photons of a specific
wavelength on the Y-axis against wavelength on the
1037
16
Absorption sprectra of cutaneous chromophores

absorbing ultraviolet radiation
EXCITED STATE MOLECULES
Absorption (not to scale)
1.2
1.0
0.8
0.6
0.4
0.2
Section 16
0
250
300
350
400
Wavelength, nm
KEY
::
NADH
Hemoglobin
7-DHC
Urocanic acid
DNA
Protein
Melanin
Figure 90-6 Absorption spectra of cutaneous chromophores absorbing ultraviolet radiation. Note that the relative amounts of ultraviolet radiation absorbed by these
chromophores in skin depend on the heights of the absorption peaks as shown in this figure, the amount of each
chromophore in skin, and the penetration of each wavelength into skin. 7-DHC = 7-dihydrocholesterol; NADH =
reduced nicotinamide adenine dinucleotide.
X-axis (Fig. 90-6). The wavelengths that have the highest probability of absorption are called absorption maxima, max, (e.g., DNA, max = 260 nm; porphyrins, max =
400410 nm). Many of the biomolecules that absorb in
the UVB spectrum actually have absorption maxima
at shorter wavelengths in the UVC range (see Fig.
90-6). These include the purine and pyrimidine bases
in DNA and RNA (max 260 nm) and 7-dehydrocholesterol (max = 285 nm). Many endogenous cutaneous
chromophores absorb UVA or a combination of UVA
and visible radiation, including hemoglobin (max =
410 nm) and bilirubin (max = 450 nm). Melanin absorbs
throughout the UV, visible, and near IR spectra without a distinct absorption maximum wavelength. The
absorption spectra of few chromophores extend into
the IR-A waveband, an exception being cytochrome
c oxidase, which is last enzyme in the mitochondrial
respiratory electron transport chain.
PHOTOCHEMICAL REACTIONS
LEADING TO SKIN RESPONSES
1038
duction processes that lead to the observed responses

in skin.
After absorbing the energy of a photon, the chromophore is in an excited state, which exists for only a
very short time before reacting with nearby molecules.
The products of these reactions initiate signal trans-
Normally, molecules are in the so-called ground state

and have a certain distribution of electrons in space
around the nuclei of their atoms. For each molecule,
a series of electronic states with higher energies and
different distributions of electrons also exist; these are
called excited states. When a molecule in the ground
state absorbs the energy of a UV or visible photon, the
molecule is promoted to an excited electronic state (Fig.
90-7). According to quantum mechanics, only certain
energy gaps are allowed to exist between electronic
states. Consequently, a molecule can absorb photons
only with certain energies; this results in a unique
absorption spectrum for each molecule.
A molecule exists in this first excited state formed for
a very brief period. It is called a singlet excited state and
exists for a few nanoseconds. The molecule may return
to the ground state by emitting light (fluorescence) or
releasing the energy as heat by a process called internal conversion (see Fig. 90-7). Alternatively, the singlet
excited state may undergo a chemical reaction to form
a photoproduct, or it may convert into another excited
state with lower energy, the triplet excited state, by a
process called intersystem crossing (see Fig. 90-7). Singlet and triplet excited states differ in the spins of a
pair of electrons in an orbital. The ground state is
almost always a singlet state. The triplet excited state
may exist for a longer time (i.e., a few microseconds). It
may emit light (phosphorescence), undergo a chemical
reaction, or return to the singlet ground state by intersystem crossing (see Fig. 90-7).
These excited state processes are responsible for the
effectiveness of light for diagnosis and therapy. For
example, fluorescence occurs every time a Woods
light is used. UVA emitted from this lamp causes autofluorescence of dermal collagen fibers. To the examining physician, this fluorescence is viewed through
Absorption of ultraviolet and visible radiation

Singlet excited
state
isc
Triplet excited
state
ic
Photoproduct
Fl
h
isc
Ph
Photoproduct
Ground state
Figure 90-7 Absorption of ultraviolet and visible radiation (h) by molecules and the dissipation of the absorbed
energy by fluorescence (Fl), internal conversion (ic), intersystem crossing (isc), phosphorescence (Ph), and photochemistry to form photoproducts.
the overlying epidermis. Thus, any epidermal lesions

such as lentigines tend to have their borders accentuated by contrast because the fluorescence is observed
most brightly around the lesion. The heat generated
by internal conversion is responsible for the effects of
pulsed lasers (see Chapter 239).
PHOTOPRODUCTS
PHOTOSENSITIZATION
When certain drugs (e.g., tetracyclines, fluoroquinolones, psoralens) and dyes absorb UV and/or visible radiation, delayed erythema or inflammation is
observed (see Chapter 92). This phenomenon is called
photosensitization, and the dyes and drugs are called photosensitizers. Photosensitization requires the presence
of oxygen in most cases and the initial photoproducts
are reactive oxygen species (ROS). ROS are small molecules and free radicals including singlet oxygen, hydrogen peroxide, superoxide anion and hydroxyl radical.
These ROS oxidize unsaturated lipids in membranes,
certain amino acids in proteins (histidine, methionine, tryptophan, cysteine), and guanine in nucleic
acids. The oxidized products initiate signal transduction processes leading to inflammatory mediators,
ACUTE RESPONSES TO UV
RADIATION
Sunburn and tanning are the most obvious responses
elicited by exposure of skin to a single dose of UV radiation. Many other responses are less visually apparent,
but have important physiologic effects including formation of vitamin D3, altered immune responses, production of antimicrobial peptides and disruption of the
epidermal barrier function. In addition, the cumulative
effect of repetitive exposures gives rise to chronic skin
changes including skin cancer development and photoaging. All of these responses result from a complex
burst of UV-induced activity in the epidermis and dermis involving cytokines, neuropeptides, prostaglandins,
ROS, and altered expression of at least 600 proteins.11,1517
Number of photoprroduct molecules formed

Number of photons abbsorbed
::
Photoproduct quantum yield =
16
Chapter 90
During a photochemical reaction, the excited state molecule is transformed into a new, stable molecule called
the photoproduct. Photoproducts in DNA are important
for UVB-induced responses in skin. The photoproduct
molecule may be produced entirely by rearrangement
of the bonds in the chromophore, for example, the formation of previtamin D3 from 7-dehydrocholesterol
or in DNA of a four-membered ring structure called
a cyclobutyl pyrimidine dimer (CPD) from adjacent thymines or cytosines. These DNA photoproducts lead to
mutations and development of nonmelanoma skin cancers (see Chapter 112). Alternatively, the chromophore
may form covalent bonds with another molecule in the
cell, for example, the formation of covalent adducts
between psoralen and DNA. The phototherapy of diseases such as psoriasis makes use of this photochemical reaction (see Chapter 238). In addition, many skin
responses to UV and visible light are initiated when
the excited state chromophore transfers its energy to
oxygen to form singlet oxygen or transfers an electron
to form superoxide anion. These forms of oxygen react
with cellular molecules, which often initiates intracellular signal transduction leading to the inflammation
seen in sunburn and drug phototoxicity.
Photochemical reactions vary in efficiency. Not every
chromophore molecule that absorbs a photon undergoes a photochemical reaction because the excited
states may fluoresce or follow other pathways (see Fig.
90-7). The term quantum yield indicates the likelihood
that one of these processes occurs. For example, the
quantum yield for forming a certain photoproduct is:
for example, prostaglandin E2 (PGE2) and tumor necrosis factor (TNF)-, that produce the inflammation
observed as erythema.
A photosensitizer molecule in an excited triplet state
can transfer its energy to an oxygen molecule, thereby
generating the ROS called singlet oxygen (1O2). Singlet
oxygen is relatively long-lived for a singlet state (<4
microseconds) and reacts with other cellular molecules
to generate additional ROS. The skin photosensitization produced by PDT drugs and by protoporphyrin
IX, the porphyrin that accumulates to abnormally high
levels in red blood cells of patients with erythropoietic protoporphyria (EPP), involves initial formation
of singlet oxygen. Oxidation of membrane lipids is
believed to initiate the signal transduction processes,
leading the wheal and flare response observed in EPP
photosensitivity. Singlet oxygen is also involved in the
phototoxicity mechanisms for some phototoxic drugs.
However, the observed skin phototoxicity responses
often differ from that seen in EPP photosensitivity,
possibly because of the presence of the photosensitizing agents in different tissue locations (e.g., epidermis,
dermis, or vasculature). The photosensitizers may also
be in different locations in the cells (i.e., nucleus, mitochondria, or cell membranes), which would influence
the photoproducts formed and the subsequent cutaneous effect observed. Endogenous UVA-absorbing chromophores generate singlet oxygen in keratinocytes
and fibroblasts and in skin.11
Endogenous chromophores and some exogenous
photosensitizers generate other ROS.12 For example,
hydrogen peroxide and superoxide anion are produced after photosensitized and direct photon damage
to mitochondria. The UVB or UVA radiation also activates ROS-producing enzymes such as nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase
in keratinocytes and fibroblasts.13,14 The UVA-induced
responses in normal skin and in photosensitivity conditions are generally dependent on production of ROS.
Recent studies suggest that ROS are important in the
development of many UVB-initiated responses. Antioxidants act by quenching (i.e., chemically reacting
with and removing) ROS and other free radicals before
they can damage cellular molecules.
1039
16
This section centers on three different parts: (1) UVinduced inflammation (sunburn), (2) vitamin D synthesis, and (3) altered immune responses. Two other
acute responses to UV, (1) tanning (melanogenesis)
and (2) abnormal acute responses to UV, are described
in Chapters 72 and 91, respectively.
ACUTE INFLAMMATIONSUNBURN
Section 16
::
1040
Erythema is the most visually apparent indicator of

UV-induced skin inflammation. Increased blood flow
in the superficial and deep vascular plexus is responsible for the appearance of erythema and also may
increase skin temperature. Two other classical signs of
inflammation, swelling caused by increased vasopermeabilty and pain caused by released mediators on
nerve endings, may also occur. Both UVB and UVA
radiations elicit inflammation although the initiating
photochemistry, cell signaling processes, and biochemical pathway processes involved are not identical. Erythema has been used as the endpoint for measuring
the relative effects of different wavelengths in the UVB
and UVA, usually expressed as an action spectrum.
ACTION SPECTRA. An action spectrum indicates

which wavelengths most effectively produce a skin
response. It is used to understand the basic science
of a photobiologic as well as a therapeutic response
because phototherapy is most efficient when the emission of the lamp matches the action spectrum for
the beneficial response. An action spectrum is most
accurately plotted as the reciprocal of the number of
incident photons required to produce a given effect
(Y-axis) against wavelength (X-axis). Conventionally
in dermatology, the reciprocal of the minimum fluence (exposure dose) to produce the response is plotted versus wavelength. In an ideal case, the action
spectrum corresponds to the absorption spectrum
for the chromophore and can be used to identify the
chromophore for a given photobiologic reaction. For
example, an action spectrum for wheal formation in a
patient with EPP showed a maximum at 400 nm, close
to the maximum of protoporphyrin IX, which supports biochemical evidence for this porphyrin as the
chromophore.18 Another example involves the action
spectrum for the clearance of psoriasis, which was
found to peak around 313 nm.3 This insight has led
to the development of so-called narrowband UVB
sources with peak output at 311 nm, and the use of
the excimer 308-nm laser for the efficacious treatment
of psoriasis. Absorption in this range suggests that
DNA is a punitive chromophore, but given the different depths of penetration of the two wavelengths into
skin and the varying clinical responses, it is possible
the relevant chromophore for the therapeutic effect of
UVB on psoriasis is not exclusively DNA. Moreover,
in some cases, the action spectrum for a response may
not directly correlate to the absorption spectrum of the
responsible chromophore because the wavelengths
actually reaching the chromophore are distorted by
absorption and scattering of light by tissue above the
level of the chromophore.
The action spectrum for erythema indicates that the

most effective wavelengths present in sunlight are in
the UVB range.1,19 UVA is roughly 1,000-fold less effective than UVB. The time in the sun required to produce
sunburn is strongly influenced by many factors including skin pigmentation, season, geographical location,
cloud cover and time of day. The relative contributions
of UVB and UVA radiation from the sun to a sunburn
response are not constant because the UVB to UVA
ratio in the solar spectrum varies with the time of day,
the season and other factors.
UVB-INDUCED INFLAMMATION
Erythema is usually apparent 35 hours after UVB
exposure, reaches a maximum intensity at 1224 hours
and generally resolves by 72 hours. However, when the
UVB dose is high, erythema appears sooner, reaches a
maximum at a later time and is more persistent, and the
response is more likely to include pain or swelling. The
minimal erythema dose or MED is the fluence that elicits minimal erythema at 24 hours. The UVB MED for
fair skin (Fitzpatrick type III) using fluorescent UVB
bulbs is about 30 mJ/cm2 (300 J/m2). Many biochemical
and cellular events occur before the erythema is evident
including increased blood flow, endothelial cell activation and elevated inflammatory mediator levels.20,21
HISTOLOGYUVB. The extent and time course

of the histological changes observed after UVB varies
with the magnitude of the exposure dose.22,23 Dyskeratotic cells, so-called sunburn cells, may appear in the
epidermis as soon as 30 minutes after a 3 MED exposure. Sunburn cells are apoptotic keratinocytes that
show condensed nuclear chromatin and eosinophilic
cytoplasm. They increase in number with a maximum
at about 24 hours and eventually (by 72 hours) form
a band at the stratum corneum. Intercellular edema
occurs early and may persist to 72 hours.
Dermal changes include early (30 minutes) and
persistent (up to 72 hours) endothelial cell swelling,
perivenular edema and degranulated mast cells.22 Neutrophils appear perivascularly shortly after UVB and
the influx peaks at about 14 hours. A later mononuclear
(macrophage) infiltrate persistes at least 48 hours.
MECHANISMUVB. Absorption of UVB photons
by chromophores in skin leads to the production of
inflammatory mediators and cytokines that characterize the sunburn response. The action spectrum for erythema closely correlates with the absorption spectrum
of DNA suggesting that DNA is one of the important
chromophores and that DNA photoproducts initiate
at least partially the biochemical pathways leading
to UV-induced inflammation.1,24 A role for DNA photoproducts is further supported by the observation
that xeroderma pigmentosum patients, who have low
ability to repair DNA, demonstrate prolonged UVBinduced erythema that can be reduced by treatment
with a DNA repair enzyme.25 The biochemical pathways linking the DNA photoproducts with inflammatory mediators are still unclear. However, an action
spectrum for TNF- followed the DNA absorption

spectrum suggesting formation of this proinflammatory cytokine is initiated by DNA photoproducts.26
In addition to DNA, other UVB-absorbing chromophores initiate formation of inflammatory mediators.27,28
A UVB-induced photoproduct of tryptophan initiates
signaling events leading to expression of cyclooxygenase-2 (COX-2), which catalyzes formation of prostaglandins, which are associated with erythema.29 UVB
exposure rapidly generates ROS that oxidize membrane
lipids leading to proinflammatory cytokines.27,28,30 The
role of ROS is supported by the ability of topical antioxidants to modulate UVB-induced erythema.12,31
INFLAMMATORY MEDIATORSUVA. Exposure of skin to UVA increased the levels of proinflammatory prostaglandins as measured in suction
blister fluid.43 A study in keratinocytes indicated that
increased prostaglandin levels were caused by UVAinduced activation of PLA2.44 In vivo UVA stimulated
an increase in the levels of PGD2, PGE2, and 6-ketoPGF1 at 59 hours, which returned to normal by 24
hours.43 Histamine also increased by 915 hours and
returned to baseline by 24 hours. UVB, but not UVA,
stimulated production of TNF- from keratinocytes
and in human skin.45,46
Sunburn elicited by UVA has been much less thoroughly examined than UVB-induced erythema even
MECHANISMSUVA. The differences in time

course and histology between UVB and UVAinduced responses suggest that different mechanisms are involved. The erythema action spectrum
supports this concept; the slope of the curve
decreases at wavelengths longer than about 330 nm
and a small shoulder is seen at about 360 nm.1,19 In
addition, UVA-induced erythema was suppressed
when the skin oxygen level was reduced whereas the
UVB erythema was not affected.40 Although several
UVA chromophores are present in skin (Fig. 90-6), the
identity of the light absorber for UVA sunburn is still
unidentified.
ROS play a significant role in UVA-induced inflammation, as suggested by the oxygen dependence of
UVA erythema.40 Singlet oxygen and other ROS are
detected by spectroscopy when skin is exposed to
UVA.11,41 These reactive species are responsible for
activating phospholipase A2, which releases arachidonic acid from membrane lipids and makes it available for enzymatic conversion into proinflammatory
eicosanoids. ROS also initiate intracellular signal
transduction pathways that activate the synthesis of
proinflammatory cytokines. In addition, UVA has been
shown to liberate nitric oxide very rapidly from storage forms in skin.42
::
UVA-INDUCED INFLAMMATION
HISTOLOGYUVA. In contrast to UVB-induced

erythema, the major histological changes after UVA
exposure occur in the dermis. Most notably, the sunburn cells that characterize UVB-exposed epidermis
are not apparent after UVA.23,39 Epidermal intercellular edema was present for at least 48 hours, and
LCs decreased over 48 hours. In the dermis, neutrophils peaked at 3 hours, earlier than after UVB, and
remained present for at least 48 hours. A lymphocytic
infiltrate was also apparent throughout the dermis at
all times after irradiation.39
16
Chapter 90
INFLAMMATORY MEDIATORSUVB. Prostaglandins and nitric oxide appear to be the major

mediators for UVB-induced inflammation. Early studies showed that PGE2 levels in suction blister fluid
increased before the appearance of erythema and continued to rise at least until 24 hours.22 More recently,
numerous proinflammatory and anti-inflammatory
eicosanoids were identified in suction blister fluid
over a 72 hours period after UVB exposure.15 Prostaglandins with vasodilatation activity (PGE2, PGF2,
and PGE3) appeared at 2448 hours, and the species
with leukocyte chemoattractant activity [11-, 12-, and
8-monohydroxy-eicosatetraenoic acid (HETE)] were
present to later times (472 hours). Interestingly, an
anti-inflammatory species, 15-HETE, was maximally
present at 72 hours. The first UVB-induced step in the
formation of these eicosanoids is a rapid (<30 minutes)
increase in the activity of phospholipase A2, which
liberates arachidonic acid from cell membranes. Arachidonic acid is then acted on by cyclooxygenases and
lipoxygenases to produce the eicosanoids. Inhibiting cyclooxygenases with indomethacin applied after
UVB suppressed erythema.21,32
A role for nitric oxide in UVB-induced inflammation was established using NG-nitro-l-arginine methyl
ester (L-NAME), a specific inhibitor of nitric oxide synthase, which suppressed erythema.21,33 Interestingly,
L-NAME effectively suppressed erythema even when
injected 48 hours after UVB indicating that nitric oxide
was continuously synthesized. Histamine, however,
which can trigger an inflammatory response, does not
appear to be a major contributor to the UVB-induced
sunburn34 even though it rises after UVB.22
Several proinflammatory cytokines, including TNF, IL-1, IL-6, and IL-8, are elevated after UVB exposure
of human skin.3538 The IL-1-like activity was detected
by 1 hour after UVB36 and TNF- was elevated by 4
hours, maximal at 15 hours, and then declined.35
Cytokines may play several roles in UVB-induced
inflammation including recruiting leukocytes from
the vasculature by acting as chemoattractants and as
inducers of endothelial cell adhesion molecules that
facilitate movement of cells across the capillary walls.
though the amount of UVA in sunlight vastly exceeds

(19-fold) the UVB portion. UVB and UVA contribute
significantly to the effects of chronic sun (and tanning
bed) exposure. Erythema is usually present at the end
of the UVA exposure using clinical or laboratory light
sources. This immediate response may fade or merge
into a delayed erythema with a maximum between 6
and 15 hours depending on the fluence, irradiance and
spectrum of the light source.20,39 The UVA MED in fair
skin is generally 3075 J/cm2.20,23,40
1041
16
Section 16
::
1042
VITAMIN D PHOTOBIOLOGY
In 1928, Adolf Windaus garnered the Nobel prize in
chemistry for his studies on the constitution of sterols
and their connection with vitamins.47 The fat-soluble
substance under his investigation was vitamin D; however, the story of vitamin D and rickets, its deficiency,
actually dates back to antiquity based on careful study
of writings and paintings. Conducting dietary studies with cod-liver oil on dogs in 1919, Mellanby first
concluded that rickets stems from the absence of an
accessory food factor.48 Three years later McCollum
et al found that heated, oxidized cod-liver oil could
cure rickets in rats.49 They named the new factor vitamin D because it was the fourth vitamin discovered.
Concurrently, an entirely different remedy for rickets appeared in the form of UV light. By the late nineteenth and early twentieth centuries, lack of fresh air
and sunshine or lack of exercise was implicated in the
etiology or rickets.50 In 1921, Hess and Unger observed
that seasonal incidence of rickets seemed to parallel
seasonal variations of sunlight.51 Chick independently
observed that sunlight would cure rickets just as well
as cod-liver oil.52 In 1919, Huldschinsky reasoned that
artificial sunlight might well do the same as natural
sunlight.53 Controlling for dietary intake and ambient
UV exposure, he irradiated severely rachitic children
with a UV-emitting quartz-mercury lamp and observed
remarkable clinical and radiographic improvement,
including fresh calcium deposition.
From cottonseed oil in 1925, Hess and his team isolated sitosterol, which was inactive against rickets in
rats until it was irradiated by UV light.54 The discovery
that irradiation of food, in particular of whole milk,
could impart antirachitic potency led to tremendous
advances in public health, producing a rapid decline
in the prevalence of rickets in children. With amazing
foresight, Hess hypothesized that cholesterol in skin is
activated by UV-irradiation and rendered antirachitic.
The complete photochemical and thermal reaction steps
in the vitamin D pathway were finally elucidated in
1955 by Velluz.55 The exact sequence of steps leading to
the cutaneous photoproduction of cholecalciferol was
reported in a comprehensive paper by Holick in 1980.56
FUNCTIONS OF VITAMIN D. Vitamin D regulates

calcium and phosphorus metabolism.56 Its major role is
to increase the flow of calcium into the bloodstream,
by promoting absorption of calcium and phosphorus
from the intestines, and reabsorption of calcium in the
kidneys, thus enabling normal mineralization of bone
and muscle function. It affects serum alkaline phosphatase level. Vitamin D also inhibits the proliferation
of T-cells and the maturation of dendritic cells (DCs)
along with affecting keratinocyte function.
Vitamin D deficiency results in impaired bone mineralization that leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly
contributes to osteoporosis.57 Deficiency can arise from
inadequate intake coupled with inadequate sunlight
exposure, disorders that limit its absorption, or conditions that impair conversion of vitamin D into active
metabolites, such as liver or kidney diseases. Most vulnerable to low vitamin D levels are elders, individuals
living at high latitudes with long winters, obese persons, and all individuals with dark skin pigmentation
living at high latitudes.5865
Toxicity from excess vitamin D may manifest itself
as hypercalciuria or hypercalcemia, the latter causing muscle weakness, apathy, headache, confusion,
anorexia, irritability, nausea, vomiting, and bone pain,
and potentially leading to complications such as kidney stones and kidney failure. Chronic toxicity effects
include the aforementioned symptoms along with
constipation, anorexia, abdominal cramps, polydipsia, polyuria, backache, and hyperlipidemia. Findings
may also include calcinosis, followed by hypertension
and cardiac arrhythmias (due to shortened refractory
period). Although information about the effects of
high doses of vitamin D is limited, 10,000 IU daily is a
safe upper limit for adult intake.66 Chronic toxic dose is
more than 50,000 IU/day in adults.
There are two major sources of vitamin D, one is
diet and the other is skin. When obtained exogenously
from food or supplements, vitamin D is absorbed in the
small intestine. Natural food sources rich in vitamin D
include certain oily fish such as salmon, mackerel, tuna,
herring, catfish, cod, sardines and eel, butter, margarine, yogurt, liver, liver oil, and egg yolks, but at least in
the United States, most dietary vitamin D comes from
the fortification of food like cereal, milk, and orange
juice.67 Fortified milk, for example, typically provides
100 IU per 8 oz glass, or only a quarter of the estimated
adequate daily intake for adults. To get the recommended daily allowance, most Americans have to take
supplemental vitamin D either alone, or with calcium
or in a multivitamin.
BIOCHEMICAL PATHWAY. (Fig. 90-8.) As a

result of UVB exposure on the skin, provitamin D3
(7-dehydrocholesterol, a precursor of cholesterol) is rapidly converted to previtamin D3, which spontaneously
isomerizes to vitamin D3, entering the circulation on a
binding protein and joining dietary D2 (or ergocalciferol) and D3 (cholecalciferol) absorbed from the gut.56
Once reaching the liver, these undergo passive hydroxylation in the endoplasmic reticulum of the hepatocytes, a process that requires NADPH, O2 and Mg2+. The
product 25-hydroxyvitamin D3 [25(OH)D3 (calcidiol)]
is stored in the hepatocytes until it is needed when it
can be released into the plasma to make its way to the
proximal tubules of the kidneys, where it is acted upon
by 25(OH)D-1--hydroxylase, an enzyme whose activity is increased by parathyroid hormone and low PO42.
People with kidney disease may not be able to convert
vitamin D to its active form. Following this conversion,
1,25-hydroxyvitamin D3 [1,25(OH)2D3 (calcitriol)] is
released into the circulation, and by binding to a carrier protein in the plasma, vitamin D-binding protein
(VDBP), it is transported to various target organs.
ACTION SPECTRUM FOR VITAMIN D FORMATION IN SKIN. Action spectra studies show that
wavelengths the most effective at bringing about the
16
Vitamin D synthesis
Dietary intake
UVB
Epidermis
Intestine
7-dehydrocholesterol
Previtamin D3
+
Vitamin D3
Vitamin D3
Chapter 90
Blood
NADPH, O2 and Mg2+

25-hydroxyvitamin D3 [25OH]D3 (calcidiol)
Kidneys
1,25(OH)2D3 (calcitriol)
Figure 90-8 Vitamin D synthesis: Vitamin D is synthesized in the epidermis in response to UVB and is also absorbed from
the intestine. It is then transported on a binding protein to the liver, where it undergoes 25-hydroxylation. This metabolite
calcidiol is the major circulating form of Vitamin D. The final step occurs mainly in the proximal tubules of the kidneys, where
it is acted upon by 25(OH)D-1--hydroxylase, an enzyme whose activity is increased by parathyroid hormone and low PO42.
This l--hydroxylation is also believed to occur peripherally such as in the skin, where Vitamin D promotes differentiation.
photosynthesis of cutaneous vitamin D lie in the range

of 295 nm to 315 nm, which ironically are some of the
same wavelengths most responsible for photocarcinogenesis.68 Optimal synthesis occurs in a very narrow
band of UVB spectra between 295300 nm with peak
isomerization at 297 nm.68,69 With a UV Index of at least
3, which occurs daily in the tropics and almost never at
high latitudes, adequate amounts of vitamin D3 can be
made in the skin after 1015 minutes of sun exposure at
least two times per week to the face, arms, hands, or back
without sunscreen. In Boston, sunlight exposure from
November through February is inadequate to result in
significant cutaneous vitamin D production.65 The available flux of UVB for the synthesis of vitamin D depends
on all the factors that determine the UV Index, including
time of day, cloud cover, smog, shade, reflection from
nearby water, sand or snow, latitude, altitude, and season of the year. Of course, individual factors such as age
(vitamin D production decreases when older70), body
mass index, clothing worn, amount of skin exposed also
have an effect.71 Individuals with higher skin melanin
content require more time in sunlight to produce the
same amount of vitamin D as individuals with lower
melanin content.
According to Holick, human beings make at least
10,00025,000 units of vitamin D upon full body expo-
sure to the sun at one minimal erythemal dose.72,73 Vitamin D production in the skin occurs within minutes
and is already maximized before your skin turns pink.
Exposure to sunlight for extended periods of time does
not normally cause vitamin D toxicity. Within 20 minutes of sun exposure in fair-skinned individuals (13
hours for pigmented skin) the concentration of vitamin
D precursors produced in the skin reaches an equilibrium, and excess vitamin D simply degrades as fast as
it is generated.
OPTIMAL LEVELS OF VITAMIN D. Ninety years

after its discovery, vitamin D has become a subject of
intense interest to dermatologists in part due to the fact
that its deficiency is being increasingly recognized and
that its deficiency may well have important health consequences beyond those related to bone health. As dermatologists counsel patients to employ sunscreens in
order to minimize subsequent risk of skin cancer, they
should be aware that sun protection recommendations
may impede the efficacy of vitamin D photosynthesis
in the skin.74 Several studies have all shown that most
people, even those living in year-round sunny locations
such as Florida and Australia have low vitamin D levels.7579 In addition, other studies have demonstrated
that minimal or even moderate UVB exposures may
Liver
::
Vitamin D3 binding protein
1043
16
Section 16
::
1044
not be sufficient to maintain 25-hydroxy vitamin D

[25(OH)D] levels at the now widely quoted sufficient
level of 30 ng/mL.75,80 Consequently, relying solely
on ambient exposure appears not to be sufficient as a
means to obtain adequate vitamin D. Nearly all randomized trials that have proven the beneficial effects of
increased vitamin D have achieved that increase by oral
supplementation. It seems most likely that skin cancer
prevention recommendations in the form of sunscreen
use and judicious use of protective clothing did not
cause the problem of low vitamin D levels and equally
unlikely that urging unprotected ambient exposure will
not fully solve this year-round problem either unless
dietary vitamin D supplementation is recommended.
Low levels of vitamin D are clearly associated with
falls and fractures in the elderly.8186 As to whether
vitamin D supplementation can reduce these complications, there is controversy with reports showing
a benefit while others do not. Capturing more attention as of late is the mounting evidence that vitamin
D plays a role in preventing colorectal cancer and to
a lesser extent cancers of the breast and prostate.8792
Other malignancies have been associated with vitamin
D insufficiency in observational studies. Moreover,
multiple other health problems have been shown to
be inversely correlated in frequency with vitamin D
levels in some studies. Examples include diabetes mellitus,93,94 multiple sclerosis,95 hypertension,96 myocardial infarction,97 cardiovascular,98 seasonal affective
disorder,99 chronic pain,100 peripheral artery disease,101
cognitive impairment, which includes memory loss,102
and infections,103,104 among others. There is an association between low vitamin D levels and Parkinsons
disease.105 Current evidence is simply insufficient to
infer a causal relationship in any of these conditions.
What is an optimal level of vitamin D? Risk of cardiovascular events in the Framingham Offspring cohort
study suggested levels as low as about 2025 ng/mL.106
The national representative National Health and Nutrition Examination Survey data suggested that overall
mortality was minimized at levels of about 3040 ng/
mL.101 Given concerns about potential confounding
factors, we cannot be certain about these estimates of
optimal levels, but the preponderance of published evidence would support values of 2540 ng/mL.107 Thirty
ng/mL (75 nmol/L) is a common estimate given current knowledge.108
Clinicians can measure individual levels and recommend supplementation accordingly. Common
guidelines include 4001,000 IU daily with or without
calcium or in a multivitamin, 10,000 IU weekly or every
10 days, or 50,000 IU every month. After correction of
their vitamin D status with oral vitamin D, patients
should have a repeat test of their 25(OH)D level to confirm that they are in the normal range. Such measurement is necessary since there is great variation in the
increment of 25(OH)D achieved from a given dose of
vitamin D supplement. If a patient remains persistently
low, despite several attempts at correction with oral
vitamin D, there may be malabsorption and referral
to a gastroenterologist is in order. A trial of UVB light
therapy may be considered to improve vitamin D status.
For patients with 25(OH)D levels less than 15 ng/mL,
one usually prescribes oral supplements of 50,000 IU
vitamin D weekly for 8 weeks and then switches to standard maintenance doses. Efficacy of vitamin D supplementation is dependent on body mass index (BMI).57
Overweight and obese patients with hypovitaminosis
D require higher doses of vitamin D to achieve vitamin
D repletion compared to individuals with normal body
weight.
In short, we can conclude that vitamin D supplementation appears to enhance musculoskeletal health
and may possibly reduce mortality in some groups.
We have evidence that vitamin D may have an influence on cancer, cardiovascular disease, autoimmune
disease, and infection, but this evidence, although
suggestive, is quite variable in strength and does not
allow the conclusion that any of these associations are
proven. These are subjects of ongoing investigation.
PHOTOIMMUNOLOGY
Skin cancer is caused largely by direct damage to DNA,
leading to specific gene mutations. However, for the
development of clinically apparent skin cancer, a second UVB-induced mechanism is required, namely,
UVB-induced immunosuppression.109,110 The connection between sun exposure and skin cancer was realized first in the beginning of the last century when
physicians observed skin tumors that grew preferentially at sites that had been extensively sun exposed.
This was followed in the 1970s by a seminal study by
Kripke,111 who discovered a connection between immunosuppression and photocarcinogenesis. In a series
of experiments, she demonstrated that UV-induced
tumors, which had been transplanted onto syngeneic
recipient mice, were rejected if the recipient mice had
not been exposed to UVB. This result implies that UVinduced tumors have a highly antigenic phenotype111
and can be rejected by a functioning immune system.
Treatment with known immunosuppressive drugs,
orthis was the novel findingwith low doses of
UVB, led to failure of tumor rejection.112,113 Both aspects
(i.e., the strong antigenicity of UV-induced tumors and
the immunosuppression by UVB) have triggered vigorous research activities in the field now termed photoimmunology. Numerous studies tried to clarify the cellular
and molecular mechanisms.114 These have turned out
to be highly complex (see Fig. 90-9). Results sometimes appear contradictory, likely due to use of various
experimental approaches and model systems.
MODEL SYSTEMS FOR ULTRAVIOLET

B-INDUCED IMMUNOSUPPRESSION
The standard model for studying UVB-induced immunosuppression is the delayed-type hypersensitivity
(DTH) to antigens and the contact hypersensitivity
reaction (CHS). The ability of UVB irradiation to block
either induction or elicitation of allergic sensitization
can then be quantified; typically a hapten such as
dinitrofluorobenzene or oxazolone is applied to the
skin as the stimulus and intensity of the subsequent
immune response is measured as tissue swelling. DTH
responses have become the model of choice to study
16
Presumed molecular and cellular events at the irradiated skin site
cis-UCA
?
Receptor
clustering
Keratinocyte
Via neuropeptides
by C fibers
Mast
cell
Langerhans cell
IL-10
ROS
?
MAPK
NF-B
p53, AP-1
TNF-
ATPase
IL-6
ROS
?
Antigen
uptake
MHC II
ICAM-1
IL-1
PAF
PGE2
Histamine
ROS
IL-10
Migration to DLN
maturation into DC
?
KEY
Normal nucleus
CD11b+
macrophage
~72h post UVB: migration

into skin by chemotaxis
Nuclear DNA damage
Figure 90-9 Ultraviolet B (UVB) radiation-induced immunosuppression: Illustration of the presumed molecular and cellular events at the irradiated skin site. ATPase = adenosine triphosphatase; DC = dendritic cell; DLN = draining lymph node;
IL = interleukin; ICAM = intercellular adhesion molecule; MAPK = mitogen-activated protein kinase; MHC = major histocompatibility complex; NF-B = nuclear factor B; PAF = platelet-activating factor; PGE2 = prostaglandin E2; ROS = reactive
oxygen species; TGF = transforming growth factor; TNF = tumor necrosis factor; UCA = urocanic acid.
the immunosuppressive effects of UVB radiation, as the
tumor-associated antigens of UVB-induced tumors are
only poorly characterized and testing DTH responses
is less time-consuming and less laborious than examining photocarcinogenesis. UVB radiation has also been
shown to affect immune responses involved in the
pathogenesis of viral, parasitic, fungal, and bacterial
infections. UVB-mediated immunosuppression is of
two types: (1) local immunosuppression in which the
immune response to antigens applied at the irradiated
site is abrogated, and (2) systemic immunosuppression
in which the immune response to antigens applied to
unexposed sites is impaired (Fig. 90-10).115 However,
some mice are more susceptible to UVB-induced
immunosuppression than others, with the genetic loci
for lipopolysaccharide, Lps, and tumor necrosis factor,
Tnf, strongly influencing the response.116
MOLECULAR TARGETS IN
PHOTOIMMUNOSUPPRESSION
DNA is a chromophore for UVB radiation and can be a
direct target (see Fig. 90-6). UVB radiation generates a
variety of photoproducts, most commonly CPDs64 and
photoproducts. Pyrimidine dimer formation is a direct

cause of UV-induced immunosuppression (Fig. 90-9).
The cells of the opossum Monodelphis domestica contain
endogenous photoreactivating enzymes, which are
capable of repairing CPDs, and UVB does not induce
immunosuppression in these animals on exposure
to photoreactivating light immediately after irradiation.117 Also in mice, a correlation between CPDs and
UVB-induced systemic immunosuppression exists.118
UVB irradiation leads to CPDs in antigen-presenting cells (APCs) and impairment of their antigenpresenting capacity. The damage persists for several
days, and the damaged cells migrate from the skin
to lymph nodes. Treatment at the site of UVB irradiation with liposomes containing the DNA repair
enzyme T4 endonuclease V prevents the impairment
in antigen presentation.119 The role of DNA damage
in UVB-induced immunosuppression was also confirmed in human skin, in which topical application
of photolyase-containing liposomes to UVB-exposed
sites prevents UVB-induced immunosuppression.120
In addition to direct DNA damage, the generation of
ROS is likely to be involved in photoimmunosuppression (see Fig. 90-9). Accordingly, topical application of
a polyphenolic fraction isolated from green tea before
PAF
::
PGE2
?
Chapter 90
TGF-
DNA repair
transcription of
UVB-target genes
1045
16
Ultraviolet B radiation - induced immunosuppression:

local vs. systemic
Local
Repeated
low dose
of UVB
(~1 kJ/m2)
Systemic
Hapten
Section 16
Hapten,
antigen
Contact hypersensitivity
::
1046
Single
high dose
of UVB
(~10-15 kJ/m2)
Contact hypersensitivity,
delayed type hypersensitivity
Susceptibility genetically
determined (LPS and
TNF- gene loci)
Figure 90-10 Ultraviolet B (UVB) radiation-induced immunosuppression: local versus systemic. TNF = tumor necrosis factor.
and after UVB irradiation to mouse skin protects against

UV-induced immunosuppression,121 an effect most
likely mediated by the antioxidant epigallocatechin-3gallate, the component of extract that has the ability to
reduce oxidative stress, inflammatory responses, and
skin cancer. It should be noted that such secondary
plant metabolites affect cell signaling, however, so that
protection against UVB-induced events may not exclusively be explained by antioxidant effects.
The cell membrane of immunocompetent skin cells
is another target for UV radiation. An important function of the cell membrane is to transfer signals from
outside into the cell via membrane receptors. UVB
exposure leads to clustering and internalization of cell
surface receptors for epidermal growth factor, TNF,
and IL-1 in the absence of the respective ligands. Clustering results in strong activation of stress-induced
c-Jun NH2-terminal kinases, which are members of
the mitogen-activated protein kinase family122 (see
Fig. 90-9). Conceivably, such aberrant receptor clustering may subvert signaling pathways normally used
by growth factors and cytokines, eventually contributing to the immunological response. The chromophore for these UVB-induced membrane alterations
is cytoplasmic tryptophan. The resulting tryptophan
photoproduct(s) bind to the transcription factor arylhydrocarbon receptor (AhR), which in its inactive form
is part of a cytoplasmic complex including c-src and
the heat shock protein Hsp90. Upon binding of the
tryptophan photoproduct to the AhR, the complex
dissociates and the AhR translocates into the nucleus
whereas c-src translocates to the cell membrane where
it subsequently causes the previously mentioned cell
membrane/surface receptor activation.29
UVB radiation can lead to lipid peroxidation,

including cell membrane lipids. Phosphatidylcholine, an important membrane lipid, can be oxidized to
platelet-activating factor(PAF)-like lipids that bind to
PAF receptors and activate cytokine synthesis. A role of
UVB-induced PAF formation in photoimmunosuppression is suggested by the observation that comparable
immunosuppression can be induced in mice when they
are irradiated with UVB, injected with carbamyl-PAF,
or injected with phosphatidylcholine that had been
exposed to UVB under atmospheric oxygen. The immunosuppressive properties of all three treatments were
equally blocked by specific PAF receptor antagonists,
indicating that UVB-induced PAF-like lipids can trigger
the PAF receptor in a way similar to PAF. In turn, PAF
receptor activation stimulates a variety of downstream
effects, including the activation of mitogen-activated
protein kinase pathway and synthesis of immunosuppressive cytokines (see Fig. 90-9).123 Interestingly, UVB
radiation-induced immunosuppression as well as formation of PAF were enhanced in mice, which were
unable to take up the osmolyte taurine. Thus, similar
to nucelotide excision repair, taurine uptake is critically
involved in protection of the skin against UVB radiation-induced immunosuppression.124
An extracellular chromophore that mediates UVBinduced immunosuppression is UCA (see Fig. 90-6).125
UV radiation isomerizes trans-UCA to cis-UCA dosedependently until a balanced photostationary state is
reached. A number of independent studies confirmed
the importance for cis-UCA in UVB-induced immunosuppression, although the exact mechanism of action is
not clear at present.
CELLULAR EVENTS INVOLVED IN

PHOTOIMMUNOSUPPRESSION
UVB radiation of keratinocytes alters their expression
of surface molecules and induces the synthesis and
secretion of a whole set of immunomodulatory soluble
factors, including IL-1, IL-6, IL-8, TNF-, and PGE2 (see
Fig. 90-9).126 Evidence for keratinocyte-derived soluble
factors with immunosuppressive function came from
experiments showing that either serum factors from
UVB-exposed mice or supernatants from UVB-irradiated murine epidermal cells suppressed hypersensitivity reactions in mice. Subsequently, it was found
that TNF- and IL-10, two potent immunosuppressive
cytokines, are produced by UVB-irradiated keratinocytes as well.125,128 IL-10 is also released by CD11b+
macrophages in human skin.129 Injection of TNF-
mimics UVB-induced alterations on Langerhans cells
(LCs). The administration of a neutralizing antibody
to TNF- before irradiation abrogates partially UVBinduced accumulation of DCs in draining lymph
nodes (DLNs) and suppression of contact hypersensitivity. The release of TNF- is of special importance for
local immunosuppression, and, as mentioned above,
the Tnfa gene locus contributes to UVB susceptibility.
IL-10 is a T-helper cell type 2 (Th2) cytokine and
abrogates the production of Th1 cytokines, in particular, interferon- (IFN-). UVB-induced IL-10 production
LCs, 2%5% of epidermal cells, are a DC subset that

originates from bone marrow precursors and populates the epidermis. They are the professional skinspecific APCs and ingest antigen locally in the skin,
but lack costimulatory capacity. After antigen uptake,
LCs migrate to the DLN, where they mature to potent
stimulators for antigen-specific T cells, expressing high
levels of major histocompatibility complex molecules
and costimulatory molecules B7.1 and B7.2 and intercellular adhesion molecule-1 on their cell surface (see
Chapter 10).
In the 1980s, it was demonstrated that epidermal
LCs play a pivotal role in the induction and regulation
of CHS reactions. LC density is an important factor
for the induction of CHS responses, and UV radiation leads to the disappearance of LC from irradiated
sites.131 In these studies, mice were sensitized with the
hapten dinitrofluorobenzene either on skin with typical amounts of LC or on LC-deficient skin. A significantly impaired CHS response was observed when the
mice were sensitized on LC-deficient skin. The capacity to deplete LCs temporarily from the skin appears to
be an important feature of UVB irradiation. Moreover,
UV exposure results in reduced surface expression of
costimulatory molecules Ia, B7.1, B7.2, and intercellular adhesion molecule-1 (see Fig. 90-9).132,133 The depletion of these molecules might account for or contribute
to immunosuppression. The loss of LCs in the skin is
accompanied by an increase in DCs in the DLN. 134 Flu-
16
::
CELLULAR MEDIATORS OF
PHOTOIMMUNOSUPPRESSION:
LANGERHANS CELLS, MACROPHAGES,
AND T CELLS
orescein isothiocyanate+ Ia+ CPD+ cells in the DLNs

were found after painting the skin with fluorescein
isothiocyanate and irradiating subsequently with UV.
This demonstrates that LCs indeed leave the skin after
UV exposure. UVB possibly induces LC migration in
the absence of exogenous antigen, although the migratory effect is enhanced by sensitization with antigen.
The ultimate fate of chronically irradiated LCs remains
to be examined. UVB-induced LC migration was also
observed in human skin in vivo.135
In addition to reducing the number of LCs in the
skin, UVB radiation affects LC function by impairing the antigen-presenting capacity in DTH and CHS.
UVB-irradiated LCs activate preferentially CD4+ Th2
cells.136 In contrast, they do not activate CD4+ T cells
of the Th1 subset, but induce clonal anergy.137 Another
cellular player in UV-induced immunosuppression is
CD11b+ macrophages, which infiltrate UVB-irradiated
human skin (see Fig. 90-9). These cells produce IL-10,
and their deletion by antibodies makes UV-irradiated
mice permissive again for CHS.138
In addition to immunologic unresponsiveness to
haptens applied after irradiation, UVB exposureinduced hapten-specific tolerance (i.e., resensitization
with the same hapten at later time points) likewise
fails.139 In adoptive transfer experiments, it was shown
that UVB induces T-suppressor cells. Elmets et al140 prepared single cell suspension of the spleen and lymph
nodes from UVB-exposed and hapten-treated mice,
injecting the cell suspension into naive mice. When the
recipient mice were sensitized and challenged with the
same hapten that was used for the donor mice, they
showed significantly impaired CHS responses.
The phenotype of the regulatory T cells and their
mechanism of action are not well understood (Fig.
90-11). Results obtained so far are difficult to compare.
Different experimental setups yielded partly contradictory results. There is evidence to suggest that CD8+ T
cells are important mediators of UVB-induced immunosuppression in the local immunosuppression.141 In
addition, T cells (not defined by CD4 or CD8) that
express cytotoxic T lymphocyte antigen (CTLA)-4 on
their surface transfer UV-induced tolerance.142 CTLA-4
appeared to be of functional relevance, because in vivo
injection of anti-CTLA-4 antibodies blocked transfer of
suppression. The physiologic function of CTLA-4 is to
end immune responses by shutting down activated T
cells, so CTLA-4 is an important molecule in immune
regulation. On stimulation with antigen-bearing DCs,
CTLA-4+ T cells secrete high levels of IL-10, transforming growth factor-, and IFN-, but low levels of IL-2
and no IL-4. Other studies showed that CD4+ T cells
from UV-exposed mice are capable to suppress CHS
when injected into untreated recipient mice.143 These
CD4+ T cells produce IL-10, but no IL-4 and IFN- on
APC coculture and inhibit IL-12 production by APCs.
Apart from CD4+ regulatory T cells, natural killer T
cells with regulatory capacities were found in UVBinduced systemic immunosuppression (see Fig. 90-10).
In particular, CD3+, CD4+, and DX5+ CD1-restricted
natural killer T cells have been described, which
secrete IL-4 and can adoptively transfer suppression of
tumor rejection as well as DTH responses.134
Chapter 90
by keratinocytes in murine or macrophages in human

skin130 shifts the immune response from a Th1 to a
Th2 type. This can explain why Th1-mediated cellular
immune reactions are impaired by UV radiation.
The interactions between the different cytokines
are not fully understood, but IL-10 certainly is a
major player. For instance, anti-IL-10 antibodies neutralize the suppressive effects of supernatants from
UVB-irradiated keratinocytes on DTH in mice.127 The
main mechanism of IL-10 is probably inhibiting the
antigen-presenting capacity of LCs. In parallel, UVexposed keratinocytes release PAF and PAF-like lipids,
which trigger the PAF receptor, as described in Section
Molecular Targets in Photoimmunosuppression.29
Presumably, PAF and its receptor enhance the production of COX-2, PGE2, IL-4, and IL-10. IL-10 production
can be reversed by IL-12. Incidentally, IL-12 can restore
UV-impaired CHS.130 Injection of mice with IL-12 after
UVB exposure prevented UVB-induced immunosuppression and suppressed partially UVB-induced tolerance obtained by resensitization 14 days after the UV
irradiation. This IL-12 effect is most likely linked to the
capacity of this cytokine to enhance the repair of UVB
radiation-induced DNA photoproducts, which form
the molecular basis for IL-10 production by irradiated
keratinocytes.
1047
16
Presumed cellular interplay in the skin-draining

lymph nodes (LNs)
PHOTOIMMUNOLOGY:
CONCLUDING REMARKS
LC
Skin
Section 16
MNC II
::
CD8+
T cell
Lymph
node
CD4+
T cell
ICAM-1
IL-12p70
IL-10
TGF-
IL-4
NKT
T cell
Periphery
Regulatory
T cell
suppress the innate immune response by increasing

the production of the antimicrobial peptides human
-defensin (HBD)-2, -3, ribonuclease 7 and psoriasin in
human keratinocytes and skin in vitro and in vivo.144
This may explain why T-cell-mediated immune reactions are suppressed on UV exposure but not host
defense reactions against bacterial attacks.
CD8+
T cell
UV radiation is a permanent environmental threat, and

adaptive responses against its damaging effects have
been developed in all living organisms. From a theoretic
point of view, it is therefore tempting to speculate that
photoimmunosuppression serves a physiologic role as
an adaptive response of the skin to UV-induced modifications of proteins and an immunologic response to
so-called neoantigens and, as a consequence, chronic
inflammation. Under these conditions, the higher risk
of skin cancer that appears to accompany UV-induced
immunosuppression appears of less significance in
evolutionary terms, as skin cancers occur principally
in late life, after the reproductive period. From a practical point of view, however, photocarcinogenesis
poses a serious health problem. Accordingly, modern
approaches to prevent UV-induced immunosuppression include broad-spectrum UV filters, liposomally
encapsulated DNA repair enzymes, antioxidants, and
osmolytes.145
KEY REFERENCES
DTH/CHS
Tumor rejection

Figure 90-11 Ultraviolet B radiation-induced immunosuppression: illustration of the presumed cellular interplay
in skin-draining lymph nodes (LNs). CHS = contact hypersensitivity reaction; DC = dendritic cell; DTH = delayedtype hypersensitivity; ICAM = intercellular adhesion molecule; IL = interleukin; LC = Langerhans cell; MHC = major
histocompatibility complex; NKT = natural killer type;
TGF = transforming growth factor.
ULTRAVIOLET RADIATION EFFECTS

ON INNATE IMMUNITY
1048
In the skin, in addition to slow but specific adaptive

immune responses, the more primitive innate immune
response can be generated as well. Essential components of the innate immune response are neutrophils,
eosinophils, natural killer cells, mast cells, cytokines,
complement, and, in particular, amtimicrobial peptides
and proteins. It is important to note that the immunosuppressive properties of UV radiation refer exclusively to the adaptive immune response. In contrast,
UV radiation has been shown to induce rather than
6. de Gruijl FR et al: Health effects from stratospheric ozone

depletion and interactions with climate change. Photochem Photobiol Sci 2:16, 2003
12. Pinnell SR: Cutaneous photodamage, oxidative stress,
and topical antioxidant protection. J Am Acad Dermatol
48:1, 2003
15. Rhodes LE et al: The sunburn response in human skin is
characterized by sequential eicosanoid profiles that may
mediate its early and late phases. FASEB J 23:3947, 2009
29. Fritsche E et al: Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc Natl Acad Sci
USA 104:8851, 2007
72. Holick MF: Environmental factors that influence the
cutaneous production of vitamin D. Am J Clin Nutr
61:638S, 1995
80. Rhodes LE et al: Recommended summer sunlight exposure levels can produce sufficient (>20 ng ml-1) but not
the proposed optimal (>32 ng ml-1) 25 (OH)D levels at
UK latitudes. J Invest Dermatol 130:1411, 2010
107. Bischoff-Ferrari HA et al: Estimation of optimal serum
concentrations of 25-hydroxyvitamin D for multiple
health outcomes. Am J Clin Nutr 84:18, 2006
118. Kripke ML et al: Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice. Proc
Natl Acad Sci USA 89:7516, 1992
131. Schwarz A et al. Interleukin-12 suppresses ultraviolet
radiation-induced apoptosis by inducing DNA repair.
Nat Cell Biol 4:26, 2002
Chapter 91 :: A
bnormal Responses to Ultraviolet
Radiation: Idiopathic, Probably
Immunologic, and Photoexacerbated

:: Travis W. Vandergriff & Paul R. Bergstresser
POLYMORPHIC (POLYMORPHOUS)
LIGHT ERUPTION
EPIDEMIOLOGY. Polymorphic light eruption
(PMLE) is common worldwide, but thought to occur
more frequently in temperate latitudes and rarely in
equatorial latitudes. However, a large-scale crosssectional study has revealed no latitudinal gradient
of Polymorphic Light Eruption
USUAL ACUTE FORM
Photoexacerbated dermatoses such as atopic or
seborrheic dermatitis or acne
Solar urticaria
Erythropoietic protoporphyria
RARE PERSISTENT FORM
Jessner lymphocytic infiltrate
Clinical presentation: a pruritic,

erythematous, symmetrically distributed,
papulovesicular eruption, usually on
exposed areas, within hours of exposure
to ultraviolet radiation, most commonly
sunlight, with full resolution in days to
several weeks.
Histopathology: epidermal spongiosis with
a superficial and deep dermal, perivascular,
mainly mononuclear cell infiltrate and
papillary dermal edema.
Genetics: most likely a genetically
determined delayed-type hypersensitivity
reaction against UVR-induced cutaneous
antigen(s).
Therapy: responds to broad-spectrum
sunscreen use, oral or topical steroids, and
prophylactic low-dose immunosuppressive
phototherapy.
TABLE 91-1
Abnormal Responses to Ultraviolet Irradiation

Acquired idiopathic, presumed immunologic
photodermatoses
Polymorphic light eruption
Actinic prurigo
Hydroa vacciniforme
Solar urticaria
DNA repair defect disorders
Cockayne syndrome
Trichothiodystrophy
Bloom syndrome
RothmundThomson syndrome (probable)
Chemical and drug photosensitivities
Exogenous
Systemic
Topical
Endogenous
The porphyrias
Photoexacerbated dermatoses
Abnormal Responses to Ultraviolet Radiation: Idiopathic
ACQUIRED IDIOPATHIC,
PROBABLY IMMUNOLOGIC
PHOTODERMATOSES
A common acquired sunlight-induced

disorder typically presenting in the spring.
::
Abnormal responses to ultraviolet radiation (UVR)

exposure divide into four categories (Table 91-1): (1)
acquired idiopathic, presumed immunologic; (2) DNA
repair defect disorders; (3) chemical and drug photosensitivity, including the porphyrias; and (4) photoexacerbated dermatoses not caused directly by UVR. The
first and last categories and an approach to assessing
photosensitivity are covered in this chapter. The other
categories are covered in other chapters in this book.
Diagnosis of photodistributed eruptions is discussed
in Box 91-1 and Figure 91-1, and the entities are discussed in the following sections.
POLYMORPHIC LIGHT ERUPTION

AT A GLANCE
Chapter 91
ABNORMAL RESPONSES TO
ULTRAVIOLET RADIATION:
IDIOPATHIC, PRESUMED
IMMUNOLOGIC, AND
PHOTOEXACERBATED
16
1049
16
Are lesions present despite rigorous

avoidance of sunlight?
OR
Are lesions present in photoprotected sites?
YES
Consider
photoexacerbated
primary dermatosis
NO
Consider patients age
Section 16
Child
Are pock scars

present?
::
Hydroa vacciniforme
Young adult
Elderly
NO
Do excoriations, swallow scars,
or dyspigmentation predominate?
YES
Actinic
prurigo
Does the patient have a history of

atopic or contact dermatitis?
OR
Does patient pursue outdoor hobbies?
NO
NO
Does the patient take a

photosensitizing medication?
YES
YES
Chronic actinic
dermatitis
NO
Phototoxic or photoallergic
drug eruption
Consider onset and duration

of lesions
Onset within hours to days,

resolution within days to weeks
Polymorphic light
eruption
Onset within minutes,

resolution within hours
Solar
urticaria
Figure 91-1 Diagnostic algorithm for abnormal responses to ultraviolet radiation.
in Europe.1 This study estimated an overall suspected

lifetime prevalence of 18% among Europeans. Previous
reports indicate a prevalence of 10%15% among North
Americans2 and southern Britons,3 and 5% among
southern Australians.3 Women are affected more than
twice as frequently as men.1 Fitzpatrick skin type also
influences the risk of developing PMLE, with the highest prevalence in people with skin type I and the lowest
prevalence in people with skin type IV or higher.1
1050
ETIOLOGY AND PATHOGENESIS. A delayedtype hypersensitivity (DTH) response to a sunlightinduced cutaneous photoantigen was first suggested
as the cause of PMLE in 1942, based on the delay
between UVR exposure and onset of the eruption,
as well as on its lesional histologic features.4 In normal skin, UVR is known to induce a transient state of
immunosuppression by depleting epidermal Langerhans cells and by promoting the release of immunosuppressive cytokines, including IL-4 and IL-10.
In patients with PMLE, the immunosuppression normally associated with UVR is diminished substantially. It is thought that this creates an environment
in which hypersensitivity responses to one or more
photoinduced neoantigens is permissible. The notion
that PMLE represents a DTH response is supported by
histopathologic, molecular, and epidemiologic data.
Histopathologic examination of biopsy specimens
from lesions of PMLE induced by solar-simulated radiation demonstrates the consistent appearance within
hours of a T-cell dominated perivascular infiltrate that
peaks by 72 hours. CD4+ T cells are most numerous in
early lesions, whereas by 72 hours CD8+ T cells predominate, perhaps abolishing the response.5 Increased
mitting some UVA and all visible light, may even have
a PMLE-enhancing effect if exposure times are lengthened. There is most likely genetic predisposition to
PMLE,19 but the intensity of initial UVR exposure may
also be important in such predisposed individuals.
16
CLINICAL FEATURES
History. PMLE usually
Figure 91-2 Polymorphic light eruption. Papular lesions

of exposed sites.
::
has onset within the first

three decades of life and affects females two to three
times more often than males. It occurs in all skin types
and racial groups, but is more common in Caucasians.
A positive family history is present in about a fifth of
patients.19
The typical PMLE eruption (Fig. 91-2) occurs each
spring or on sunny vacations after the first substantial UVR exposure following a prolonged period with
little exposure. It can also occur after recreational sunbed use or, very rarely, after exposure to visible light,18
and it often abates with continuing exposure. It is rare
in winter except after extended outdoor recreational
activities. Sufficient exposure may also occur through
window glass. The threshold required to trigger PMLE
varies from patient to patient and is usually from 30
minutes to several hours, although it may occur several days into a vacation. Lesions appear in hours to
days following exposure, but usually in not less than
30 minutes. Patients may note itching as the first sign
of an impending PMLE eruption. Once UVR exposure
ceases, all lesions gradually resolve fully without scarring over one to several days, occasionally taking a
week or two. In any given patient, PMLE outbreaks
always tend to affect the same exposed sites. The distribution is generally symmetric. Only some of the
exposed skin is usually affected, particularly skin that
is habitually covered, and large areas may be spared.
An apparent extreme example of PMLE is juvenile
spring eruption,20 which tends to affect boys in the
Chapter 91
numbers of epidermal Langerhans cells and dermal

macrophages are also present. Additionally, it has
been demonstrated that neutrophil infiltration into the
skin following UVB irradiation is deficient, leading to
impaired IL-4 and IL-10 release.6 Whereas a Th2 cytokine milieu is favored in normal skin following irradiation, a Th1 cytokine profile is favored in patients with
PMLE.7
Molecular studies have revealed increased intercellular adhesion molecule-1 expression on keratinocytes
overlying the perivascular infiltrate in PMLE,8 as has
been noted in DTH reactions but not in irritant contact
dermatitis or after the UVB (290320 nm) irradiation
of normal skin.9
More recently, the induction of allergic contact sensitivity to dinitrochlorobenzene after solar-simulated
irradiation of sensitization sites has been shown to
occur more easily in PMLE patients than in normal
individuals,10,11 which suggests that sensitization to
a putative UVR-induced cutaneous antigen may also
be easier during disease-inducing exposure. On the
other hand, elicitation of allergic contact responses to
dinitrochlorobenzene in previously sensitized PMLE
patients and normal individuals were equally suppressed by irradiation,12 which explain the frequent
development of immunologic tolerance, often called
hardening or desensitization, as summer progresses or
during prophylactic phototherapy. In fact, normalization in the depletion of epidermal Langerhans cells in
response to UVR has been observed in patients with
PMLE after undergoing therapeutic hardening.13
Finally, epidemiologic studies also point to hypersensitivity in patients with PMLE. The prevalence
of PMLE is much lower in patients with skin cancer,
suggesting that UVR-induced immunosuppression
that may allow the persistence of malignant cells also
inhibits hypersensitivity to photoantigens.14 Also,
PMLE is quite uncommon in iatrogenically immunosuppressed transplant recipients, occurring in only 2%
of this population.15
The photoinduced neoantigens that initiate PMLE
have not been identified, but several molecules
may play roles, even in a single patient. The altered
molecule(s) itself may hypothetically become antigenic
directly by UVR, or secondarily through UVR-induced
free radicals that modify nonantigenic peptides in
such a way that they become antigenic. Of course, both
mechanisms may even take place simultaneously.
UVA radiation (320400 nm) usually seems more
effective than UVB (290320 nm)12,16 at initiating
PMLE. In one study, UVA irradiation elicited the eruption successfully in 56% of patients exposed to UVA
or UVB daily for 48 days, in 17% of those exposed
to UVB, and in 27% of those exposed to both.17 However, other reports have suggested that UVB radiation
may be implicated in up to 57% of patients. Therefore,
it could broadly be said that approximately 50% of
PMLE patients seem sensitive to UVB radiation and
75% to UVA, including in each case approximately
25% who are sensitive to both. Even visible light may
be responsible on rare occasions.18 As a result, paradoxically, patients may note that the use of sunscreens,
which tend preferentially to remove UVB while trans-
1051
16
Small papular PMLE, generally sparing the face and

occurring after several days of continuing exposure,
has been designated benign summer light eruption in
Europe.22
LABORATORY TESTS
Histology. The histologic features of PMLE are char-
Section 16
Figure 91-3 Polymorphic light eruption. Papulovesicular

lesions on the arm.
::
spring and is characterized by pruritic papules and

vesicles on their ear helices, although typical PMLE
sometimes coexists. Systemic symptoms in PMLE are
rare, but malaise and nausea may occur.
Cutaneous Lesions. PMLE has many morphologic forms, all probably with similar pathogenesis and
prognosis. The term polymorphous describes the
variability in lesion morphology observed among different patients with the eruption. In fact, the lesions are
usually quite monomorphous in an individual patient.
Papular, papulovesicular (Fig. 91-3), plaque (Fig. 91-4),
vesiculobullous, insect bite-like, and erythema multiforme-like forms have been described, and pruritus
alone may even occur, albeit rarely.21 The papular form,
characterized by large or small separate or confluent
erythematous and edematous papules that generally
tend to form clusters, is most common. Papulovesicular
and plaque variants occur less frequently, and the other
forms are rare. An eczematous form has been claimed
but probably refers to mild chronic actinic dermatitis
or photoexacerbated seborrheic or atopic dermatitis.
acteristic but not pathognomonic,23 and they vary with

clinical presentation. There is generally a moderate to
dense perivascular infiltrate in the upper and mid dermis in all forms. The infiltrate consists predominantly
of T cells, with neutrophils and infrequent eosinophils.
Other common features are papillary, dermal and perivascular edema with endothelial cell swelling. Epidermal change, not always present, may include variable
spongiosis and occasional dyskeratosis, exocytosis,
and basal cell vacuolization.
Blood Tests. Assessment for circulating antinuclear
antibodies (ANA) and extractable nuclear antibodies

(ENA) is advisable to exclude subacute cutaneous or
other form of cutaneous lupus erythematosus (LE),
and, if there is uncertainty, red blood cell protoporphyrins should be assessed to exclude erythropoietic
protoporphyria (EPP). Approximately 11% of patients
with PMLE have been found to have a positive ANA,
with the vast majority having insignificant titers of less
than 1:160.24 An even smaller fraction (less than 1%) of
patients with PMLE have anti-Ro antibodies.24 Clinical
correlation is necessary in these patients to exclude the
possibility of cutaneous LE.
Phototesting. Cutaneous phototesting with a

monochromator confirms photosensitivity in up to half
of cases,25 but usually does not differentiate PMLE from
other photodermatoses. However, provocation testing with a solar simulator or other broadband source,
sometimes repeated over 2 or 3 successive days, may
induce the eruption, allowing a subsequent skin biopsy.
This is most appropriate when the history and clinical
features are not diagnostic.
DIFFERENTIAL DIAGNOSIS. (See Box 91-1)
COMPLICATIONS. A very few patients with PMLE
may develop LE, as there is a higher than normal prevalence of prior PMLE in patients with LE.26 However,
the presence of autoantibodies does not portend development of LE. Patients with PMLE may also experience
significant disease-related psychosocial morbidity. The
rate of both anxiety and depression in patients with
PMLE are twice that of the general population, and
these rates are similar to those observed in patients
with psoriasis and atopic dermatitis.27
PROGNOSIS AND CLINICAL COURSE. Over 7
years, 57% of 114 patients reported steadily diminishing sun sensitivity, including 11% in whom the condition cleared.28
1052
Figure 91-4 Polymorphic light eruption. Variably sized

itchy plaques on the cheek.
PREVENTION. PMLE may often be avoided by moderating sunlight exposure, wearing protective clothing,
and applying broad-spectrum high-protection-factor

sunscreens regularly. Sunscreens with UVA and UVB
protection may prevent PMLE eruptions in photoprovocable patients,29 but sunscreens without UVA
protection are generally ineffective. Prophylactic phototherapy each spring or before sunny vacations tends
to prevent attacks.
TREATMENT. The first goal in treating PMLE is to
A persistent variant of the sometimes

coexistent polymorphic light eruption.
Similar to the hereditary or familial variant
of PMLE that affects native North and
South Americans predominantly but which
is usually more severe, persisting into
adulthood.
Prevention through avoidance of sunlight is
the first line therapy; thalidomide or other
immunosuppressive agents may be required.
PATHOGENESIS. AP appears to be UVR-induced in

that it is more severe in spring and summer and often
demonstrates abnormal skin phototest responses to
UVB and/or UVA radiation.41 UVA is implicated more
often than UVB.42 The cytokine TNF- is overexpressed
by keratinocytes in lesions of AP, creating a proinflammatory environment.40 Sunlight exposure and solar
simulating irradiation may sometimes induce an eruption resembling PMLE in patients with AP, and many
patients have close relatives with PMLE.19 A dermal,
perivascular mononuclear cell infiltrate similar to that
of PMLE may be seen in early lesions.
Therefore, AP may be a slowly evolving, excoriated
variant of PMLE, and thus also a DTH reaction. The
human leukocyte antigen (HLA) DRB1*0407 (DR4)
is found in 60%70% of patients with AP but in only
4%8% of normal DR4 positive controls.42 Additionally, HLA DRB1*0401 is found in approximately 20%
of affected individuals.42 These immunogenetic features may well be responsible for modulating conventional PMLE into AP. In addition, in some patients, AP
appears to transform into PMLE and, in others, PMLE
appears to transform into AP,43 all of which suggests a
relationship between the two disorders. The cutaneous
UVR chromophores responsible for the eruption are
not known, but they are likely to be diverse.
EPIDEMIOLOGY. Actinic prurigo (AP) occurs

throughout much of the world. Native North and
South Americans are particularly affected. The disease is estimated to occur in 2% of the Canadian Inuit
population.39 In Mexico, AP is seen most commonly in
the indigenous and Mestizo populations living at altitudes greater than 1,000 m.40 Less commonly, inhabitants of Europe, United States, Australia, and Japan are
reported to develop AP.
Beginning in childhood, it may remit at

puberty, exacerbate most often in summer,
and fade in winter.
::
ACTINIC PRURIGO
A rare, persistent, pruritic and excoriated

papular or nodular eruption of sun-exposed
and, to a lesser extent, nonexposed skin.
Chapter 91
prevent it. As noted above, one should advise restricting midday sunlight exposure and employing frequent applications of broad-spectrum, high-protection
sunscreens. If this is not fully effective, patients who
have outbreaks only infrequently, such as on vacations,
usually respond well to short courses of oral steroids
that are prescribed and taken with them to use in the
event of an eruption.30 If PMLE does develop, approximately 2030 mg prednisone taken at the first sign of
pruritus and then each morning until the eruption
clears usually provides relief within several days, and
recurrences are then uncommon during the same vacation. This treatment, if well tolerated, may be repeated
safely every few months.
More severely affected individuals who experience
repeated attacks of PMLE throughout the summer
may require prophylactic courses of low-dose photochemotherapy (psoralen and UVA radiation: PUVA)
in the spring. This appears to be more effective than
broadband UVB radiation, controlling symptoms in
up to 90% compared to approximately 60% of cases.31
Narrowband (311-nm) UVB phototherapy, effective in
70%80% of cases, is now probably the treatment of
choice, because of ease of administration.32 Prophylactic PUVA or UVB irradiation may sometimes trigger
the eruption, particularly in severely affected patients,
in which case a brief course of oral steroid therapy is
indicated.
Various other therapies have also been tried but
appear largely ineffective. These include hydroxychloroquine,33 which is perhaps occasionally useful;
-carotene,34 which is rarely effective; nicotinamide,35
which is usually ineffective; and -3 polyunsaturated
fatty acids, which are perhaps of moderate assistance
in some patients.36
A small percentage of patients remain who are
unsuitable for, unable to tolerate, or not helped by any
of these measures. For these patients, when severely
affected, oral immunosuppressive therapy, usually
intermittent, with azathioprine or cyclosporine can be
helpful.37,38
ACTINIC PRURIGO AT A GLANCE
16
CLINICAL FEATURES
History. AP occurs more commonly in females, with
a female to male ratio of about 2:1.42 The eruption has its

onset in childhood, usually present by age 10 years.41 A
positive family history of either AP or PMLE is present
in about a fifth of patients.19 The eruption is often present all year round, but it is commonly worse in summer. Very rarely it is worse in winter or both spring and
1053
16
Section 16
::
Figure 91-6 Cheilitis of actinic prurigo seen in a Mexican

landscape gardener.
Figure 91-5 Actinic prurigo. Papules and nodules on the

legs of a 15-year-old girl.
fall, with immunologic tolerance presumably developing during the summer. Exacerbations tend to begin
gradually during sunny weather in general rather than
after specific sun exposure, although PMLE-like outbreaks may also occur.
Cutaneous Lesions. The primary lesion of AP

is a pruritic papule or nodule that occurs singly or
in clusters (Fig. 91-5). Papules and nodules are often
excoriated and crusted, and plaques may assume a
lichenified or eczematous appearance. Vesicles are not
seen unless superinfection is present.42 Sun-exposed
areas are most often affected, particularly the forehead,
chin, cheeks, ears, and forearms. There is a gradual fading toward habitually covered skin, and the sacral area
and buttocks may be mildly affected. Lower lip cheilitis and conjunctivitis are also possible, particularly in
Native Americans44 (Figs. 91-6, and 91-7). Healed facial
lesions may leave dyspigmentation and sall pitted or
linear scars.
Blood Tests. Assessment of ANA and ENA should

be undertaken to exclude subacute cutaneous or other
forms of cutaneous LE. The finding of HLA type
DRB1*0401 (DR4) or DRB1*0407, especially the latter,
supports the diagnosis of AP.
Phototesting.
Cutaneous phototesting with a

monochromator confirms light sensitivity in up to half
of cases,41 but, as in PMLE, does not differentiate other
photodermatoses. Most patients with positive monochromator testing have reduced minimal erythema
doses (MED) in the UVA spectrum or in the combined
UVA/UVB spectra.42 Provocation testing with a solar
simulator or other broadband sources induces typical
lesions of AP in about two-thirds of patients.42
LABORATORY TESTS
Histology. Early papular lesions show changes similar
1054
to those of PMLE, namely, mild acanthosis, exocytosis,

and spongiosis in the epidermis and a moderate lymphohistiocytic superficial and middermal perivascular infiltrate.23 A dense dermal lymphoid infiltrate and lymphoid
follicles may be seen in lesions from the lip.40 In persistent
lesions, however, excoriations, more acanthosis, variable
lichenification, and a dense mononuclear cell infiltrate
produce a nonspecific appearance.
Figure 91-7 Lip biopsy from a patient with actinic prurigo

shows a dense lymphohistiocytic infiltrate as well as a lymphoid follicle in the lamina propria.

of Actinic Prurigo
Most Likely
Atopic eczema
Photoexacerbated atopic or seborrheic eczema
Insect bites
Prurigo nodularis
Always Rule Out
Scabies
TREATMENT. In less severe cases of AP, sufficient

relief may be achieved by restricting sun exposure and
by using broad-spectrum, high-protection-factor sunscreens alone.47 Higher potency topical corticosteroids
may be used to relieve the inflammation and pruritus
associated with the disease. Phototherapy with narrowband UVB or PUVA may occasionally help,48 perhaps
more reliably if the skin is cleared first with oral steroids.
Topical tacrolimus or pimecrolimus may also help,
again if the skin is cleared first. The treatment of choice
in more severe or recalcitrant cases is thalidomide, with
initial doses of 50100 mg daily, preferably given intermittently. Responses to thalidomide are evident in most
patients within several weeks. The most serious complication associated with thalidomide is teratogenicity, so
pregnancy must be rigorously avoided. Other potential
adverse effects are typically mild, including drowsiness,
headache, constipation, and weight gain. An increased
risk of thromboembolism and dose-related peripheral
(mostly sensory) neuropathy are other potential adverse
effects of thalidomide. In cases where thalidomide is
unavailable or otherwise not appropriate, oral immunosuppressive therapy with azathioprine or cyclosporine
may also be considered.
A rare, chronic, scarring photodermatosis

sometimes associated with EpsteinBarr
virus infection
Characterized by recurrent sunlight-induced
crops of papulovesicles and vesicles, most
commonly on the face and dorsa of the
hands.
Onset commonly in childhood, remitting
most often at puberty.
May be a scarring variant of polymorphic
light eruption.
Focal intraepidermal vesiculation, reticular
keratinocyte degeneration, epidermal and
upper dermal necrosis, and sometimes
ulceration are virtually pathognomonic
histologic changes.
Avoidance of ultraviolet radiation, including
the use of broad-spectrum high-protectionfactor sunscreens, is the only established
therapy.
Prophylactic immunosuppressive
phototherapy, administered with great care
to avoid induction of new lesions, may help.
EPIDEMIOLOGY. Hydroa vacciniforme (HV)

occurs in North America, Europe, Japan, and very
likely elsewhere. However, its rarity and lack of universally acknowledged diagnostic criteria may make
the diagnosis difficult to establish.
ETIOLOGY AND PATHOGENESIS. The pathogenesis of HV is not known. No chromophores have
been identified, and although UVB minimal erythemal dose responses are normal in most patients, some
have increased UVA sensitivity.49 Blood, urine, and
stool porphyrin concentrations are normal, as are all
other laboratory tests. Nevertheless, its clear relationship to sunlight exposure, its distribution, and its early
clinical appearances are all similar to that of PMLE,
which suggests a relationship. On the other hand, fully
developed HV eruptions are more severe than those
found in PMLE, are associated with permanent scarring, and are unresponsive to treatments ordinarily
effective in PMLE, apart perhaps from sunscreens and
occasionally prophylactic phototherapy. Reports from
Asia and Mexico have linked HV to chronic Epstein
Barr virus (EBV) infection,50,51 although a relationship
PREVENTION. Prevention begins by restricting

midday sunlight exposure and the compulsive use of
broad-spectrum sunscreens.46 In addition, topical calcineurin inhibitors tacrolimus and pimecrolimus may
be effective in preventing recurrences in patients with
previously documented disease. Of course, there is no
known way to prevent its initial onset.
HYDROA VACCINIFORME
AT A GLANCE
::
PROGNOSIS AND CLINICAL COURSE. AP

commonly arises in childhood and often improves
or resolves in adolescence, although persistence into
adult life is possible. Persistent cases may assume features of PMLE in adulthood. More rarely, the disorder
arises in adulthood and persists indefinitely.46
16
Chapter 91
COMPLICATIONS. Mild scarring, especially on

the face, and hypopigmentation may result from excoriations associated with AP. Additionally, two cases
of primary cutaneous B-cell lymphoma arising on the
face in patients with AP have been reported.45
HYDROA VACCINIFORME
1055
16
between EBV and HV in all populations has not been

established. Japanese reports indicate that EBV nucleic
acids are found in the cutaneous lesions of HV in
85%95% of patients but not in lesional skin of control
patients.51,52 A recent report from France has now provided substantial evidence that EBV infection persists
in adult patients with HV and that it plays an important pathogenic role.53
CLINICAL FINDINGS
History. HV commonly develops in early childhood
Section 16
::
and resolves spontaneously by puberty, although,

in some patients, it is lifelong. There is male predominance for severe forms, whereas milder disease
is more common in females.49,54 Familial incidence
is exceptional. One estimate of the prevalence of HV is
0.34 cases per 100,000 with an approximately equal sex
ratio; males had a later onset and longer duration of
the disorder than females.54
HV eruptions typically occur in summer,41 often
with an intense burning or stinging sensation followed
by the appearance of individual or confluent papules
and then vesicles, all within hours of sunlight exposure
(Fig. 91-8). This is followed by umbilication, crusting,
and progression to permanent pock scarring within
weeks. The eruption affects the cheeks and, to a lesser
extent, other areas of the face as well as the backs of the
hands and outer aspects of the arms. The distribution
tends to be symmetrical.
Cutaneous Lesions. HV is characterized by initial

erythema, sometimes with swelling, followed by symmetrically scattered, usually tender papules within 24
hours; vesiculation, occasionally confluent and hemorrhagic (Fig. 91-9); umbilication; then crusting and
detachment of the lesions with permanent, depressed,
hypopigmented scars within weeks. These scars are
Figure 91-9 Typical hydroa vacciniforme lesions provoked by repeated ultraviolet A irradiation.
invariably present. Oral ulcers and eye signs also occur

rarely.55,56
LABORATORY TESTS
Histology. Early histologic changes include intraepi-
dermal vesicle formation with subsequent focal epidermal keratinocyte necrosis and spongiosis. There
is a dermal perivascular neutrophil and lymphocyte
infiltrate.23 Older lesions show necrosis, ulceration,
and scarring. Vasculitic features have been reported.49
Blood Tests. Blood, urine, and stool porphyrin con-
centrations should be assessed to exclude cutaneous

porphyria, and an ANA and ENA to exclude the small
possibility of cutaneous LE.
Phototesting.
Phototesting may show increased

sensitivity to short-wavelength UVA in some patients,
but phototesting usually does not discriminate HV
from other photodermatoses. Simulated solar irradiation may also induce erythema at reduced doses or
occasionally provoke the typical vesiculation of HV
(see Fig. 91-7).
Other Tests. Viral studies for herpes infection or

other viral disorders should be undertaken if photoexacerbation or photoinduction of these other disorders
seems at all possible.
1056
Figure 91-8 Hydroa vacciniforme. Vesicular, bullous, and

crusted facial lesions, which are precursors of vacciniform
scars.
DIFFERENTIAL DIAGNOSIS. (See Box 91-3).

There are reports of severe HV-like eruptions occurring in patients with chronic EBV infection and other
associated disorders such as hypersensitivity to mosquito bites and the hemophagocytic syndrome. HVlike eruptions are distinguished from true HV by the
development of lesions in both exposed and sun-protected skin and by the presence of systemic symptoms
such as fever, hepatosplenomegaly, and wasting.51,57

of Hydroa Vacciniforme
Photoexacerbated viral dermatoses such as
herpes simplex
Erythropoietic protoporphyria
A rare acquired persistent eczematous

eruption of exposed skin, sometimes having
pseudolymphomatous features.
Commonly affects older men, but sometimes
young atopic patients and rarely patients
with hydroa vacciniforme or human
immunodeficiency virus infection.
Histologic features are eczematous, but
pseudolymphomatous forms may be
virtually indistinguishable from cutaneous
T-cell lymphoma.
Pock scarring is an inevitable

sequela of HV. Cases of severe HV-like eruption may
progress to lymphoproliferative disease.
Persistent light reaction, actinic reticuloid,

photosensitive eczema, and photosensitivity
dermatitis are all considered clinical variants.
PROGNOSIS AND CLINICAL COURSE. HV

often resolves in adolescence but may occasionally
persist into adult life.
Very likely due to a delayed-type

hypersensitivity reaction against an
endogenous photoinduced epidermal
antigen(s).
PREVENTION. Sun avoidance and sunscreen use, as

well as prophylactic phototherapy annually in spring,
tend to prevent HV in some patients.
TREATMENT. Treatment of HV consists of restricting
sunlight exposure and use of high-protection-factor
broad-spectrum sunscreens. Occasionally, antimalarials appear to have helped, but their true value has not
been established. As with PMLE, prophylactic phototherapy with narrowband UVB or PUVA, particularly
the latter, may be helpful but must be administered
with care to avoid disease exacerbation.49,53,61 If conservative measures are ineffective, however, as often
occurs, topical or intermittent oral steroids, topical
calcineurin inhibitors, or even oral immunosuppressive medication may be tried if clinically appropriate, though these agents too are usually ineffective.
In patients with chronic EBV infection, antiviral therapy with acyclovir and valacyclovir was reported in
a small series of patients to reduce the frequency and
severity of eruptions.62
CHRONIC ACTINIC DERMATITIS
EPIDEMIOLOGY. Chronic actinic dermatitis (CAD)
has regularly been diagnosed in Europe, North America, Africa, Australia, New Zealand, Japan, and India.
The disorder therefore appears to have worldwide
distribution, affecting all skin types, although it is perhaps more common in temperate regions.
Therapy consists of strict avoidance of

ultraviolet radiation, along with topical
and intermittent oral steroids, topical
calcineurin inhibitors, or prolonged lowdose immunosuppressive phototherapy.
Oral immunosuppression with cyclosporine
or azathioprine is often required.
ETIOLOGY AND PATHOGENESIS. Studies of the

clinical, histologic, and immunohistochemical features
of CAD all show it to resemble the DTH reaction of allergic contact dermatitis,7375 even in its severe pseudolymphomatous form (formerly called actinic reticuloid),
in which the clinical and histologic features duplicate
those seen in long-standing allergic contact dermatitis.76
It is therefore highly probable that CAD is an allergic
reaction. In addition to hypersensitivity to cutaneous
photoantigens, patients with CAD often have concomitant allergic contact dermatitis to airborne or other
ubiquitous allergens, including plant compounds, fragrances, and medicaments.77 Commonly implicated
allergens include sesquiterpene lactone from plants of
the Compositae family and sunscreens. A recent study
indicates that sesquiterpene lactone remains the most
common allergen in patients with CAD, with positive
and clinically relevant photopatch testing to this allergen documented in approximately 20% of patients.78
COMPLICATIONS.
::
Ordinarily induced by small amounts of

ultraviolet B radiation, often with ultraviolet
A radiation, and sometimes even visible
light; in rare cases, induced by UVA
radiation or visible light alone.
Chapter 91
The distinction between an HV-like eruption and true

HV is important because patients with a severe HVlike eruption may rarely go on to develop potentially
fatal hematologic malignancy.5659 Finally, a recent
quality-of-life study indicates that HV causes embarrassment and self-consciousness among children with
the disease.60 The negative impact of HV on quality of
life exceeds previously reported indices for atopic dermatitis and psoriasis.60
CHRONIC ACTINIC DERMATITIS

AT A GLANCE
16
1057
16
TABLE 91-2
Original Criteria for the Eczematous

Photosensitivity Disorders
Section 16
::
1058
Persistent light reaction62: Eczema of predominantly

light-exposed skin sensitive to UVB UVA following acute
photoallergic contact dermatitis
Actinic reticuloid63: Infiltrated papules and plaques of
mainly light-exposed skin with lymphoma-like histologic
features and sensitivity to UVB + UVA visible light;
negative results on photopatch testing
Photosensitive eczema64: Morphologic and histologic
eczema of mainly light-exposed skin with photosensitivity
only to UVB; negative results on photopatch tests
Photosensitivity dermatitis65: Morphologic and histologic
eczema of mainly light-exposed skin with photosensitivity
to UVB UVA; positive results on photopatch testing in
some of the patients
Chronic actinic dermatitis66: Syndrome encompassing
photosensitive eczema, photosensitivity dermatitis,
and actinic reticuloid; persistent light reaction also now
included
UVA = ultraviolet A radiation; UVB = ultraviolet B radiation.
In addition, cc has emerged as an increasingly common

antigen in CAD78 as has balsam of Peru.79
When CAD occurs in the absence of an obvious epicutaneous contact allergen, the relevant novel antigen
must be either directly radiation-induced or formed
indirectly as a result of secondary oxidative metabolism. Important support for the latter possibility comes
from the fact that albumin can become antigenic in vitro
through photooxidation of its histidine moieties.80 There
is no evidence for a genetic susceptibility to CAD; however, one stimulus for the acquisition of skin reactivity
may be concurrent allergic contact dermatitis to recognized exogenous sensitizers or photosensitizers,81,82 often
airborne, which may predispose by altering cutaneous
immunity, and thus permitting immunological recognition of an endogenous photoantigen. Long-standing
endogenous eczema,68,69,83,84 drug-induced photosensitivity,85 human immunodeficiency virus infection,86 and
possibly PMLE75 may also play similar roles. On the
other hand, in addition or instead, chronic photodamage in frequently sun-exposed elderly outdoor enthusiasts, those who most often develop CAD,75 may impair
normal UVR-induced skin immunosuppression sufficiently for endogenous UVR-induced photoantigens
to be recognized, as apparently also occurs for genetic
reasons in PMLE.19 Clearly, there is much work left to
be done to identify the immunologic mechanisms that
account for CAD.
Determining the action spectrum for CAD should
theoretically help identify the postulated antigens,
and the action spectra for CAD have been shown to
resemble that of sunburn in many patients.87 However,
the eruption in CAD is eczematous, and much lower
doses of UVR are required to evoke CAD than to produce erythema. In any event, the UVR chromophore
for some patients may be the same as that of sunburn,
namely DNA,87 with UVR-damaged DNA serving
directly as an antigen in CAD. In other patients with
CAD, however, the photoallergen must be different,

because these patients react only to UVA radiation,88
and some patients react only to visible light.89
In summary, CAD appears to be an allergic contact
dermatitis-like reaction against UVR-altered DNA or
similar or associated molecules, perhaps as a result of
enhanced immune reactivity due to concomitant airborne contact dermatitis or a reduced immunosuppressive capacity in photodamaged skin. The eruption
occurs most often in patients with long-standing exposure to sunlight and airborne contact allergies.
CLINICAL FEATURES
History. CAD may arise
de novo in apparently
normal skin or in the skin of patients with previous
endogenous eczema, photoallergic or allergic contact
dermatitis, or rarely PMLE.75,90 Concurrent allergic
contact sensitivity to plant allergens, fragrances, or
sunscreens is common.82 The condition usually affects
middle-aged or elderly men,75 as CAD is rarely seen in
patients under 50 years of age, except for those with
prior atopic eczema.83,84 The disorder is worse in summer, developing within minutes to hours after sunlight
exposure and producing a pruritic confluent erythematous eruption that occasionally remits over several
days with scaling, if exposure ceases and if the reaction is mild. However, severely affected patients frequently do not even recognize that exacerbations are
related to sunlight exposure, especially when affected
all year round.
Cutaneous Lesions. The lesions of CAD are

eczematous, patchy or confluent, and acute, subacute, or chronic (Figs. 91-10 and 91-11). In severe
cases, lichenification is common. Less commonly, scattered or widespread erythematous, shiny, infiltrated
pseudolymphomatous papules or plaques are present on a background of erythematous, eczematous,
Figure 91-10 Chronic actinic dermatitis. Infiltrated eczematous eruption on the face.
16
Chapter 91
::
Figure 91-11 Chronic actinic dermatitis. A, B. Severe lightinduced eczema of the face and neck. C, D. Patient in full remission after low-dose psoralen plus ultraviolet A irradiation
over weeks, with initial high-dose oral steroid cover to prevent
initial exacerbation.
or normal skin.75 Habitually exposed areas are most
often affected, commonly with sharp cutoff at lines of
clothing. There is sparing of deep skin creases, upper
eyelids, finger webs, and skin behind the earlobes. In
severe disease, eczema of the palms and soles may also
be found. Eyebrows, eyelashes, and scalp hair may be
stubbly or altogether lost from constant rubbing and
scratching. Erythroderma, usually but not always
accentuated on exposed sites, supervenes rarely. Variable, sometimes geographic, sparing of exposed areas
of the face or elsewhere, as well as irregular hyperpigmentation and hypopigmentation, sometimes vitiligolike,91 may also occasionally be found.
LABORATORY TESTS
Histology. Histologic features
include epidermal
spongiosis and acanthosis, sometimes with hyperplasia. There is usually a predominantly perivascular
lymphocytic cellular infiltrate confined to the upper
dermis that in milder cases may resemble chronic

eczema.23 Severe CAD, however, may mimic cutaneous T-cell lymphoma (CTCL), on occasion being virtually indistinguishable. Features mimicking CTCL
include epidermal Pautrier-like microabscesses and
deep, dense epidermotropic mononuclear cell infiltration, sometimes with atypia. Typically, there is no
marked increase in mitoses. T-cell receptor gene rearrangement studies should be undertaken if there is
suspicion of CTCL. However, T-cell receptor clonality
may also be observed in benign dermatoses.
Blood Tests. Assessment of the ANA and ENA is
advisable in all patients to exclude the unlikely possibility of cutaneous LE. In severe or erythrodermic CAD, there may be large numbers of circulating
CD8+ Szary cells without other suggestions of malignancy.92,93 Human immunodeficiency virus status
should be assessed if there is suspicion that this may
be a predisposing factor.86 Serum IgE may be elevated,
1059
16
with higher levels of IgE correlating with more severe

disease.79
Phototesting. Phototesting is essential, if available,
Section 16
to confirm the diagnosis of CAD. Almost invariably

one finds low erythemal thresholds and eczematous
or pseudolymphomatous responses after irradiation
with UVB, usually with UVA, and rarely with visible
wavelengths.75 A small number of patients react only
to UVA,88 and fewer still only to visible light,89 in which
case, drug photosensitivity must be excluded. Testing
should be done on uninvolved skin of the back with
no topical or systemic steroid therapy for at least the
preceding few days to avoid false-negative results.94
Monochromatic and broad-spectrum sources both
induce abnormal responses, with the former determining the action spectrum for disease induction and the
latter tending to demonstrate acute eczema.
::
Patch and Photopatch Testing. Patch and

photopatch testing is also essential in suspected CAD,
because contact sensitivity to airborne allergens such
as Compositae oleoresins, phosphorus sesquisulfide,
and colophony alone may resemble CAD or even
coexist. In addition, occasional secondary contact or
photocontact sensitivity to sunscreens or other topical
therapies may complicate the clinical picture further.
Positive results with photopatch testing are found in
approximately 80% of patients.78,79
COMPLICATIONS. A relationship to CTCL seems
likely to be coincidental, especially because results of
T-cell receptor, immunoglobulin gene rearrangement,
and other studies are negative in CAD.92,95,96 In addition, CAD gradually resolves in many patients, there is
no higher incidence of malignancies, and life expectancies are thought to be normal.97 However, CTCL itself
may present very rarely with severe CAD-like photosensitivity, and careful investigation to exclude CTCL
is necessary when the disease suspected.98
PROGNOSIS AND CLINICAL COURSE. Once
established, CAD usually persists for years before
resolving gradually.98
TREATMENT.
Treatment of CAD is often difficult

and not fully effective. Rigorous avoidance of UVR
and exacerbating contact allergens is essential, along
with regular application of high protection-factor
broad-spectrum topical sunscreens of low irritancy

of Chronic Actinic Dermatitis

1060
Photoexacerbated atopic or seborrheic eczema

Drug or chemical photosensitivity
Eczematized actinic prurigo
and allergenic potential. Strong topical steroids such

as clobetasol propionate are also often needed and frequently produce marked symptomatic relief without
adverse effects, even after long-term use, if confined
to affected skin. Occasional oral steroid use is often
helpful for disease flares. In more resistant disease,
the topical calcineurin inhibitorstacrolimus and
pimecrolimussometimes produce good results if tolerated.99,100 For refractory CAD, however, oral immunosuppressive therapy is almost always necessary and
generally helpful if tolerated. Azathioprine 1.52.5 mg/
kg/day often produces remission in months,101 after
which it may be reduced in dosage, or perhaps discontinued in the winter. Cyclosporine 3.5 to 5.0 mg/kg/
day is usually rapidly effective,102 but is more likely to
produce adverse effects, which sometimes necessitate
withdrawal. Mycophenolate mofetil is less often useful. Finally, long-term low-dose phototherapy with
PUVA, usually several times weekly initially followed
by maintenance exposures about every 3 weeks may be
helpful,103 generally accompanied initially by oral and
topical steroid therapy to avoid disease flares.
PREVENTION. The risk of CAD can probably be

reduced by moderating outdoor pursuits, especially
those associated with plant allergen exposure such as
gardening, even more so for individuals who already
have a tendency to develop eczematous eruptions
in exposed areas. Avoidance of UVR is critical, and
patients should be aware that indoor lighting may
also be a source of UVA exposure. Compact fluorescent lamps even emit UVR at wavelengths as low as
254 nm, and some patients with CAD appear to be
susceptible to disease flares after exposure to such
lamps.104
SOLAR URTICARIA
EPIDEMIOLOGY. Solar urticaria (SU) has been
reported in Asia, Europe, and the United States, and,
thus, probably occurs worldwide. Perhaps 3 per
100,000 are affected.105 Ultraviolet and visible radiation
are causes of this form of urticaria, but SU accounts for
less than 0.1% of all cases of chronic urticaria.106
ETIOLOGY AND PATHOGENESIS. Primary
SU is an immediate type I hypersensitivity response
against a cutaneous or circulating photoallergen(s)
generated from a precursor at the time of irradiation.
Both circulating photoallergens and relevant IgE antibodies have been demonstrated. This has been termed
primary SU, for which no genetic basis has been identified. Very rarely, SU may occur in association with
drug photosensitivity, such as chlorpromazine and
coal tar,106 cutaneous porphyria, or LE. This has been
termed secondary SU.
Two types of primary SU have been proposed, both
involving immunoglobulin E-mediated hypersensitivity against a neoantigen that is photoinduced. In type
1, the photoallergen is the chromophore, which is generated only in patients with SU. Type 2 is mediated
by circulating antibodies found only in patients and
SOLAR URTICARIA AT A GLANCE

An uncommon sunlight-induced whealing
disorder that occurs more often in females.
Rarely is secondary to phototoxic drug use
or with cutaneous porphyria.
Onset within 5 to 10 minutes of sunlight
exposure. Resolves in an hour or two; may
be disabling and, rarely, life threatening.
Clinical and histologic features are those of

urticaria.
Sunlight avoidance prevents solar urticaria,

and high protection-factor broad-spectrum
sunscreens and antihistamines may help.
When necessary, phototherapy,
plasmapheresis, or oral immunosuppressive
drugs may be helpful in management.
directed against a common chromophore-generated

antigen.106 The wide range of inducing wavelengths
is attributed to the unique action spectra of different
photoallergens (chromophores). Patients with type 1
SU appear to have photoallergens of molecular mass
2534 kilodaltons (kDa) and action spectra within the
visible region, whereas type 2 SU has photoallergens of
251,000 kDa and variable action spectra.107 The range
of eliciting wavelengths can narrow or broaden over
months or even years, suggesting that the relevant
choromophores may vary over time.
Exposure to visible or UVA irradiation before, during, or after the urticaria-inducing irradiation inhibits
whealing in some patients, possibly by inactivation
of the initial photoproduct or the inhibition of subsequent reactions.108,109
skin with an initial macular erythema, followed by

whealing and a surrounding patchy erythematous flare
(Fig. 91-12), often with clear demarcation at lines of
clothing. Rarely, there is sparing of the face and hands,
perhaps as a result of UVR-induced tolerance. In some
patients, specific sites may be affected repeatedly.
LABORATORY TESTS
Histology. There is dermal
vasodilation, edema,
and predominantly perivascular neutrophil and eosinophil infiltration at 5 minutes and at 2 hours, but not
24, hours.23 Endothelial cell swelling occurs early on,
with mononuclear cell infiltration later following
higher irradiation doses. Extensive eosinophil granule
major basic protein deposition is also present in the
dermis at 2 and 24 hours, which suggests eosinophil
degranulation.113 Histologic features do not distinguish SU from other causes of urticaria.
Sensitivity may be to ultraviolet B,

ultraviolet A, visible light, and/or any
combination, but most commonly to
ultraviolet A and visible light.
Cutaneous Lesions. SU usually affects all exposed
::
Phototesting may confirm the diagnosis and

identify the action spectrum.
16
Chapter 91
An immediate type I hypersensitivity

response against a cutaneous or circulating
photoallergen(s).
other photosensitive skin disorders more often than

expected.110 Typically, 510 minutes or, rarely, 2030
minutes of exposure leads to itching and erythema,
followed by patchy or confluent urticarial whealing,
with gradual resolution within 2 hours. Rarely, patients
report itching alone, and the onset of symptoms may
be delayed for up to several hours.111 A rare variant
termed fixed solar urticaria has been reported and
is characterized by urticarial lesions that are induced
repeatedly in the same location.112 In patients with mild
disease, or in those who quickly recognize their SU
onset and avoid further exposure, whealing may not be
reported, even if it may be elicited during phototesting.
Patients having extensive whealing may also describe
headache, nausea, bronchospasm, and syncope, which
rarely may be life threatening. Angioedema and anaphylaxis are exceedingly rare but have been reported.
Secondary SU should be excluded by ruling out drug
photosensitivity, cutaneous porphyria, and LE.
Clinical Features
History. Primary SU is
slightly more common in

females and may arise at any age, although most
patients develop the disease in childhood or young
adulthood.106 The first episode typically occurs after
prolonged sunlight exposure or occasionally following tanning bed use. It also seems to be associated with
Figure 91-12 Solar urticaria. Pruritic wheals with a surrounding patchy flare occurring within 15 minutes of sun
exposure after irradiation of the patients back through a
template.
1061
16
Blood Tests.
Tests for an ANA and ENA should

be employed to exclude cutaneous LE, as should the
blood, urine, and stool porphyrins to exclude cutaneous porphyria.
Phototesting.
Section 16
::
Phototesting with a monochromator, broad-spectrum source, or sunlight allows confirmation of the diagnosis of SU and identification of the
inducing wavelengths. However, negative phototest
results do not exclude the disorder, because the ease
of SU induction, particularly when mild, may vary. If
no monochromator is available, appropriately filtered
broadband sources can be used, and minimal urticarial
dose estimation may help in assessing treatment efficacy. Patients with SU may have a biphasic response
to phototesting whereby wheals develop in response
to one action spectrum but are inhibited by another
action spectrum.114 Most commonly, shorter wavelengths induce wheals on phototesting while longer
wavelengths may inhibit wheal formation.114

COMPLICATIONS. Severe primary SU may lead to
anaphylactic shock, which is rarely fatal. The rare secondary SU related to drug or chemical photosensitivity,
cutaneous porphyria, or cutaneous lupus may be associated with the complications of the primary conditions.
COURSE AND PROGNOSIS. SU often persists

indefinitely, sometimes with deterioration but also
sometimes with improvement, with the probability of
clinical resolution at 5, 10, and 15 years of 12%, 26%,
and 46%, respectively.105,106
TREATMENT. Restricting sun exposure and using
high protection-factor broad-spectrum sunscreens and
appropriate clothing may be helpful in preventing SU.
Sunscreens with UVA and UVB protection effectively
increase the minimal urticarial dose on phototesting.115
Antihistamines have been demonstrated to suppress
wheal and itch formation in patients with SU, and,
when combined with sunscreens, the increase in UV
tolerance may be remarkable.115 Phototherapy may be
helpful in those patients who commonly develop SU
tolerance as summer advances and also sometimes
of Solar Urticaria (SU)
Polymorphic light eruptiona
Subacute cutaneous lupusa,b
Photoexacerbated dermatoses such as atopic or
seborrheic eczema
Erythropoietic protoporphyriab
Hepatic porphyriasb
Drug or chemical photosensitivityb
a
Rarely may coexist with SU.

A rare cause of secondary SU.
1062
in those with persistent disease. Unfortunately, phototherapy usually needs to be continued to maintain
its effect, and, consequently, carries the usual risks
of long-term phototherapy. In addition, phototherapy should be undertaken with caution early on to
avoid the risk of anaphylaxis, particularly in severely
affected individuals.113 Multiple UVA exposures with
increasing doses during the same day (so-called rush
hardening) have helped some patients.116 Others with
recalcitrant disease have been reported to respond
to plasma exchange, or plasmapheresis, particularly
if they are found to have circulating SU-associated
serum factors; these remissions may be long-lived.117,118
Intravenous immunoglobulin has also been helpful on
occasion,119 as has oral cyclosporine. Partial improvement has recently been reported with omalizumab, a
monoclonal antibody directed against IgE.120
PHOTOEXACERBATED
DERMATOSES
Several dermatoses that are not caused by UVR may be
worsened by it (Table 91-3). Mechanisms of this phenomenon, termed photoexacerbation, have rarely been
studied. The initial condition may be severely worsened
even if it was originally only mild or subclinical.121,122
These disorders are relatively common and account for
a significant percentage of all photodermatoses. Such
conditions, especially the eczemas, psoriasis, and acne,
improve with UVR exposure in most patients, perhaps because cutaneous reactivity is reduced, but in
a small proportion of individuals, it is instead aggravated. If photoexacerbation does occur, the new eruption generally develops or worsens initially at sites
typical of the basic disorder (Fig. 91-13), followed at
times by extension to other areas. In photoexacerbated
TABLE 91-3
Selection of Diseases Sometimes Exacerbated

by Ultraviolet Irradiation
Acne
Atopic eczema
Carcinoid syndrome
Dermatomyositis
Disseminated superficial actinic porokeratosis
Erythema multiforme
Familial benign chronic pemphigus (HaileyHailey disease)
Keratosis follicularis (Darier disease)
Lichen planus
Lupus erythematosus
Pellagra
Pemphigus foliaceus (erythematosus)
Psoriasis
Reticulate erythematous mucinosis syndrome
Rosacea
Seborrheic eczema
Transient acantholytic dermatosis (Grover disease)
Viral infections
CLINICAL FEATURES
Patients with abnormal photosensitivity present in
three ways: (1) sporadic or (2) persistent eruptions in
sunlight-exposed areas, or, infrequently, (3) erythroderma. When sporadic, the patient usually considers
sunlight exposure to be responsible; when persistent,
the physician often must identify the association. However, careful history taking is essential, first to confirm
that sunlight exposure is responsible and then to make

WITH ABNORMAL SKIN
PHOTOSENSITIVITY
::
seborrheic eczema, however, an unpleasant sensation at

the exposed sites may be the first or only feature. Treatment consists of minimizing UVR exposure, protection
with suitable clothing, application of high protectionfactor broad-spectrum sunscreens, and careful treatment of the underlying disorder. Taking these steps
alone, frequently, if perhaps surprisingly, even may
abort the photosensitivity.121 If these actions are inadequate, low-dose phototherapy, as for PMLE, can sometimes help, for example, in seborrheic or atopic eczema
and psoriasis, but its use is contraindicated in cutaneous LE or dermatomyositis, in which aggravation of the
systemic disease is a risk. Photoexacerbated acne commonly requires treatment with oral isotretinoin.
Individual diseases for which photoexacerbation
may occur are discussed in more detail in the online
sections of this chapter include the disorders many of
the disorders in Table 91-3.
16
Chapter 91
Figure 91-13 Photo-exacerbated seborrheic dermatitis,

affecting the face only at sites of predilection for the seborrheic eruption.
a diagnosis. Information of considerable importance

are age at disease onset, gender, family history, previous sunlight sensitivity, occupation, leisure pursuits,
and systemic and topical drug (or chemical) use. Additional relevant details include distribution of lesions,
effects of season, exposure times required for induction,
time between exposure and the appearance of lesions,
duration of the eruption after exposure ceases, effects
of sunlight received through window glass (implicating UVA and visible light), presence of systemic symptoms, and patient-assessed morphologies (progression
of the disease before the clinic visit).
In terms of age and sex, young woman are more
likely to develop PMLE; women or girls more commonly develop AP; children of either gender may have
HV, xeroderma pigmentosum (XP), or EPP; elderly
men or younger individuals with a history of eczema
most often develop CAD.
A family history of sunlight sensitivity may be
present in patients with PMLE, AP, XP, and the porphyrias. CAD is more common in outdoor enthusiasts exposed to both sunlight and airborne allergens,
although exacerbations of disease, despite sunscreen
use, invoke the possibility of sunscreen allergy. On the
other hand, exacerbations with sunscreens may even
occur in the absence of allergy in PMLE. An eruption
appearing in minutes and remitting within 2 hours
suggests SU or occasionally photosensitivity to drugs,
such as amiodarone. Onset within 20 minutes to several hours, with resolution over days suggests PMLE,
HV, EPP, cutaneous LE or other photoexacerbated dermatoses, or other drug photosensitivities, such as to
thiazides. Systemic malaise is uncommon in PMLE,
HV, and SU. Development of lesions after exposure
through window glass suggests an inducing spectrum
that includes UVA, although it may occur in virtually
all of the photodermatoses.
The eruption described by patients with PMLE is
generally that of small or large, elevated, pruritic, red or
skin-colored, and often clumped spots of blisters, sometimes confluent, that usually involve several, but not
all exposed sites. In HV, blistering with scar formation
occurs, and in SU, elevated pruritic wheals are often
confluent. In EPP and amiodarone drug photosensitivity, a marked burning sensation, without visible change,
has been reported. In EPP, relatively lengthy exposure
may lead to firm, colorless or pink, diffuse swelling,
rarely with scattered blisters. In most drug photosensitivity reactions and in XP, an exaggerated sunburn-like
reaction is possible, which is often maximal in XP at
23 days. Finally, in photoexacerbated dermatoses, the
eruption resembles that of the primary disorder.
Photosensitivity eruptions are usually present on
some, and occasionally all, of the forehead, nose, upper
cheeks, tip of the chin, rims of the pinnae, back and
sides of the neck, upper chest, backs of the hands and
feet, and extensor aspects of the limbs. Covered areas
may also be involved, but to a lesser extent. On the
other hand, portions of the face protected by hair or
customarily shown in shadow such as upper eyelids,
finger webs, skin creases and skin under the nose, lower
lip, chin, and earlobes are frequently unaffected, except
when there is associated airborne contact dermatitis.
1063
16
Excoriated papules suggest AP, whereas eczematous

lesions, or very rarely light-associated erythroderma,
suggest CAD or photoexacerbated atopic or seborrheic
eczema. Finally, skin fragility, bulla formation, and
atrophic superficial scarring suggest hepatic porphyria
or pseudoporphyria, especially if there has been drug
or excessive alcohol intake.
Clinical appraisal along with the history usually
results in a diagnosis, although for complete certainty,
several of the studies listed below may be appropriate.
LABORATORY STUDIES
Section 16
::
If the diagnosis is not certain, appropriate additional

studies include an assessment of the ANA and ENA.
If present at significant titers, cutaneous LE should be
considered. In addition, examination of blood, urine,
and stools for porphyrins should be considered.
Biopsies may be helpful. Lesional histologic features are characteristic in several photodermatoses,
especially PMLE, HV and CAD. However, with the
exception of HV, histopathologic changes in photodermatoses are rarely entirely diagnostic. These are
reviewed in the preceding disease descriptions.
Phototesting of normal back skin with a monochromator in CAD and SU often produces the papules or
wheals of the condition itself, frequently at low irradiation doses, and this also may identify the action spectrum. Phototesting also helps to confirm XP through
the delayed development of erythema over 23 days,
with an abnormally low-dose threshold, often eventuating in blister formation (Table 91-4). In eczematous
photosensitivity, patch and photopatch testing are also
essential to identify relevant allergens. Finally, special
techniques such as the assessment of DNA excision
repair or of RNA synthesis recovery rate in cultured
fibroblasts after UVR exposure are essential for the
diagnoses of certain genophotodermatoses.
PHOTOTESTING. Techniques of phototesting vary

greatly from country to country and from center to center. Although it is the investigational technique of choice
for photodermatoses when the diagnosis is uncertain
or when details of the inducting action spectrum are
required, it remains primarily a research tool employed

in a limited number of clinical centers. The cost of the
equipment and its infrequent use in most clinical practices means that patients should be referred for consultation to such centers whenever indicated.
Phototesting falls into two categories: (1) Monochromatic phototesting, usually of the upper back with
selected wavelengths and selected doses to identify
the action spectrum for the disorder and (2) photoprovocation with a broad-spectrum source to induce
the eruption for its clinical appearance and subsequent
biopsy if indicated. Table 91-4 lists the disorders for
which monochromatic testing may be helpful.
For precise characterization of the wavelength
dependency of a disorder, monochromatic testing,
preferably with a xenon arc irradiation monochromator, should be employed. For photoprovocation, the
favored device is a solar simulator, usually a xenon
arc-filtered source that produces a spectrum that
resembles the terrestrial sunlight spectrum at noon on
a midsummers day in temperate regions of the world.
Keep in mind that the terrestrial spectrum at noon in
June varies considerably between Iceland and Kenya,
as it also does between high elevations and sea level.
Several suitable protocols have also been described
for using simple broad-spectrum metal halide or fluorescent light sources with filters if necessary. In some
parts of the world, sunlight with filters has also been
used, although this method is generally too unpredictable for clinical use.148,149
The mainstay of phototesting is a monochromator. It
is composed of a high-pressure xenon arc source that
emits radiation along a pathway incorporating a diffraction grating angled to produce the required waveband at the exit slit. Such equipment needs regular
calibration of output and wavelength. Because even
large centers cannot always afford such equipment,
lesser alternatives have been created, for example,
metal halide or fluorescent light sources of sufficient
output intensity. With such sources, the UVB, UVA,
and visible light components of patient photosensitivity can be studied, based on deviation from normal
erythemal reactions throughout the UVR spectrum.
Monochromatic phototesting is preferably performed on unaffected skin of the upper back, lateral
TABLE 91-4
Usual Monochromatic Phototest Responses in Idiopathic, Probably Immunologic Photodermatoses
1064
Disease
Action Spectrum
Frequency of Abnormal Findings
UVA more often than UVB
Only sometimes
Actinic prurigo
UVA more often than UVB
Only sometimes
Hydroa vacciniforme
More often UVA
Only sometimes
UVB UVA visible light
Virtually always
Solar urticaria
UVB, UVA, or visible, or combination
Usual
UVB
Usual
Photoexacerbated dermatoses
UVB, UVA, or combination
Rare
UVA = ultraviolet A radiation; UVB = ultraviolet B radiation.
16
KEY REFERENCES
1. Rhodes LE et al: Polymorphic light eruption occurs in

18% of Europeans and does not show higher prevalence
with increasing latitude: Multicenter survey of 6,895
individuals residing from the mediterranean to scandinavia. J Invest Dermatol 130(2):626-628, 2010 [Epub Aug
20, 2009]
6. Wolf P et al: New insights into the mechanisms of polymorphic light eruption: Resistance to ultraviolet radiation-induced immune suppression as an aetiological
factor. Exp Dermatol 18:350, 2009
9. van de Pas CB et al: Walker SL: Ultraviolet-radiationinduced erythema and suppression of contact hypersensitivity responses in patients with polymorphic light
eruption. J Invest Dermatol 122:295, 2004
10. Palmer RA, Friedmann PS: Ultraviolet radiation causes
less immunosuppression in patients with polymorphic
light eruption than in controls. J Invest Dermatol 122:291,
2004
19. McGregor JM et al: Genetic modeling of abnormal photosensitivity in families with polymorphic light eruption
and actinic prurigo. J Invest Dermatol 115:471, 2000
23. Hawk JLM, Calonje E. The photosensitivity disorders. In:
Levers Histopathology of the Skin, 9th ed, edited by DE
Elder et al. Philadelphia, Lippincott Williams & Wilkins,
2005, p. 345
27. Richards HL et al: Evidence of high levels of anxiety
and depression in polymorphic light eruption and their
association with clinical and demographic variables. Br J
Dermatol 159:439, 2008
41. Hnigsmann H, Hojyo-Tomoka MT. Polymorphic light
eruption, hydroa vacciniforme, and actinic prurigo. In:
Photodermatology, edited by HW Lim, H Hnigsmann,
JLM Hawk. New York, Informa Healthcare, 2007 p. 149
43. Grabczynska SA, McGregor JM, Kondeatis E, Vaughan
RW, Hawk JL: Actinic prurigo and polymorphic light
eruption: common pathogenesis and the importance of
HLA-DR4/DRB1*0407. Br J Dermatol 140:232, 1999
60. Huggins RH et al: Quality of life assessment and disease
experience of patient members of a web-based hydroa
vacciniforme support group. Photodermatol Photoimmunol
Photomed 25:209, 2009
75. Hawk JLM, Lim HW: Chronic actinic dermatitis. In: Photodermatology, edited by HW Lim, H Honigsmann, JLM
Hawk. New York, Informa Healthcare, 2007 p. 169
120. Waibel KH et al: Partial improvement of solar urticaria
after omalizumab. J Allergy Clin Immunol 125:490, 2010
142. Orteu CH, Sontheimer RD, Dutz JP: The pathophysiology of photosensitivity in lupus erythematosus. Photodermatol Photoimmunol Photomed. 17:95, 2001
148. Neumann NJ, Lehmann P. Photodiagnostic modalities. In: Dermatological Phototherapy and Photodiagnostic
Method, edited by J Krutmann et al. Berlin, SpringerVerlag, 2001, p. 329
150. Bruynzeel DP et al: Photopatch testing: A consensus
methodology for Europe. J Eur Acad Dermatol Venereol
18:679, 2004
::
PHOTOPATCH TESTING. (See Chapter 92.) Photopatch testing is an established investigational tool
designed to identify photoallergic contact dermatitis, although it can also be employed to help identify
phototoxic agents. It is essentially a more complex
version of patch testing, and it is used in patients with
exposed-site eczema, whether or not they also have
another photodermatoses, to determine whether photoallergy is also present.
The methodology of photopatch testing has received
less attention than allergen testing or phototesting, as
it resides between the two specialty areas of photodermatology and contact dermatology. However, consensus methodology is now available.150
Using this approach, test materials (usually sunscreens, topical nonsteroidal and anti-inflammatory
agents, and other possible causative agents) are applied
in duplicate for 2448 hours to normal skin. One set
of test sites is then uncovered and irradiated with a
broad-spectrum UVA source, usually at 5 J/cm2 from
fluorescent PUVA lamps, and the results read 24 and 48
hours later. Strongly positive reactions at sites exposed
to both chemical agent and UVA, with no reactions at
the covered control sites, confirms a diagnosis of photoallergy. Occasionally, however, contact irritation or
contact allergy occurs in both sites, making a diagnosis of photoallergy uncertain. One should also be alert
to the possibility that all irradiated sites may become
positive, suggesting that underlying widespread UVA
photosensitivity is responsible. Furthermore, the identification of potential photoallergens is still primitive,
often with separation of phototoxicity from photoal-
lergy uncertain. Once again, testing for photoallergy

is best conducted in regional centers or by physicians
with appropriate experience.
The current authors (Travis W. Vandergriff and Paul
R. Bergstresser) are grateful to the authors of this chapter in the previous edition for leaving behind an outstanding framework that we employed as our starting
point for this updated edition. Special thanks go to
John L. M. Hawk and James Ferguson.
Chapter 91
to the paravertebral groove whereas lesion induction,

except when done relatively easily with the monochromator, as in SU and CAD, is best undertaken using
broadband sources with output directed over larger
areas of skin known to be susceptible to the eruption.
PMLE, AP, and HV are conditions in which repeated
irradiation with UVA- or UVB-emitting or combined
sources is often required to reproduce the disease.
It is important that the use of potent topical and systemic steroids be avoided when possible for at least several days before phototesting to prevent false-negative
results. It is not certain how much the other oral immunosuppressive agents affect testing, but they should
be stopped whenever possible, as well. False-positive
results may also occur in patients with widespread disease, and the eruption should first be well controlled
whenever possible, if necessary by keeping the patient
in a reduced-light environment. However, it is often
difficult to fulfill these requirements if the eruption is
active, and in such circumstances, testing may need to
be undertaken with knowledge of its limitations.
All phototesting should be undertaken at carefully
standardized sequential doses (often a geometric
series) and wavelengths, and the results read at consistent times after exposure in carefully controlled conditions of light and temperature. Furthermore, because
testing involves UVR exposure, potentially noxious
to both skin and eyes, the patient and the investigator
should be protected with appropriate clothing, shielding and goggles.
1065
16
Chapter 92 :: A
bnormal Responses to Ultraviolet
Radiation: Photosensitivity Induced
by Exogenous Agents

:: Henry W. Lim
ABNORMAL RESPONSES TO
ULTRAVIOLET RADIATION
AT A GLANCE
::
Phototoxicity occurs in anyone exposed to

sufficient phototoxic agent and UV radiation
and usually manifests as an exaggerated
sunburn reaction.
Section 16
Photosensitivity is broadly divided into

phototoxicity and photoallergy, caused
by topical or systemic agents that absorb
ultraviolet A (UVA) energy.
1066
Photoallergy is an immune reaction to a

UVA-modified chemical, commonly topical
sunscreen agents and antimicrobials in the
United States and the United Kingdom
and topical nonsteroidal anti-inflammatory
agents in Europe. It presents as eczematous
eruption on sun-exposed areas.
History taking is an important part of the
evaluation; phototesting and photopatch
testing are sometimes helpful.
individuals exposed to adequate doses of the agent

and the activating wavelengths of radiation (Table
92-1). In contrast, photoallergy is a type IV delayed
hypersensitivity response to a molecule that has been
modified by absorption of photons. It has a sensitization phase, occurs only in sensitized individuals, and
requires only a minimal concentration of the photoallergen (see Table 92-1).
INCIDENCE
Over 350 medications in the United States have been
reported to cause photosensitivity.1 Only a small number of them, however, induce reactions frequently or
have been well studied (Tables 92-2, 92-3, 92-4, and
92-5). In evaluations performed at photodermatology centers in New York City, Melbourne, Singapore,
and Detroit, photosensitivity induced by a systemic
drug was documented in 5% to 15% of the referred
patients.25 In studies performed in the United States,
United Kingdom, Europe, and Australia, the percentage of photopatch-tested patients who had clinically
relevant reactions leading to a diagnosis of photoallergic contact dermatitis ranged from 1.4% to 12.0%, with
the value in most series being around 10%.2,511
Differential diagnosis includes contact

allergic or contact irritant dermatitis,
airborne contact dermatitis, and other
photodermatoses.
PHOTOTOXICITY
Management consists of identification

and avoidance of the precipitating agent,
photoprotection, and symptomatic therapy.
Several pathways eventuate in the development of

phototoxic tissue damage, and for many phototoxic
agents more than one pathway is responsible.
Photosensitivity may be caused by exogenous or endogenous agents. It occurs when a compound, classically
one with unsaturated double bonds in a six-carbon
ring, absorbs radiation energy in its action spectrum,
usually ultraviolet A (UVA) wavelengths. Exogenous
photosensitizers can be agents administered systemically or applied topically. Well-characterized examples
of photosensitivity induced by endogenous photosensitizers are the cutaneous porphyrias, which are associated with enzymatic defects in heme biosynthetic
pathways that result in elevated levels of porphyrins,
known phototoxic agents (see Chapter 132).
Photosensitivity induced by exogenous agents can
be divided into phototoxicity and photoallergy. Phototoxicity is the result of direct tissue injury caused by
the phototoxic agent and radiation. It can occur in all
PATHOPHYSIOLOGY
PHOTODYNAMIC PROCESSES. On absorption

of radiation energy by the photosensitizer (P) at its
ground state, formation of an excited (usually triplet)
state (3P) molecule occurs. The excited state molecule
may then participate in oxygen-dependent processes
(i.e., photodynamic processes) via two major pathways,
type I and type II reactions, both of which result in cytotoxic injury.12
The type I reaction involves transfer of an electron
or a hydrogen atom to the excited state photosensitizer
(3P), which results in the formation of free radicals [Eq.
(92-1)]. These may then participate in an oxidation
reduction reaction that results in peroxide formation
and subsequent cell damage [Eqs. (92-2) and (92-3)].
3
P + RH PH + R
PH + PH P + PH2
PH2 + O2 P + H2O2
( 92-1)
( 92-2)
( 92-3)
16
Table 92-1
Characteristics of Phototoxicity and Photoallergy

Phototoxicity
Photoallergy
Clinical presentation
Exaggerated sunburn reaction: erythema,

edema, vesicles, and bullae; burning,
stinging; frequently resolves with
hyperpigmentation
Eczematous lesions; usually pruritic
Histologic features
Eosinophilic keratinocytes, epidermal

necrosis, dermal edema, sparse dermal
infiltrate of lymphocytes, macrophages,
and neutrophils
Spongiotic dermatitis, dermal

lymphohistiocytic infiltrate
Onset after exposure
Minutes to hours
24 to 48 hours
Dose of agent needed for reaction
Large
Small
Cross-reactivity with other agents
None
Common
Diagnosis
Topical agent
Systemic agent
Clinical
Clinical + phototests
Photopatch tests
Clinical + phototests; possibly photopatch tests
Alternatively, interaction of 3P with ground state

oxygen could result in the formation of superoxide
anion (O2.), which, in turn, can be converted into
highly reactive and cytotoxic hydroxyl radicals (OH).
The type II reaction is also known as an energy transfer process. Transfer of energy to ground state oxygen
results in the formation of singlet oxygen (1O2), which
is highly reactive and has a lifetime of 50 ns [Eq. (92-4)]:
3
P + O2 P + 1O2
( 92- 4 )
Cytotoxic injury occurs upon singlet oxygeninduced oxidation of amino acids and unsaturated
fatty acids; interaction with the latter results in the
TABLE 92-2
Topical Phototoxic and Photosensitizing Agents
Agent
Exposure
Fluorescein
Used topically to visualize the anterior

surface of the eye
Fluorouracila
Topical treatment of actinic keratoses
Furocoumarins
Occur naturally in plants (especially

Compositae species), including fruits
and vegetables (lime, lemon, celery, fig,
parsley, and parsnip); used in topical
photochemotherapy
Retinoidsa
For treatment of acne and photoaging
Rose Bengal
Used in ophthalmologic examinations
Tar
Used as topical therapeutic agent;

found in roofing materials
Induces exaggerated UV response due to skin irritancy.
formation of hydroperoxides, which initiate lipid and

protein oxidation.
Phototoxicities induced by porphyrins,12 quinolones,13 nonsteroidal anti-inflammatory agents, tetracyclines, amitriptyline, imipramine, sulfonylureas,
hydrochlorothiazide, furosemide, and chlorpromazine14
are examples of photodynamic phototoxic reactions.
GENERATION OF PHOTOPRODUCTS. Exposure to radiation may result in the generation of stable

photoproducts that are responsible for tissue injury.
Phototoxic products have been demonstrated on
irradiation of phenothiazines, chlorpromazine, tetracyclines, quinolones, and nonsteroidal anti-inflammatory agents.15
BINDING TO SUBSTRATE. Another mechanism of
phototoxicity is radiation-mediated binding of the photosensitizer to its biologic substrate. A photoaddition
reaction occurs when the excited state molecule covalently binds to a ground state molecule. An example is
the covalent binding of 8-methoxypsoralen to pyrimidine bases of the DNA molecules, which results in the
formation of a cross-link between the DNA strands.
Abnormal Responses to Ultraviolet Radiation: Exogenous
Type IV delayed hypersensitivity response

No
::
Direct tissue injury

Yes
Chapter 92
Pathophysiology
Occurrence after first exposure
INFLAMMATORY MEDIATORS. Mediators of

inflammation and inflammatory cells participate in
phototoxic tissue injury. Biologically active products
of complement activation, mast cell-derived mediators, eicosanoids, proteases, and polymorphonuclear
leukocytes contribute to the development of phototoxicity induced by porphyrins, demeclocycline, and
chlorpromazine.16
APOPTOSIS. Photodynamic therapy (PDT) involves
the use of a photosensitizer and electromagnetic
1067
16
TABLE 92-3
Systemic Phototoxic Agents

Class
Antifungal
Chloroquine (Aralen)
Quinineb
Antimicrobials
Sulfonamides
Tetracyclines
Demeclocycline (Declomycin)c
Doxycycline (Adoxa, Doryx,
Monodox, Periostat, Vibra-Tabs,
Vibramycin)c
Minocycline (Arestin, Dynacin,
Minocin)
Tetracycline (Helidac, Sumycin)
Trimethoprim (Bactrim, Polytrim,
Primsol, Septra)
Quinolones
Ciprofloxacin (Cipro)
Enoxacin (Penetrex)b
Gemifloxacin (Factive)
Lomefloxacin (Maxaquin)b,c
Moxifloxacin (Avelox)
Nalidixic acid (NegGram)b,c
Norfloxacin (Chibroxin, Noroxin)
Ofloxacin (Floxin, Ocuflox)
Sparfloxacin (Zagam)c
Section 16
::
1068
Griseofulvin (Fulvicin, Grifulvin V,

Gris-PEG)b
Voriconazole (Vfend)
Antimalarials
Cardiac drugs
Amiodarone (Cordarone, Pacerone)c

Quinidine (Quinaglute, Quinidex)b
Diuretics
Furosemide (Lasix)c
Thiazides
Bendroflumethiazide (Corzide)
Chlorothiazide (Aldoclor, Diuril)c
Hydrochlorothiazide (Accuretic,
Aldactazide, Aldoril, Atacand,
Avalide, Capozide, Diovan,
Dyazide, Hyzaar, Inderide,
Lopressor, Lotensin, Maxzide,
Micardis, Microzide, Moduretic,
Prinzide, Teveten HCT, Uniretic,
Vaseretic, Zestoretic, Ziac)c
Dyes
Fluorescein (AK-Fluor, Fluorescite)

Methylene blue
Furocoumarins
Psoralens
5-Methoxypsoralenc
8-Methoxypsoralen
(Oxsoralen-Ultra)c
Hypoglycemics
Generic Name (Common US

Trade Names)a
Sulfonylureas
Acetohexamide (Dymelor)
Chlorpropamide (Diabinese)
Glipizide (Glucotrol, Metaglip)
Glyburide (DiaBeta, Glucovance,
Glynase PresTab, Micronase)
Tolazamide (Tolinase)
Tolbutamide (Orinase)c
Class
Generic Name (Common US

Trade Names)a
Immunosuppressant
Azathioprine (Azasan, Imuran)
Nonsteroidal antiinflammatory drugs
Acetic acid derivative

Diclofenac (Arthrotec, Cataflam,
Voltaren)
Alkanone derivative
Nabumetone (Relafen)c
Anthranilic acid derivative
Mefenamic acid (Ponstel)
Cyclooxygenase-2 inhibitor
Celecoxib (Celebrex)
Enolic acid derivative
Piroxicam (Feldene)b,c
Propionic acid derivatives
Ibuprofen (Advil, Motrin, Nuprin,
Vicoprofen)
Ketoprofen (Orudis, Oruvail)
Naproxen (Aleve, Naprelan,
Naprosyn)c
Oxaprozin (Daypro)
Tiaprofenic acid
Salicylic acid derivative
Diflunisal (Dolobid)
Oncologic drugs
Dacarbazine (DTIC-Dome)
Docetaxel (Taxotere)
Fluorouracil (Adrucil)
Methotrexate (Rheumatrex)d
Paclitaxel (Taxol)
Vinblastine (Velban)
Photodynamic
therapy agents
Porfimer (Photofrin)c
Verteporfin (Visudyne)c
Psychotropic drugs
Alprazolam (Xanax)
Chlordiazepoxide (Librax, Librium,
Limbitrol)
Clozapine (Fazaclo)
Phenothiazines
Chlorpromazine (Thorazine)c
Perphenazine (Triavil, Trilafon)
Prochlorperazine (Compazine)c
Thioridazine (Mellaril)
Trifluoperazine (Stelazine)
Tricyclics
Amitriptyline (Elavil, Limbitrol,
Triavil)
Desipramine (Norpramin)
Imipramine (Tofranil)
Other
Dapsone
Flutamide (Eulexin)
Hypericin (St Johns wort)
Pyridoxine (vitamin B6)
Ranitidine (Zantac)
Although it is the policy not to use trade names in this book, exceptions are made in cases in which we consider this information highly useful.
Also reported as a systemic photoallergen.
c
Commonly reported.
d
Induces erythema on previously UV-exposed sites.
b
TABLE 92-4
Topical Photoallergens
Group
Sunscreens (see
Chapter 223)
Chemical Name
Trade Namea
Anti-infective
agents
Surface disinfectants: halogenated

salicylanilides
Dibromosalicylanilide (dibromsalan, DBS)b
Tetrochlorosalicylanilide (Irgasan BS200)b
Tribromosalicylanilide (tribromsalan, TBS)b
Skin cleansers
Chlorhexidine (Hibiclens)
Hexachlorophene (pHisoHex)
Pesticides
Bithionol (thiobis-dichlorophenol)b
Dichlorophene (G4, Korium, Teniatol)
Dimethylol dimethyl hydantoin
Fenticlor (bis-hydroxy-chlorophenyl sulfide)b
Personal care products
Triclosan (Irgasan DP300, Microban,
Lexol 300)
Topical antifungals
Buclosamide (Jadit,
butylchlorosalicylamide)
Multifungin (bromochlorosalicylanilide,
BCSA)
Others
Antibiotic for cattle

Olaquindoxb
Nonsteroidal anti-inflammatory agents
(topical)
Etofenamate
Fepradinol
Flufenamic acid
Ketoprofenb
Phenothiazines
Chlorpromazine (Thorazine)b
Promethazine (Phenergan)b
Miscellaneous
Acyclovir cream (Zovirax)
Clioquinol (Vioform,
iodochlorhydroxyquin)
Cadmium sulfide
Cinchocaine (Dibucaine)
Thiourea (thiocarbamide, sulfourea)
PABA = para-aminobenzoic acid.

Although it is the policy not to use trade names in this book, exceptions
are made in cases in which we consider this information highly useful.
b
Commonly reported to be photoallergens.
a
Generic Name
(US Trade Namea)
Antifungal
Griseofulvin (Fulvicin, Grifulvin V,

Gris-PEG)
Antimalarial
Quinine
Antimicrobials
Quinolone
Enoxacin (Penetrex)
Cardiac medication
Quinidine (Quinaglute, Quinidex)
Nonsteroidal antiinflammatory drugs
Ketoprofen (Orudis, Oruvail)

Piroxicam (Feldene)
Vitamin
Pyridoxine hydrochloride
(vitamin B6)
a
Although it is the policy not to use trade names in this book, exceptions are made in cases in which we consider this information highly
useful.
radiation in the presence of oxygen to treat premalignant and malignant skin conditions. In addition to
generating reactive oxygen species, which results in
cytotoxicity, PDT also is a potent inducer of apoptosis.12
ACUTE PHOTOTOXICITY. (See Table 92-1.) Acute
phototoxicity occurs within hours of exposure to the
phototoxic agent and UV radiation. Symptoms are
drug-dose and UV-dose dependentusually asymptomatic, but at sufficient doses, the patient complains
of a burning and stinging sensation on exposed areas,
such as forehead, nose, V area of the neck, and dorsa
of the hands (Fig. 92-1). Erythema and edema may
appear within hours of exposure; in severe cases, vesicles and bullae may develop accompanied by pruritus.
Protected areas, such as nasolabial folds, postauricular and submental areas, and areas covered by clothing, are spared. A notable exception to these kinetics
is psoralen-induced phototoxicity, in which often the
acute response first appears after 24 hours, and peaks
at 4872 hours, which is the rationale for administering psoralen plus UVA (PUVA) photochemotherapy
doses 4872 hours apart. The phototoxic response
resolves with a varying degree of hyperpigmentation,
which may last for months. At lower drug/UV doses,
gradual tanning only, without preceding sunburn-like
reaction, can be seen.
PHOTO-ONYCHOLYSIS. Separation of the distal
nail from the nail bed, usually painful, is a manifestation of acute phototoxicity, with the nail plate serving
as a lens to focus UV energy on the nail bed. It has been
reported with doxycycline and other tetracyclines, fluoroquinolones, psoralens, benoxaprofen, clorazepate
dipotassium, olanzapine, aripiprazole, indapamide,
and quinine (Fig. 92-2).17
6-Methylcoumarinb
Musk ambretteb
Sandalwood oil
Property
::
Fragrances
Systemic Photoallergens
Chapter 92
Benzophenones
Benzophenone-3 (oxybenzone)b
Benzophenone-4 (sulisobenzone)
PABA derivatives
Ethylhexyl dimethyl PABA (padimate O)b
PABAb
Cinnamates
Ethylhexyl methoxycinnamate (octinoxate)
Cinoxate (cinoxate)
Others
Butyl methoxydibenzoylmethane
(avobenzone, Parsol 1789)b
Octocrylene (octocrylene)
Octyl triazone
Phenylbenzimidazole sulfonic acid
(ensulizole)
16
TABLE 92-5
1069
16
Section 16
Figure 92-3 Minocycline-induced bluegray pigmentation on cheeks and upper lip.
::
Figure 92-1 Amiodarone-induced phototoxicity. Note

the erythema and slate-gray pigmentation (nose, forehead) on the sun-exposed area.
SLATE-GRAY PIGMENTATION. Asymptomatic

bluegray pigmentation on sun-exposed areas has
been associated with exposure to several agents.18,19
One percent to ten percent of patients taking amiodarone develop this side effect (Fig. 92-1). Chlorpromazine and clozapine can induce a similar change. The
tricyclic antidepressants imipramine and, less commonly, desipramine have also been reported to cause
slate-gray pigmentation. A drug metabolitemelanin
complex has been postulated to be the cause of this
alteration. Minocycline can induce bluegray pigmentation on the face (Fig. 92-3), frequently on sites of acne
scars, although similar pigmentation on forearms and

shins can also occur. Chronic exposure to diltiazem, a
benzothiazepine calcium channel blocker, has resulted
in photodistributed, reticulated, slate-gray pigmentation. Slate-gray pigmentation seen in argyria involves
the nail lunulae, mucous membranes, and sclerae. A
photochemical reaction, in which silver granules are
deposited in the dermis, results in these pigmentary
alterations.
LICHENOID ERUPTION. Lichenoid eruption has

been reported as a form of phototoxicity, but is controversial.
PSEUDOPORPHYRIA. The development of porphyria cutanea tarda-like cutaneous changes of skin
fragility, vesicles, and subepidermal blisters is associated with several phototoxic agents (Fig. 92-4).
Although histologic and immunofluorescence findings
are similar to those of porphyria cutanea tarda, the porphyrin profile is normal or in the upper range of normal in these patients. Naproxen is the most commonly
reported causative agent. Other drugs incriminated
include amiodarone, -lactam antibiotics, celecoxib,
ciprofloxacin, cyclosporine, diflunisal, etretinate, furosemide, imatinib, nabumetone, nalidixic acid, narrowband UVB, oral contraceptives, oxaprozin, ketoprofen,
mefenamic acid, the tetracyclines, tiaprofenic acid,
torsemide, and voriconazole.20,21
ACCELERATED PHOTO-INDUCED CHANGES.
This has been uniquely described with voriconazole, a

broad spectrum antifungal agent. Immunosuppressed
patients receiving voriconazole for >12 weeks can
develop photosensitivity, pseudoporphyria, photoaging, lentigines, premature dermatoheliosis; in addition,
squamous cell carcinoma and melanoma have been
described in this group of patients who were on voriconazole for >12 months.21
1070
Figure 92-2 Distal onycholysis in a patient receiving psoralen plus ultraviolet A therapy.
PHOTODISTRIBUTED TELANGIECTASIA. Telangiectasia on sun-exposed areas has been reported

with calcium channel blockers, including nifedipine, amlodipine, felodipine, and diltiazem, with the
16
Chapter 92
Figure 92-4 Pseudoporphyria. Note subtle erosions on

dorsum of hand and at the base of the index finger, and
crusting on the knuckle.
::
PERSISTENCE OF PHOTOSENSITIVITY AND

EVOLUTION TO CHRONIC ACTINIC DERMATITIS. Although phototoxicity usually resolves after
discontinuation of the causative agent, there are reports

of persistence of photosensitivity for many years after
the cessation of exposure, which results in the development of chronic actinic dermatitis (Fig. 92-5). The condition presents with pruritus and lichenification and
excoriation on sun-exposed sites; it has been reported
with thiazides, quinidine, quinine, and amiodarone.23
CHRONIC EFFECTS. Cutaneous effects of longterm, repeated phototoxic tissue injury are best exemplified by the manifestations in patients who have
received long-term PUVA photochemotherapy, which
is known to affect DNA. These effects include premature aging of the skin, lentigines, squamous cell and
basal cell carcinomas, and melanoma. These are discussed in greater detail in Chapter 238.
PHOTOTOXIC AGENTS
TOPICAL AGENTS. Table 92-2 lists the major topical phototoxic and photosensitizing agents. It should
be noted that fluorouracil and retinoids induce exaggerated UV response due to their irritant effect on the
skin. Therapeutic or occupational exposures to these
agents are the common route of contact.
Furocoumarins. Topical exposures to furocoumarins may occur in individuals in certain occupations
(bartenders, salad chefs, gardeners) and in patients
receiving topical photochemotherapy with psoralens.
Tar.
Crude coal tar, although no longer commonly

used in dermatologic therapy, is well documented to
produce a burning and stinging sensation on exposure to UVA (tar smarts). In addition to phototoxicity, occupational exposure to tar is associated with
increased risk of nonmelanoma skin cancers.
Figure 92-5 Chronic actinic dermatitis. Note the lichenification and hyperpigmentation on sun-exposed areas, and
sparing of skin folds.
SYSTEMIC AGENTS. Table 92-3 lists the major systemic phototoxic agents.2428 They commonly produce
an exaggerated sunburn reaction but, like most phototoxins, may also induce an eczematous photoallergic
response in a small percentage of users, especially after
topical exposure. As a rule, the action spectra are in
the UVA range; notable exceptions are the porphyrins,
fluorescein, and other dyes, whose action spectra are in
the visible light range.
HISTOPATHOLOGY
Acute phototoxicity is characterized by individual
necrotic keratinocytes and, in severe cases, epidermal necrosis (see Table 92-1). There may be epidermal
spongiosis, dermal edema, and a mild infiltrate consisting of neutrophils, lymphocytes, and macrophages.
Slate-gray pigmentation is associated with increased
dermal melanin and dermal deposits of the drug or its
metabolite.18,19 Histologic features of lichenoid eruptions are similar to those of idiopathic lichen planus;
however, there may be a greater degree of spongiosis
and dermal eosinophilic and plasma cell infiltrates,
and a larger number of necrotic keratinocytes and
cytoid bodies. In pseudoporphyria, as in porphyria
cutanea tarda, there is dermalepidermal separation at
the lamina lucida and deposits of immunoglobulins at
the dermalepidermal junction and surrounding blood
vessel walls.20,21
antibiotic cefotaxime, and with antidepressant venlafaxine. In some of these patients, provocation with
UVA resulted in the development of telangiectasia.22
MANAGEMENT
Identification and avoidance of the causative phototoxic
agent are the most important steps in management.
1071
16
Section 16
Beyond this or if the agent cannot be removed, sun

avoidance is essential. Because the action spectrum
for most agents is in the UVA range, high sun protection factor, broad-spectrum sunscreens containing
efficient UVA filters should be used (see Chapter 223).
Acute phototoxicity can be managed with topical corticosteroids and compresses; systemic corticosteroids
should be reserved for only the most severely affected
patients. Management of patients with slate-gray pigmentation, lichenoid eruption, pseudoporphyria, and
photodistributed telangiectasia is symptomatic only,
and patients should be advised that it will take months
after the discontinuation of the offending agent for the
condition to resolve. Patients with nonsteroidal antiinflammatory drug-induced (NSAID-induced) pseudoporphyria who require NSAIDs should be switched
to a different class of agents or to those that are less
photosensitizing, such as indomethacin or sulindac.29
::
PHOTOALLERGY
PATHOPHYSIOLOGY
Photoallergy is a type IV delayed hypersensitivity
response requiring the presence of both photoallergen
and the activating wavelengths of radiation, which for
most agents are in the UVA range.30 After the absorption of UV energy, a photoallergen may be converted to
an excited state molecule, which subsequently reverts
to ground state by releasing the energy. In this process,
the molecule may conjugate with a carrier protein to
form a complete antigen. This is thought to be the
mechanism of photoallergy induced by halogenated
salicylanilides, chlorpromazine, and para-aminobenzoic acid (PABA). Alternatively, a photoallergen may
form a stable photoproduct on exposure to radiation,
which in turn may conjugate with a carrier protein
to form a complete antigen. Sulfanilamide and chlorpromazine have both been shown to participate in this
reaction.
Once the complete antigen is formed, the mechanism
of photoallergy is identical to that of contact allergy. The
antigen is taken up and processed by Langerhans cells,
which then migrate to regional lymph nodes to present the antigen to T lymphocytes. Cutaneous lesions
develop when the activated T lymphocytes circulate to
the exposed site to initiate an inflammatory response.
1072
In sensitized individuals, exposure to the photoallergen and sunlight results in the development of a pruritic, eczematous eruption within 24 to 48 hours after
exposure (see Table 92-1). Although the morphology is
clinically indistinguishable from that of allergic contact dermatitis, the distribution of the eruption in photoallergy is predominantly confined to sun-exposed
areas; however, in severe cases, it may spread to the
covered areas, albeit at a lower intensity. Unlike the
lesions in phototoxicity in fair-skinned individuals,
those in photoallergy usually resolve without signifi-
cant postinflammatory hyperpigmentation. Lichenoid

eruption has also been reported.
Currently, in the United States, United Kingdom,
and France, UV filters in sunscreen products (especially benzophenone-3) and antimicrobial agents are
the most common cause of photoallergy, whereas
NSAIDs are the leading topical photoallergens in Eur
ope.10,11,3032 Although there have been reports of systemic agents inducing a photoallergic response, the
evidence of such response remains unclear.30
As with phototoxicity, persistence of photosensitivity and evolution to chronic actinic dermatitis (see
Chapter 91) have been reported after exposure to
photoallergens, including chlorpromazine, dioxopromethazine, halogenated salicylanilides, ketoprofen,
musk ambrette, olaquindox, and quinidine.33,34 The
mechanism is not completely understood. One possible explanation is that UV radiation alters the carrier
protein that originally binds the photoallergen; this
results in the formation of a neoantigen that stimulates
the immune system over the long term. This hypothesis is supported by the observation that the histidine
moiety in albumin can undergo oxidation in the presence of salicylanilide, which binds to albumin.
PHOTOALLERGENS
TOPICAL AGENTS. Topical exposure is the most
common route of sensitization to photoallergens.30,35
Table 92-4 lists the common groups of photoallergens.
SYSTEMIC AGENTS. Photoallergy caused by systemic agents is much less frequent, and not as well
documented, than that induced by topical agents. All
but one of these photoallergenic agents (pyridoxine)
are also phototoxic and have been discussed previously in this chapter (see Section Systemic Agents
under Section Phototoxic Agents and Table 92-3).
HISTOPATHOLOGY
The histologic features of photoallergy are similar to
those of allergic contact dermatitis. There is epidermal
spongiosis associated with infiltrate of mononuclear
cells in the dermis (see Table 92-1).
MANAGEMENT
Management is identical to that of phototoxicity: identification and avoidance of the photoallergen, sunprotective measures, and symptomatic therapy.
EVALUATION OF PATIENTS
WITH PHOTOTOXICITY AND
PHOTOALLERGY
The evaluation of patients with phototoxicity and
photoallergy is similar to the evaluation of patients
PORPHYRIA CUTANEA TARDA

(See Chapter 132)
Ingestion of wheat treated with hexachlorobenzene
(HCB) as a preservative resulted in an outbreak of a
porphyria cutanea tarda-like syndrome in Turkey in
the 1950s.36 Inhibition of the enzyme uroporphyrinogen decarboxylase by HCB was thought to be responsible for the clinical manifestations. However, a study
of adults highly exposed to HCB in Catalonia, Spain,
and of children from the same area, did not show any
increase in prevalence of porphyria cutanea tarda or
increased urinary concentrations of porphyrins.37
LUPUS ERYTHEMATOSUS
(See Chapter 155)
Drug-induced systemic lupus erythematosus present with purpura, erythema nodosum, urticarial and
necrotizing vasculitis, and/or photosensitivity. It is
most commonly associated with exposure to hydralazine, procainamide, isoniazid, and minocycline;
antinuclear antibody (ANA) test is positive and antihistone antibodies are characteristically present.38
Drug-induced subacute cutaneous lupus erythematosus (SCLE) presents with similar cutaneous lesions as
idiopathic SCLE, although blisters and targetoid lesions
may occur, and lower extremities may be involved. Antinuclear antibody and anti-Ro/SSA antibodies are frequently present, while antihistone antibodies are usually
absent. Drugs associated with this condition include calcium channel blockers, angiotensin-converting enzyme
inhibitors, thiazide diuretics, terbinafine and tumor
necrosis factor(TNF)- antagonists.38
Drug-induced discoid lupus erythematosus is very
rare; it has been reported with exposure to fluorouracil
and TNF- antagonists.
Identification and avoidance of the precipitating
agent is the treatment of drug-induced lupus erythematosus.
Airborne allergic contact dermatitis is characterized

by involvement of skinfolds on exposed areas, such as
the nasolabial folds, and the eyelids that receive minimal direct sunlight. It also involves exposed areas that
are relatively sun protected, such as the postauricular
areas and area under the chin. Allergic contact derma-
OTHER EXOGENOUS AGENTINDUCED PHOTODERMATOSES

AND PHOTOEXACERBATED
DERMATOSES
16
::
OF PHOTOTOXICITY AND
PHOTOALLERGY
titis and irritant contact dermatitis occur at sites of contact, in both sun-exposed and in sun-protected areas.
Other photodermatoses can be differentiated from
phototoxicity and photoallergy by their characteristic
time course and morphology and lack of a compatible
exposure history. Polymorphous light eruption manifests itself within a few hours of sun exposure as pruritic papules, plaques, and, uncommonly, vesicles on
sun-exposed sites and resolves in a few days. Chronic
actinic dermatitis presents as chronically lichenified
plaques on sun-exposed areas. Lesions of solar urticaria appear within minutes of sun exposure as mildly
pruritic urticaria and resolve within a few hours.
Chapter 92
with other photosensitivity disorders and is described

in greater detail in Chapter. A history of exposure to
known photosensitizers is most important. It is also
helpful to ascertain whether window glass-filtered
sunlight can induce the cutaneous eruption, because
UVB is filtered out by window glass. Distribution of
the cutaneous eruption is a helpful clue to the type
of photosensitizer responsible. Widespread eruption
suggests systemic photosensitizers, whereas topical
photosensitizers produce lesions only in areas that
have been exposed to both sensitizers and radiation.
Vesicular and bullous eruptions are most commonly
associated with phototoxicity, whereas eczematous
eruptions strongly suggest photoallergy; usually, the
former is associated with a burning sensation, the latter with pruritus. Skin biopsy findings may also be
helpful in differentiating these two conditions: necrotic
keratinocytes are commonly seen in phototoxicity,
whereas spongiotic dermatitis is associated with photoallergy (see Table 92-1).
Phototests and photopatch tests are an integral part
of the evaluation of photosensitivity when history and
physical examination alone are insufficient to determine the responsible agent. Approximately 10% of
patients who undergo photopatch testing have clinically relevant positive results, which leads to the diagnosis of photoallergic contact dermatitis.2,11
The procedures for phototesting and photopatch
testing are generally as follows, although there are
variations in testing methods.5,10 On day 1, exposure
to UVB and UVA to determine minimal erythema dose
(MED) is carried out, and duplicate sets of photoallergens are applied symmetrically to another site on
the back and covered by an opaque tape. On day 2,
the MEDs are determined. One of the duplicate set of
photoallergens is exposed to 10 J/cm2 of UVA or 50%
of the MED to UVA, whichever is lower. After irradiation, the exposed site is covered again with an opaque
tape. On day 3, both irradiated and nonirradiated test
sites are uncovered, and the reactions are graded. On
day 5 or day 8, the irradiated and nonirradiated sites
are evaluated for delayed reactions. Reaction only at
an irradiated site indicates photoallergy. Reaction of
equal intensity at both irradiated and covered sites
indicates allergic contact dermatitis. Reaction at both
sites, but with higher intensity at the irradiated site,
signifies both photoallergy and allergic contact dermatitis. Well-defined erythema that resolves promptly
indicates an irritant dermatitis.
1073
16
KEY REFERENCES
5. Kerr HA, Lim HW: Photodermatoses in African Americans: A retrospective analysis of 135 patients over a 7-year
period. J Am Acad Dermatol Oct;57(4):638-43, 2007
10. Victor FC, Cohen DE, Soter NA: A 20-year analysis of previous and emerging allergens that elicit photoallergic contact dermatitis. J Am Acad DermatolApr 62(4):605-10, 2010
Section 16
::
1074
13. Ferguson J, DeLeo VA: Drug and chemical photosensitivity: Exogenous. In: Photodermatology, edited by HW Lim,
H Hnigsmann, JLM Hawk. New York, Informa Healthcare, 2007, p. 199-218
14. Moore DE: Drug-induced cutaneous photosensitivity: Incidence, mechanism, prevention and management. Drug
Saf 25:345-72, 2002
30. Kerr A, Ferguson J: Photoallergic contact dermatitis. Photodermatol Photoimmunol Photomed 26(2):56-65, 2010
35. Scheuer E, Warshaw E. Sunscreen allergy: A review of
epidemiology, clinical characteristics, and responsible
allergens. Dermatitis 17(1):3-11, 2006
Skin Changes Due to Other Physical

and Chemical Factors
Chapter 93 :: Thermoregulation

:: Dean L. Kellogg, Jr.
HUMAN THERMOREGULATION
AT A GLANCE
Thermoregulatory reflexes involve changes
in skin blood flow and sweating that act to
preserve thermal balance with an internal
temperature of approximately 37C (98.6F).
Thermal balance is determined by metabolic
heat production; evaporative heat loss; heat
gain or loss through radiant, convective,
and conductive mechanisms; and useful
mechanical work done.
Dermal papillary loops, arteriovenous
anastomoses, and sweat glands are the major
skin effectors of thermoregulation.
Heat stress evokes large increases in skin
blood flow and sweating through cholinergic
cotransmitter and nitric oxide-dependent
mechanisms to facilitate heat dissipation.
Local skin heating causes a local vasodilation
through antidromic neurotransmitter release
from afferent skin nerves and increased nitric
oxide generation.
Cold stress evokes reduced skin blood
flow through noradrenergic cotransmitter
mechanisms to facilitate heat conservation.
Local skin cooling causes a local
vasoconstriction through noradrenergic
and afferent neural mechanisms as well as
nonneural mechanisms.
THE ROLE OF SKIN IN HUMAN

THERMOREGULATION
Human beings are homeotherms: we maintain our
internal, or core temperature of the body within a narrow range despite thermal stresses. Thermal stress can
arise from variations in environmental temperature or

from the human body itself, as with heat generation
by skeletal muscle during dynamic exercise. When
thermal stresses arise from the environment, changes
in skin temperature occur prior to any change in internal temperature. When thermal stresses arise from the
body itself as with exercise, changes in core temperature occur prior to any change in skin temperature. In
either case, thermal gradients are established between
the skin and the body core. If skin temperature is lower
than core temperature, heat will be lost from the body
unless skin blood vessels constrict. If skin temperature
is greater than core temperature, the body will gain
heat, unless skin vessels dilate and sweat glands produce perspiration. The skin is thus a crucial component of human thermoregulation.
Human thermoregulation is achieved through
an integration of several physiological processes.
These integrated processes make up thermoregulatory reflexes that maintain a stable internal temperature at a set point of 37C (98.6F) despite thermal
stresses. The set point is not invariant and may fluctuate as much as 0.5C1.0C (0.9F1.8F) according
to circadian rhythms and during the menstrual cycle
in females. The thermoregulatory reflexes designed
to preserve internal temperature at the set point are
coordinated by thermally sensitive neurons in the
anterior hypothalamicpreoptic area and spinal cord,
which respond to the changes in internal and skin
temperatures. For example, cold-sensitive neurons in
the anterior hypothalamicpreoptic area and spinal
cord integrate afferent sensory inputs and activate
heat-conserving mechanisms that include cutaneous vasoconstriction and increased metabolic heat
production (shivering). Conversely, the stimulation
of heat-sensitive neurons in the anterior hypothalamicpreoptic area and spinal cord integrate afferent
sensory inputs and activate heat-dissipating mechanisms that include cutaneous vasodilation and sweat
production.
HEAT TRANSFER
To maintain thermal balance, heat gained or lost by the
body must equal heat dissipated from, or produced
17
by the body. This concept can be mathematically

expressed as:
S = M E R C K W
where
Section 17
::
Skin Changes Due to Other Physical and Chemical Factors
1076
S = change in heat storage by the body

M = metabolic heat production and is defined as the
rate of transformation of chemical energy into
heat and mechanical work
E = evaporative heat loss and is defined as the
rate of heat loss by evaporation of water from
skin and surfaces of the respiratory tract. E is
dependant on (1) rate of sweat secretion, (2)
water vapor pressure of the environment, and
(3) the area of evaporative surface.
R = radiant heat gain or loss and is defined as heat
exchange by emission and absorption of electromagnetic (infrared) radiation. This component accounts for 50%60% of the heat loss in
a thermally comfortable (thermoneutral) individual, but can easily become a net heat gain as
when one is in direct sunlight.
C = convective heat gain or loss and is defined as
heat exchange due to forced movement of a
fluid, either liquid or gas. This component is
responsible for the transfer of heat to the skin
through skin blood flow and transfer from the
skin to the environment by air or water movement. Within the body, the cardiovascular system is the major mediator of convective heat
transfer. C is dependent on (1) body surface
area, (2) temperature differences, and (3) fluid
(or air) movement.
K = conductive heat gain or loss and is defined as
heat transfer by flow down a temperature gradient, as between tissues and blood, between
blood and skin, and between skin and the environment. This is usually combined with convective heat transfer.
W = useful mechanical work
The sum of R, C, and K is determined by the temperature gradient between the skin and the environment.
If S is zero, the body is in heat balance. This thermoneutral condition is characterized as having low
skin blood flow of approximately 5% of cardiac output.
Sweating does not occur during thermoneutrality.
If S < 0, the body is losing heat, core temperature
is falling, and thermoregulatory reflexes are evoked to
conserve heat. Thermal stability is maintained through
reduction of skin blood flow that can approach zero
during maximal vasoconstriction. Reduction in skin
blood flow increases the thermal insulation between
the body and the environment by minimizing losses
through conductive (K), convective (C), and radiant
(R) mechanisms. If heat loss continues despite low skin
blood flow, metabolic generation of heat (M) through
the shivering of skeletal muscle is initiated to restore
and maintain core temperature. Brown adipose tissue can also be a source of metabolic heat generation
through nonshivering thermogenesis.1 Although originally thought to be important only in human neonates
where brown adipose tissue is 2%5% of body weight,
some brown adipocytes persist into adulthood.2 These

adipocytes can directly generate heat (M) to maintain
core temperature.3 If, despite all these mechanisms, S
remains negative, core temperature will fall and lifethreatening hypothermia may result.
If S > 0, the body is gaining heat and core temperature is rising. Under this circumstance of heat stress,
thermal stability is maintained by increases in skin
blood flow to facilitate heat loss through K, C, and even
R losses. If heat gain continues despite these mechanisms, sweating is evoked to increase heat loss through
evaporation (E) of perspiration. If S remains positive,
blood flow is diverted from skeletal muscle and gastrointestinal beds, providing for dramatic increases in skin
blood flow. Sweat rate will also increase until maximal
levels are achieved. If, despite maximal skin blood
flow and maximal stimulation of sweating, S remains
positive, core temperature will rise and life-threatening
hyperthermia, i.e., heat stroke, will occur.
THERMOREGULATION
AND THE SKIN
ANATOMIC CONSIDERATIONS
The critical role of the skin in human thermoregulation is well understood: thermoregulation is achieved
through variations in blood flow and sweat production
so as to maintain thermal stability.4 Without these variations, thermal stability cannot be maintained resulting
in risk of hypothermia or hyperthermia (see Chapters
94 and 95). Under normothermic conditions, skin blood
flow ranges from 3040 mL/min/100 g of skin in resting humans. However, the cutaneous vasculature is
exceedingly compliant so that skin blood flow can vary
from nearly zero during cold stress periods with maximal vasoconstriction to 8 L/min over the bodys surface during maximal vasodilation in heat stress.5
Blood vessels in the skin are arranged in several
plexuses in superficial and deep layers parallel to the
skin surface. Most vessels are in the superficial layer
and consist of high-resistance terminal arterioles, papillary loops, and postcapillary venules. Papillary loops
are true capillaries. Blood flow through the loops is
controlled by highly innervated arterioles. The loops
are located near the dermalepidermal junction, a
region characterized by a maximal thermal gradient
because of its proximity to the skin surface. Since the
papillary loops also have a large surface area, blood
flow through these vessels is a major determinant of
heat exchange through vasodilation during heat stress
and vasoconstriction during cold stress.
While papillary loops are found in both glabrous
(palms, plantar aspect of feet, and lips) and nonglabrous skin (most of the bodys surface, including the
limbs, head, and trunk), arteriovenous anastomoses
(AVAs) are found mainly in glabrous skin. They represent direct connections between arterioles and venules
that bypass the high-resistance arterioles and capillaries of the papillary loops. AVAs have thick muscular
walls with rich noradrenergic innervation and lie deep
SWEATING
Heat dissipation through the secretion and evaporation
of eccrine sweat is critical to maintaining thermal stability in hot environments or during heat stress induced
by strenuous dynamic exercise. Indeed, when environmental temperature exceeds blood temperature, the
evaporation of sweat is the sole mechanism for heat dis-
NEURAL CONTROL MECHANISMS OF

THE CUTANEOUS VASCULATURE
In glabrous skin, cutaneous arterioles are innervated
by sympathetic vasoconstrictor nerves that release norepinephrine and other cotransmitters.7,1316 All thermoregulatory reflex changes in blood flow in these areas
are caused by changes in noradrenergic vasoconstrictor activity and the effects of local temperature on the
skin blood vessels themselves (Fig. 93-1).4,7,17
In nonglabrous skin, changes in skin blood flow are
mediated by two branches of the sympathetic nervous system: (1) noradrenergic vasoconstrictor nerves
as found in glabrous skin and (2) a cholinergic active
vasodilator system.4,7,17 These dual sympathetic neural
control mechanisms are the major effectors of thermoregulatory responses. Vessels in nonglabrous skin also
respond to the effects of local temperature changes
(Fig. 93-2).4,7,17
In normothermia, cutaneous arterioles are under
little neural tone. During cold stress, reduction of skin
temperature and/or internal temperature cause a thermoregulatory reflex-mediated reduction in skin blood
flow to conserve body heat. Enhanced noradrenergic
vasoconstrictor tone mediates an arteriolar vasoconstriction and, thus, decreases skin blood flow.
Conversely, during heat stress, thermoregulatory
reflexes that facilitate body cooling are affected. As
internal temperature continues to rise over a threshold value of approximately 37C (98.6F), a cutaneous
vasodilation begins. At this threshold, active vasodilator tone to the cutaneous arterioles is enhanced. At rest,
sweating also begins at the same internal temperature
threshold. Vasodilator tone increases as internal temperature increases. Enhanced vasodilator activity decreases
smooth muscle tone, leading to an arteriolar vasodilation, and, thus, an increase in skin blood flow, especially
through the papillary loops. High skin blood flow delivers heat to the body surface where it is dissipated to the
environment in conjunction with the evaporation of
sweat. Overall, the active vasodilator system is responsible for 80%95% of the elevation in skin blood flow that
accompanies heat stress. A small, but significant portion
of the vasodilation is mediated by the direct vasodilator
effects of local heat on the cutaneous vessels.18
Dual vasoconstrictor nerves and vasodilator nerves
in skin were first suggested in 1931 by Lewis and Pickering19 and confirmed by Grant and Holling.20 They
measured skin temperature as an index of blood flow
in the human forearm and found that large increases
in response to heat stress could be abolished by sympathectomy or nerve blockade. They noted that while
sympathectomy or nerve blockade caused only a slight
Thermoregulation
Cutaneous circulation is a major effector of human

thermoregulation.4 During heat stress, elevated internal temperature and skin temperature lead to cutaneous vasodilation through neural mechanisms and the
local effect of higher temperatures on the skin vessels
themselves. During the periods of cold stress, reduced
temperatures mediate a cutaneous vasoconstriction
through neural as well as local vascular effects. Under
normothermic conditions, skin blood flow averages
approximately 5% of cardiac output; however, the
absolute amount of blood in the skin can vary from
nearly zero during periods of maximal vasoconstriction in severe cold stress to as much as 60% of cardiac
output in severe heat stress.5
17
::
CUTANEOUS THERMOREGULATORY
MECHANISMS
persal. Sweat secretion is controlled primarily by sympathetic cholinergic nerves that release acetylcholine
(Ach) to activate muscarinic receptors on the glands.
Sweat secretion can be augmented by local production
of nitric oxide near sweat glands.12 Stimulated glands
produce an isotonic fluid that becomes progressively
hypotonic as the Na+ is reabsorbed in the sweat gland
duct by active ion transfer (see Chapter 84).
Chapter 93
to papillary loops.6 Because of their deeper location

in the dermis and smaller surface area, AVAs are less
efficient in heat transfer than papillary loops. While
AVAs dilate in response to heat stress and constrict
during mild-to-moderate cold stress, their major role
is to mediate local vasodilation during prolonged cold
exposure. AVA vasodilation delivers warm blood to
maintain tissue temperature and thus tissue viability
through cold-induced vasodilation.7
Sweat glands also play a major role in human thermoregulation (see Chapter 83). The critical thermoregulatory role of the eccrine sweat glands that are found
over most of the body surface is well known. Clearly,
the main function of eccrine sweat glands is to increase
heat loss through the evaporation of sweat. The density
of these glands varies from 700 glands per cm2 in planar
and plantar skin to 64 glands per cm2 on the back8; these
glands may hypertrophy with repeated heat exposure.9
Each gland is made up of a secretory coil found in the
dermis with a duct that extends through the dermis and
epidermis to the surface of the skin. Sweat is secreted as
an isotonic fluid by the coils. NaCl is reabsorbed within
the ducts so sweat that is finally delivered to the surface
is hypotonic.10 Each liter of sweat evaporated is capable
of removing 580 kcal from the body. Although apocrine
sweat glands have been dismissed as atavistic scent
glands, this has recently been questioned.11 Apocrine
glands are usually associated with hair follicles and are
most developed on the scalp, face, upper back, and chest.
It has been proposed that sebum from apocrine glands
acts as a surfactant at high temperatures and, thus, facilitates dispersion of eccrine sweat over the skins surface.
At low temperatures, sebum may function to repel water
from the skin and, thus, reduce heat loss.
1077
17
Summary of neural controls of thermoregulatory effectors in human skin

Neural control mechanisms in non-glabrous skin
Thermoregulatory
inputs
Afferent inputs
CNS
Internal temperature
Preoptic-anterior
hypothalamus
and
spinal cord
Skin temperature
Noradrenergic
vasoconstrictor nerves
Cholinergic
submotor nerves
Cutaneous
arterioles and
arteriovenous
anastomoses
Sweat
glands
Section 17
Neural control mechanisms in glabrous skin
::
Thermoregulatory
inputs
Afferent inputs
CNS
Internal temperature
Preoptic-anterior
hypothalamus
and
spinal cord
Skin temperature
Efferent controls
Noradrenergic
vasoconstrictor nerves
Cholinergic
vasodilator nerves
Cholinergic
submotor nerves
Cutaneous
arterioles and
arteriovenous
anastomoses
Sweat
glands
Figure 93-1 Summary of neural controls of thermoregulatory effectors in human skin: Thermoregulatory reflexes are mediated by the afferent inputs of internal and skin temperature. These afferent inputs are integrated in the preoptic anterior
hypothalamus and spinal cord areas of the central nervous system. Efferent control of blood vessels and sweat glands in
glabrous skin is mediated by noradrenergic vasoconstrictor nerves and cholinergic sudomotor nerves, respectively. In
nonglabrous skin regions, efferent control of blood vessels is effected through a system of dual sympathetic innervation,
noradrenergic active vasoconstrictor nerves and cholinergic active vasodilator nerves. Sweat glands also receive cholinergic sympathetic innervation; however, whether cholinergic active vasodilator nerves and cholinergic sudomotor nerves
are one and the same is not known.
cutaneous vasodilation during normothermia, heat
stress elicited a much greater increase in skin blood
flow. In addition, nerve blockade during established
heat stress abolished any cutaneous vasodilation. These
results suggested that cutaneous vessels in nonglabrous
skin are innervated by sympathetic active vasodilator as
well as sympathetic vasoconstrictor nerves. In the 1950s,
their findings were confirmed by Edholm et al21 and by
Roddie et al.22 In addition, it has been shown that bretylium tosylate (a prejunctional noradrenergic neuronal
blocking agent) abolishes the cutaneous vasoconstriction induced by cold stress, but does not alter the vasodilator responses induced by heat stress.23 This confirmed
that dual efferent neural systems control the cutaneous
arterioles: a noradrenergic vasoconstrictor system and a
nonadrenergic active vasodilator system.
FACTORS THAT ALTER RESPONSES

TO HEAT AND COLD
1078
Efferent controls
Thermoregulatory responses undergo physiological

acclimatization after repeated thermal challenges over
a prolonged (2-week) time period. After repeated exposure to a hot environment, sweat glands hypertrophy
to produce more sweat and cutaneous active vasodilation begins at lower internal and skin temperatures to
facilitate long-term thermal stability by favoring earlier and greater heat dissipation.87 Humans also acclimate to cold environments after repeated exposure by
increasing metabolic heat generation (in part through
increased amounts of brown adipose tissue) and habituating to cold. These adaptations are less effective in
promoting thermal stability than adaptations to heat.88
Acute and chronic dermatological disorders can
impair thermoregulation. For example, sunburn compromises sweat production, thus impairing evaporative cooling and reducing heat tolerance. At the same
time, the inflammatory vasodilation that accompanies
sunburn can compete against thermoregulatory reflex
vasoconstriction during cold exposure. This will compromise the ability to reduce skin blood flow to conserve body heat, thus reducing cold tolerance.87 Other
inflammatory skin conditions, of which erythroderma
is the most extreme, have the same effect.
Medications can alter thermal tolerance, especially
during heat exposure. Numerous medications have
anticholinergic effects. Since the cutaneous active vasodilator system and sweat glands are both controlled by
cholinergic sympathetic nerves, it is not surprising that
such agents have deleterious thermoregulatory consequences. Examples of commonly used medications
that can compromise heat stress responses include first
generation antihistamines, H2-receptor antagonists,
and tricyclic antidepressants. These systemic agents
Skin blood flow responses to cold stress and

heat stress in non-glabrous skin
20
15
Normal
neural
tone
10
Increased Normal
active
neural
vasotone
constrictor
tone
Increased active
vasoconstrictor
tone
5
0
Normothermia
Cold
stress
Normothermia
Heat stress
KEY REFERENCES
Cold Injuries
4. Kellogg DL, Jr: In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans. J Appl Physiol
100:1709-1718, 2006
7. Johnson JM, Proppe DW: Cardiovascular adjustments
to heat stress. In: Handbook of physiologyenvironmental
physiology, edited by M Fregly, and C Blatteis. New York,
Oxford University Press, 1996, p. 215-243
19. Lewis T, Pickering GW: Vasodilation in the limbs in response to warming the body; with evidence for sympathetic vasodilator nerves in man. Heart 16:33-51, 1931
20. Grant RT, Holling HE: Further observations on the vascular responses of the human limb to body warming; evidence for sympathetic vasodilator nerves in the normal
subject. Clin Sci 3:273-285, 1938
22. Roddie IC, Shepherd JT, Whelan RF: The vasomotor nerve
supply of the human forearm. Clin Sci 16:67-74, 1957
37. Kellogg DL, Jr. et al: Cutaneous active vasodilation in humans is mediated by cholinergic nerve co-transmission.
Circ Res 77:1222-1228, 1995
::
Figure 93-2 Skin blood flow responses to cold stress and

heat stress in nonglabrous skin: under normothermic conditions, skin blood flow is relatively low (approximately 5%
of cardiac output) and skin vessels receive relatively minor
neural inputs from active vasoconstrictor and vasodilator
nerves. During cold stress, reductions of skin and internal temperatures lead to reflex increases in sympathetic
noradrenergic vasoconstrictor nerve activity. Increased
vasoconstrictor system tone reduces skin blood flow, thus
increasing thermal insulation and conserving body heat.
During heat stress, increasing skin and internal temperatures lead to reflex increases in sympathetic cholinergic
active vasodilator nerve and cholinergic sudomotor activity. Increased activity of the vasodilator system leads to
potentially dramatic increases in skin blood flow that can
reach 60% of cardiac output. High skin blood flow delivers
heat to the skin surface where it is removed to the environment primarily through evaporation of sweat.
17
Chapter 94
Skin blood flow (mL/100 g/skin/min
25
(and many others) can reduce sweat secretion, attenuate cutaneous active vasodilation, and increase the risk
of thermoregulatory failure.17
Aging also modifies thermoregulatory reflexes.
Relative to younger subjects, in healthy older persons,
noradrenergic mechanisms are more important than
cotransmitter mechanisms in vasoconstricting skin
during cold stress.89 During heat stress, older subjects
show a delay in the onset and reduced magnitude of
cutaneous vasodilation.90 These alterations in cutaneous responses to thermoregulatory challenges contribute to increased morbidity and mortality during
thermal stresses in older persons.
Chapter 94 :: Cold Injuries

:: Grald E. Pirard, Pascale Quatresooz, &
Claudine Pirard-Franchimont
COLD INJURIES AT A GLANCE
Skin is important for maintaining core body
temperature within a narrow physiologic range.
Winter xerosis and acrocyanosis are common

consequences of prolonged exposure to cold.
Cold weather, wind, humidity, dampness, and

altitude combine to inflict skin damage.
Erythrocyanosis tends to occur over skin areas

with thick adipose tissue, whereas chilblain is
more frequently seen in lean persons.
Nonfreezing and freezing conditions can both

produce cold injuries.
Frostbite occurs after exposure to intensely cold
air, liquids, or metals. Several degrees of frostbite
are recognized.
Cold urticaria is rare and occurs at the sites of

localized cooling.
Primary erythromelalgia is a rare neuropathic
disorder to which there is a genetic predisposition.
1079
17
The human capacity for physiologic adaptation to

cold is minimal. This deficiency may cause problems,
because seasonal changes in the outdoor environment
are quite prominent, even in the temperate zones of
the world. In this context, skin is important in thermoregulation, and cutaneous blood flow and the resulting
skin temperature may vary widely to help preserve the
core body temperature.13 Physiologic, behavioral, and
environmental factors modulate skin responses to cold
exposure.
Core body temperature is maintained within a narrow range by thermoregulatory mechanisms that rely
largely on control of the cutaneous blood flow. Arteriovenous anastomoses are abundant in acral areas, and
they regulate the volume of blood that passes through
the skin. When the skin is cooled, there is usually an
immediate acute reduction in the amount of blood
that flows to the surface. These events alter skin temperature, heat loss, and color. Skin reactivity and the
anatomic pattern of blood supply differ in the skin of
newborns, adults, and older people. For instance, a
reticulate appearance of cooled skin is a common finding in young infants (Fig. 94-1).
The parallel arrangement of large arteries and veins
in the limbs allows countercurrent exchange of heat.
Vasoconstriction due to cold results in shunting of
blood from the superficial to the deep venous system,
and heat is transferred from arteries to veins. Thus, the
blood going to the acral part of the limbs is precooled,
and less heat is lost to the environment. With such
thermoregulation, the body can maintain a constant
core temperature of approximately 37C (98.6F) over
a range of external temperatures between 15C and
54C (59F and 129.2F).
Normally, the skin is to some extent adapted to a
cooler environment than the 37C (98.6F) of internal organs. Given the presence of many cold-adapted
1080
Figure 94-1 Reticulate appearance of cooled skin in the

newborn due to the anatomic pattern of the blood supply
and factors influencing flow such as arteriolar vasoconstriction and the increased viscosity of cooled blood.
::
Section 17
PHYSIOLOGIC RESPONSE
TO COLD
enzymes, the skin may even function more effectively

when slightly cooled. In the case of adipose tissue,
mild long-term exposure to cooling may lead to progressively better insulation. Habitually cold-exposed
skin also develops a more efficient system for shunting
blood away from the surface. These adaptive mechanisms are most flexible during the first years of life.
Tissues in the aged are less able to develop new shunts.
The effect of swimming in cold water after extreme
heatingfor example, after using a sauna4is somewhat comparable to accidental cold water immersion.
Well-being depends substantially on the degree of
subcutaneous insulation, so that overweight persons,
as well as those who are well clothed, can survive prolonged accidental cold-water exposure.5
Viscosity of fluids generally increases as temperature
decreases. However, blood is a non-Newtonian fluid
that exhibits thixotropy, i.e., it becomes less viscous
with increasing flow velocity, independent of temperature. This effect is strongly influenced by hematocrit
and by packing of erythrocytes. Macrophages also can
block capillaries when they develop pseudopods as a
result of reduced flow. The combination of slow flow
and leukocyte conformational changes is, in part, a
physiologic process that enables these cells to migrate
through the endothelial lining.6 Other factors affecting
blood viscosity include increased platelet adhesiveness, changes in concentrations of proteins, and the
presence of abnormal proteins. Fibrinogen level is particularly important.
THERMOREGULATION AND
HUNTING REACTION
Local and systemic thermoregulation is complex. A
group of neurons in the hypothalamus responds directly
to temperature. When the temperature decreases, the
rate of discharges decreases. From this temperaturesensitive area, signals radiate to various other portions
of the hypothalamus to control either heat production or
heat loss. Stimuli that influence the autonomic nervous
system, such as painful stimuli, mental stress, arousal
stimuli, and deep breaths, can all produce cutaneous
vasoconstriction in warm subjects but vasodilation in
cold subjects.7,8
Cold exposure produces an initial massive cutaneous
vasoconstriction, which results in a fall in skin temperature. This change serves to maintain core temperature,
but at the expense of the skin. Conversely, cold-induced
vasodilation represents a protective mechanism to prevent skin necrosis. This physiologic reflex, known as
the hunting reaction of Lewis, involves transient cyclic
vasodilation caused by the opening of arteriovenous
anastomoses.9,10
A chilling effect is produced by applications of dedicated hydrogel pads or cushions previously stored in a
refrigerator.11,12 This biothermal procedure is commonly
used during laser therapy. It also serves to achieve a
sustained removal of heat from the skin and its underlying tissues. It produces discrete skin hemodynamic
changes and may relieve pain.
COLD, WIND, HUMIDITY,

AND ALTITUDE
::
Cold Injuries
Figure 94-2 Bullous frostbite following contact with a

cold steel sheet.
17
Chapter 94
Outdoor work and winter sports are common risk situations for cold damages. A cold environment can be a
threat to the skin, leading to a subsequent fall in core
body temperature. Many physiologic, behavioral, and
environmental factors predispose to the global effects
of cold injuries. Marked increases in convective, conductive, or radiant heat loss are responsible for the
immediate effects of cold exposure. For instance, touching cold metal objects considerably increases conductive cooling (Fig. 94-2). Other predisposing factors
increasing heat loss and/or decreasing heat production
and insulation from clothing make people especially
susceptible to cold.13
There is ample evidence that the effect of low temperature on skin biology is, in part, a function of environmental humidity, wind speed, and altitude. In this
respect, the wind chill index is indicative of the convective heat loss. Wind chill affects the gradients of temperature and water content across the stratum corneum,
which result in an imbalance in condition between outer
and deeper epidermal layers.14 High altitude, which
reduces the oxygen supply to tissues, also contributes to
increase the skin damage induced by cold.15
Transepidermal water loss (TEWL) plays a prominent role in evaporative thermal loss. The skin temperature and the relative and absolute environmental
humidity are key factors affecting cold injuries. The
ambient humidity indicates the mass of water vapor
present in a unit volume of the atmosphere. An accurate representation of the amount of moisture in the air
as a function of temperature is given by the calculation
of the dew point,11,16 which is defined as the temperature of the air at which the gaseous moisture begins
to condense, that is, the temperature at which relative
humidity reaches 100%.
Poor clothing insulation is a common reason for cold
injuries. The insulation is insufficient when clothing is
too light, wet, tight, permeable to wind, or inadequate
to cover the cold sensitive body parts. Individual factors predisposing to cold injuries are physical injuries,
leanness, low physical fitness level, fatigue, dehydra-
tion, previous cold injuries, sickness, trauma, poor

peripheral circulation, the wearing of tight constrictive clothing, and old age.13 Newborns, the elderly, and
individuals with impaired mental faculties remain the
most vulnerable. Injury is often increased by alcohol,
smoking, and psychotropic drug use.
Severe cold injuries have historically influenced the
outcome of battles and wars.17,18 Peacetime military
operations also impose risks.1922 However, cold injuries are becoming more prevalent among the general
population.21 Many cases are associated with alcohol
consumption, homelessness in urban centers, and car
breakdown. Frostbite also prevails among winter sport
enthusiasts such as cross-country skiers and backpackers who get lost or trapped in a snowstorm.2,2226 Accidental exposure to liquefied gas is another cause of
severe cold injuries.27
Adaptation to cold protects one from responding
inappropriately, and a moderate degree of exposure
to cooling might be health promoting by stimulating
a responsive and protective vasculature. In contrast,
individuals who have experienced severe cold injury
may have a profoundly delayed or abolished hunting
reaction in the affected limbs.28 They are rendered more
susceptible to recurrent cold injury with pain, hyperesthesia, or paresthesia.29 Some of these individuals also
have coldness of the skin, which is very persistent and
probably related to a functional imbalance in the sympathetic nervous system that results from increased
-adrenergic receptor density or affinity for norepinephrine.30 In addition, altered vascular structure may
reduce vasocompliance after cold exposure. There may
also be impairment of normal vascular reflexes to various stimuli, including deep inspiration, venous occlusion, neck cooling, and ipsilateral skin cooling.30
CLASSIFICATION OF SKIN
COLD INJURIES
Freezing and nonfreezing injuries can be distinguished
according to the severity and duration of chilling. However, the damage caused depends on many variables
other than the actual temperature. Recognition is generally easy at a clinical level, but awareness of potential
uncommon underlying disorders is important. Treatment, both physical and pharmacologic, is aimed at
keeping the body warm and maintaining vasodilation.
Frostbite is the consequence of extreme and prolonged freezing conditions. In addition, the whole body
may cool down so much that life-threatening hypothermia may ensue. This is an important concern for people
who enjoy cold weather sports, particularly in mountains and circumpolar regions. Prompt recognition and
treatment are of paramount importance, because many
hypothermia victims can recover from very low body
temperatures. Treatment in an adequate medical facility can make the difference between full recovery and
lifelong problems. Even if the victim appears to be dead
from exposure to cold, resuscitative efforts should be
started and continued until the proper core body temperature is reached.31
1081
17
Section 17
::
1082
Figure 94-3 Hemorrhagic bulla and necrosis of the skin

induced by freezing a wart with liquid nitrogen.
Extreme and often conductive heat loss at a given

body site freezes the tissues and results in localized
blistering and necrosis (Fig. 94-3). Several cutaneous
disorders also occur when the tissue temperature is
maintained just above freezing for long periods. These
conditions include chilblains, cold urticaria, cold panniculitis, erythrocyanosis, and acrocyanosis, among
others. These disorders may be a consequence of
impaired blood flow, reduced sensory perception, or a
change in the physical properties of the tissues, such as
in adipose tissue.
Minor but long-term cold exposure combined with
environmental desiccation may have profound effects
on the biology of the epidermis, leading, for example,
to winter xerosis.32,33 Persistent erythema of the face
and the hands is not a rare finding (Fig. 94-4).
FROSTBITE
Frostbite occurs when tissue freezes after exposure
to extremely cold air, liquids, or metals. The clinical
effects of accidental injury that leads to the death of tissues are similar to those caused by cryosurgery.34 The
components of tissue that may lead to damage when
frozen are water, with formation of ice crystals at 0C
(32F), and lipids such as fat globules or cell membrane
constituents.
Contrasting with damaging cryoinjuries, cryopreservation is used to preserve or to freeze in vitro most
of the biomolecules present in tissues.35 Any metabolic
activity is blocked in these circumstances. Cryoscopy
is a diagnostic procedure applicable in vivo.36 It relies
on an acute but short icing of the stratum corneum in
order to disclose some structures exhibiting different
capacities of thermal conductivity.
The rate of freezing determines the site of injury at
the cellular level.37 Extracellular formation of ice occurs
most commonly with slow freezing, whereas fast
Figure 94-4 Facial redness in a person exposed to cold

winters in a temperate climate.
freezing tends to produce intracellular ice. The formation of ice crystals in the extracellular space alters the
osmotic properties of the tissues and disturbs the flow
of water and electrolytes across the cell membranes.
Thawing may be as damaging as the freezing itself,
and repeated freeze and thaw cycles, as may occur
in accidental injury, compound the damage, making
more water available, which rapidly leads to intracellular flooding. The rewarming rate is also important.
In slow rewarming, ice crystals become larger and
more destructive. Cells are also exposed to a high concentration of electrolytes for a longer period than with
rapid rewarming.
As the body cools, there is a reflex constriction of the
arteries and veins in the extremities.31 This results in
increased venous pressure, decreased capillary perfusion, and sludging. Cooling also creates a leftward
shift in the oxygen dissociation curve, and hemoglobin
gives up its oxygen less readily. These two conditions
result in hypoxia and damage to the capillaries and surrounding tissue. Oxygen tension is further decreased
by thrombus formation in the microvasculature, which
results in arteriovenous shunting. Arterial and arteriolar constriction, mediated by sympathetic outflow,
initiates and probably maintains circulatory impairment. In addition, segmental vascular necrosis occurs
in areas of erythrostasis, which suggests that ultimate
damage may depend more on insufficient clearance of
toxic substances than on initial vasoconstriction.
Cell types vary in their susceptibility to cold injury.
Melanocytes are very sensitive to cold, and irreversible damage may occur at 4C to 7C (24.8F19.4F).
This sensitivity explains the hypopigmentation that
often follows cryotherapy. In addition, it appears that
black persons are more susceptible to frostbite than
whites. Nerve axons are also easily damaged by cold,
17
TABLE 94-1
Consequences of Cold Injuries

Arterial and arteriolar vasoconstriction
Excessive venular and capillary vasodilation
Increased endothelial leakage
Erythrostasis
Arteriovenous shunting
Segmental vascular necrosis
Massive thrombosis
Figure 94-5 Frostnip.
Chapter 94
::
Frostnip involves only the skin and causes no irreversible damage. There is a sensation of severe cold
progressing to numbness followed by pain. Erythema
is usually present on the cheeks, ears, nose, fingers,
and toes (Fig. 94-5). There is no edema or bleb formation. Frostnip is the only form of frostbite that can be
treated safely in the field with first aid measures.
Superficial frostbite involves the skin and immediately subcutaneous tissues. It includes the previously
described signs but with the pain subsiding to feelings
of warmth. This is a sign of severe involvement. The
skin has a waxy appearance, but deeper tissues remain
soft and resilient. Clear blebs form, accompanied by
edema and erythema within 2436 hours after thawing. Lesions may become eroded (Fig. 94-6).
Deep frostbite extends to the deep subcutaneous tissue. The injured skin becomes white or bluish
white with a variable degree of anesthesia. Most often
the affected skin becomes deceptively pain free, and
the discomfort of feeling cold vanishes. The tissue is
Cold Injuries
and nerve injury may occur with axonal degeneration

of large myelinated fibers. Autonomic fibers are also
affected, and this may account for the abnormal sweating and cold sensitivity that follow nonfreezing cold
injury.38,39 Nerve sheaths are quite resistant to cold,
as are bone and cartilage.28 Desolidification of lipids
in adipose tissue and disruption of endothelial cells
lining blood vessels and lymphatics, with secondary
disturbances of permeability and blood flow, are other
consequences of severe cold. In the overall assessment,
there are marked similarities in the pathologic processes to those seen in thermal burns and in ischemiaperfusion injuries.
Three stages of cooling are recognized. The first is
massive vasoconstriction, which causes a rapid fall in
skin temperature. In a second step, the hunting reaction
follows with a cyclic rise and fall in skin temperature.
If cold exposure continues, the third stage of freezing
occurs as the skin temperature falls to approach ambient temperature. The events that ensue in freezing and
nonfreezing cold injuries are similar.17,40 Consequences
of cold injuries and their classification are presented in
Tables 94-1 and 94-2, respectively.
Frostbite commonly affects fingers, toes, ears, nose,
and cheek.41,42 The clinical presentation of frostbite falls
into three categories corresponding to mild frostbite or
frostnip, superficial frostbite, and deep frostbite with
tissue loss.
Figure 94-6 Superficial frostbite.
1083
TABLE 94-2
Classification of Nonfreezing Cold Injuries to

the Skin
Vasoconstriction
Hunting reaction
Immersion foot
Pulling-boat hands
Acrocyanosis
Chilblains
Cold urticaria
Cold panniculitis
Erythromelalgia
Raynaud phenomenon
Sclerema neonatorum
Subcutaneous fat necrosis of the newborn
Livedo reticularis
Cryoglobulinemia
Cold agglutinins
Cryofibrinogenemia
17
Section 17
::
1084
Figure 94-7 Deep frostbite after rewarming. Large blisters have formed. Note cyanosis of toes as a sign of developing necrosis. This cold injury occurred in a homeless
person who was found on the street after heavy alcohol
consumption and overnight snowfall.
totally numb, indurated with immobility of joints and
extremities. Muscles may be paralyzed. Nerves, large
blood vessels, and even bone may be damaged. Large
blisters form 1 to 2 days after rewarming, and they
can be classified according to depth, as in heat-induced
burns (Fig. 94-7). Frostbite blister fluid contains high
amounts of prostaglandins, including prostaglandin
F2 and thromboxane A2. These mediators may contribute to increased vasoconstriction, platelet aggregation,
leukocyte adhesiveness, and ultimately progressive
tissue injury. The blister fluid begins to be resorbed
within 5 to 10 days, which leads to the formation of
hard, black gangrene. Weeks later, a line of demarcation occurs, and the tissues distal to the line undergo
autoamputation (Fig. 94-8).
PREVENTION
Prevention is key to protecting individuals from the
effects of cold weather; and frostbite, frostnip, and hypothermia always should be taken seriously. Prognostic
factors25,4346 are listed in Table 94-3. Wearing protective
clothing, warm hat, earflaps and scarf together with preventive behavior such as turning bare areas away from
the wind are the most important procedures for preventing frostbite. Nonmedicated waterless ointments are traditionally used for protection against facial frostbite, but
their benefit is undocumented. The thermal insulation
they provide is indeed minimal.41,42 The use of protective emollients seems to cause a false sensation of safety,
which leads to an increased risk of frostbite, probably
through neglect of other, more efficient protective measures.47,48 In less extreme conditions, however, some specific topical formulations bring beneficial effects.49 The
most effective products are those reducing TEWL and
perspiration because these biological functions cause
emission of body thermal energy and thus cool the skin.
Figure 94-8 Dry gangrene of all fingers in a mountain

climber 5 weeks after being caught in a snowstorm.
MANAGEMENT
The first consideration in frostbite treatment is to be
aware that the victim may be suffering from hypothermia.25,31,50,51 Because of the difficulty in assessing the
depth of frostbite injury, conservative waiting after the
frostbite episode is often encouraged in an attempt to
delineate the extent of tissue loss. Beyond this, the main
principles are to avoid trauma, friction, pressure, massaging with snow, and refreezing. Slow rewarming increases
tissue damage, and therefore rapid rewarming is the
keystone of treatment.20 It should be performed in a
TABLE 94-3
Prognostic Signs of Frostbite

Good prognostic signs
Large, clear blebs extending to

the tips of the digits
Rapid return of sensation
Rapid return of normal (warm)
temperature to the injured area
Rapid capillary filling time after
pressure blanching
Pink skin after rewarming
Poor prognostic signs
Hard, white, cold, insensitive skin

Cold and cyanotic skin without
blebs after rewarming
Dark hemorrhagic blebs
Early evidence of mummification
Constitutional signs of tissue
necrosis, such as fever and
tachycardia
Cyanotic or dark red skin
persisting after pressure
Freezethawrefreeze injury
NONFREEZING COLD INJURY

AND DAMPNESS
Nonfreezing cold injury occurs when tissues are
cooled to temperatures between approximately 15C
(59F) and their freezing point for prolonged periods.
This type of injury, which is exacerbated by dampness,
has claimed numerous casualties in warfare. Nonfreezing cold injury may be followed by cold sensitivity and
hyperhidrosis, which may persist for years.
During World War I, trench foot was identified as a
separate entity. Wet conditions at temperatures above
freezing and limb dependency due to immobility and
constrictive footwear were important pathogenic factors. Three stages were described. Stage I consisted
of initial erythema, edema, and tenderness. Stage II
followed within 24 hours with paresthesia, marked
edema, numbness, and sometimes blisters. Stage III
corresponded with progression to a usually superficial
gangrene. Immersion foot, similar to trench foot, was
described in shipwreck survivors during World War II.
Many individuals present with dryness of the skin,

particularly on the lower extremities, during wintertime. The hands, forearms, cheeks, lips, and trunk also
may be affected. Itching, a dry appearance, chapping,
and cracking of the stratum corneum are more or less
prominent. The condition is markedly influenced by
cold environments, especially in combination with
low humidity.38,39 Predisposing factors include atopic
dermatitis, ichthyosis, and increasing age. Excessive
washing exacerbates winter xerosis. Indeed, irritant
dermatitis of the hands worsens in a cold and dry environment.60 Emollients and improvement in the environmental temperature and humidity are helpful in
controlling this condition.
Cold Injuries
Sequelae of frostbite include permanent hypersensitivity to cold and, less often, hyperhidrosis.38 Squamous
cell carcinoma is a rare outcome, usually occurring on
the heel 2030 years later.57 Epiphyseal plate damage
or premature fusion may occur in children. Premature
fusion can result in shortened digits, joint deviation, and
dystrophic nails. In addition, frostbite arthritis, resembling osteoarthritis, may occur weeks to years later.
WINTER XEROSIS
17
::
SEQUELAE
Tropical immersion foot was described during the

Pacific campaign in World War II. Occurring after
exposure to the warm, wet conditions of jungle warfare, this condition differed from classic trench foot
and immersion foot in that it caused less tissue destruction, numbness, and anesthesia and was followed by
more rapid complete recovery. The role of temperature
in tropical immersion foot is unclear and may not be
important.58 As with trench foot and immersion foot,
prevention is most important.
Another specific condition known as pulling-boat
hands was described, characterized by the presence
of erythematous macules and plaques on the dorsum
of the hands and fingers of sailors aboard rowboats.59
Small vesicles developed later, accompanied by itching, burning, and tenderness. These individuals were
exposed to long periods of high humidity, cool air, and
wind, an ideal setting for the development of nonfreezing cold injury. In addition, hours of vigorous rowing
daily produced repetitive hand trauma.
Chapter 94
water bath no warmer than 40C42C (104F to 107.6F)

until the most distal parts of the body are flushed. Large
amounts of analgesics may be required. The damaged
part should be elevated, and blisters should be left
intact. Surgical debridement is often best delayed until
1 to 3 months after demarcation. However, triple-phase
bone scans, magnetic resonance imaging, and magnetic
resonance angiography can be used to predict ultimate
tissue loss and to assess the possibility of earlier surgical
intervention.40,52,53
There is no uniformly accepted protocol for other
measures allegedly beneficial in the treatment of frostbite injury.51 Intra-arterial reserpine and sympathectomy have been used to reverse vasospasm, which
may contribute to tissue loss. Their role is controversial, although some patients have benefited from this
therapy. To counteract vasoconstriction caused by
local release of inflammatory mediators, the use of
topical aloe vera, which inhibits thromboxane synthetase, and systemic ibuprofen, which inhibits cyclooxygenase, have been advocated. Oxpentifylline has
been presented as an advanced therapy.54 In addition,
several adjunctive therapies, including vasodilators,
thrombolysis, and hyperbaric oxygen, are sometimes
useful.55 Tetanus toxoid should be given in the case
of open wounds. Surgery and amputation remain the
ultimate strategies to help the victims.56
ACROCYANOSIS
Acrocyanosis is a bilateral dusky mottled discoloration
of the hands, feet, and sometimes the face. It is persistent and accentuated by cold exposure. When the
temperature is very low, the skin may be bright red.
Trophic changes and pain do not occur, and pulses are
present. This condition must be distinguished from
Raynaud phenomenon (see Chapter 170), which is
clearly episodic, often segmental, and painful, as well
as from obstructive arterial disease (see Chapter 173).
Acrocyanosis is genetically determined and usually
starts in adolescence. Chronic vasospasm of small cutaneous arterioles or venules with a secondary dilatation of the capillaries and subpapillary venous plexus
has been postulated. Stasis in the papillary loops with
aneurysmal dilatation at the tips redistributes blood
flow to the subpapillary venous plexus. The blood flow
may be compromised by altered erythrocyte flexibility, increased platelet adhesiveness, and other plasma
viscosity factors. Cold agglutinins may exacerbate
the acrocyanosis manifestations.61,62 The puffy hand
1085
17
Section 17
::
1086
syndrome is defined by the presence of hand edema

superposed on acrocyanosis.63
Tissues are less sclerotic in acrocyanosis than in Raynaud phenomenon. They contain twisted collagen fibrils
and large pericytes. In cases developing for the first time
late in life, an underlying myeloproliferative disorder
should be excluded. Remittent necrotizing acrocyanosis is associated with enhanced susceptibility to cooling
and pain, as well as ulceration and gangrene of the fingers. Arteriolar occlusion by thrombi or intimal proliferation may occur. Cold pain should be distinguished
from cold allodynia and cold hyperalgesia.
There is no effective treatment for acrocyanosis. Supportive measures to keep the skin warm are helpful.
ERYTHROCYANOSIS
Erythrocyanosis is a dusky cyanotic discoloration,
worse in winter, which occurs over areas with a thick
layer of subcutaneous fat (Fig. 94-9). The condition is
seen most often on the lower legs and thighs of adolescent girls and middle-aged women. Nodular lesions
similar to chilblains may occur and have been described
in women with severe erythrocyanosis and paraplegia.
Keratosis pilaris, angiokeratomas, and telangiectasia
are commonly associated. Spontaneous improvement
often occurs after a few years. However, the disease
may persist with long-standing edema and fibrosis.
The wearing of warm clothes and weight reduction
are important to decrease the insulating effect of the
subcutaneous fat, which is responsible for a chronically low skin temperature. The outcome remains
unpredictable.
CHILBLAINS
Chilblains, also called pernio or perniosis (Fig. 94-10), are
localized inflammatory lesions caused by continued
exposure to cold above the freezing point.64,65 Dampness and wind that increase thermal conductivity and
convection play a part. Absolute temperature is less
important than the cooling of nonadapted tissue. The
Figure 94-9 Erythrocyanosis of plump upper arms of a

woman.
Figure 94-10 Chilblains are common at such sites as the

hands and feet when they are exposed to both cooling
and tight garments. A. Chilblains on the toes. B. Chilblains
on the dorsum of the foot. Children and the elderly are
most commonly affected, perhaps, because they take less
care to protect themselves from cooling. C. Equestrian
chilblains from horse riding on a cold morning with inadequate clothing.
condition shows a genetic predisposition. It has been
described most often in temperate regions, where
winters are occasionally cold and damp. Chilblains
are seen less often in very cold climates, where wellheated houses and warm clothing are available. Both
acrocyanosis and chilblains appear to be more common
in children, women, and persons with low body mass
index. Spontaneous remission is common when spring
arrives, and relapse is frequent during the following
winters. However, chilblains do not always occur at the
time of maximum cold.
Chilblains develop acutely as single or multiple,
burning, erythematous, or purplish swellings (see Fig.
9410A and C). Patients may complain of itching, burning, or pain. In severe cases, blisters (see Fig. 94-10B),
pustules, and ulceration may occur. Characteristic
locations include the proximal fingers and toes, plantar surfaces of the toes, heels, nose, and ears, but other
sites like the calves and thighs can be affected66,67 (see
Fig. 94-10C). Lesions usually resolve in 1 to 3 weeks
but may become chronic in elderly people with venous
stasis. Tight garments such as gloves, stockings, and
shoes are especially to be avoided in cases in which
there is also peripheral vascular disease. A papular
form of chilblains resembles erythema multiforme and
occurs at all times of the year, usually in crops on the
sides of the fingers,68 often superimposed on a background of acrocyanosis.
edematous papules and plaques, often with headache,

fever, arthralgia, and leukocytosis. Swelling of the oral
mucosa and esophagus may occur on ingestion of cold
liquids. A rather distinctive combination of cold urticaria and dermographism or cholinergic urticaria is not
uncommon. Alarming signs resembling those of histamine shock may lead to loss of consciousness. Death
while swimming in cold water has been reported.
Familial cold urticaria is a rare autosomal dominant
condition with onset at an early age.84,85 A mutation in
the gene responsible for the cold-induced autoinflammatory syndrome-1 (CIAS1) has been identified.85
Urticaria develops when the patient is exposed to
generalized cooling, particularly chilling wind, rather
than local cold application. The delayed type of familial cold urticaria is characterized by localized angioedema developing 9 to 18 hours after cold exposure.
Cold urticaria may occur in 3%4% of patients with
cryoglobulinemia, and it also may be associated with
cold agglutinins, cryofibrinogens, and cold hemolysins.
Cold urticaria has been reported in cases of infectious
mononucleosis in association with either cryoglobulins or cold agglutinins, but such occurrences are rare.
Cold urticaria may also be a sign of the MuckleWells
syndrome that associates urticaria, deafness and amyloidosis.86 In this rare genetic disorder recurrent bouts
of urticaria, fever, chills and malaise may occur from
birth and persist throughout life. Helicobacter pylori has
been suggested as a causative agent in some cases of
acquired cold urticaria.87
Diagnosis of cold urticaria is confirmed by a cold
challenge induced by an ice cube wrapped in a plastic bag placed on the skin of the forearm for periods
varying from 30 seconds to 10 minutes (see Fig. 94-11).
Wheals form on rewarming. Sometimes water at 7C
(44.6F) is more effective, presumably because it causes
less severe vasoconstriction. Peltier effect-based temperature challenge appears to be an improved method
for diagnosis.88 The Peltier effect relies on using two
different heat-transferring metals to generate a precise
skin surface temperature, sufficiently cold, to induce
lesions. The temperature is regulated by a microprocessor control unit monitoring the actual temperature
at the test site.
Cold erythema seems to be a related disorder with
erythema and pain but without urticaria. Familial polymorphous cold eruption is a rare autosomal dominant
disease characterized by childhood onset of nonpruritic,
Cold Injuries
Acquired cold urticaria is a form of physical urticaria

(Fig. 94-11). Lesions occur at sites of localized cooling, usually when the area is rewarmed. The disease is
recognized by wheal and flare-type reactions and/or
angioedema. The condition may be idiopathic or associated with some serologic abnormality.7983 It accounts for
approximately 2% of cases of urticaria (see Chapter 38).
Most cases fall into the group of essential cold urticaria. They can be subdivided into a rare familial type
and an acquired form. Immunoglobulin E and, more
rarely, immunoglobulin M have been implicated in the
pathogenesis. The antigen is likely a normal metabolite
produced on exposure to cold. Histamine is one of the
most important mediators, but leukotrienes, plateletactivating factor, and others have been incriminated.
In this disease, exposure to cold causes prolonged
Figure 94-11 Cold urticaria induced by the application of

ice to the skin.
::
COLD URTICARIA AND

POLYMORPHOUS COLD ERUPTION
17
Chapter 94
A peculiar clinical presentation may occur in young

women riding horses for several hours daily during winter.69,70 Indurated red-to-violet tender plaques
develop on the lateral calves and thighs (see Fig. 94-10C).
The condition is quite similar to the nodular perniotic
lesions described in adolescent girls with erythrocyanosis. For prophylaxis, experienced riders usually wear
baggy breeches that provide insulation and are not tight
enough to compromise the circulation.
Perniotic lesions have been described in association
with myeloproliferative disorders,71 probably as a consequence of blood flow changes, presence of cold agglutinins, and altered inflammatory response on cooling.
Idiopathic perniosis is characterized histologically
by edema of the papillary dermis and by the presence
of superficial and deep perivascular lymphocytic infiltrates. Necrotic keratinocytes and lymphocytic vasculitis also have been reported. Thickening of blood vessel
walls with intimal proliferation may lead to obliteration of the vascular lumen.7274
Chilblain lupus is a distinct disease and is similar
to discoid lupus erythematosus.75,76 Lupus pernio is a
variant of sarcoidosis (see Chapter 152) and is unrelated to cold injuries.
The unfamiliarity of physicians with chilblains sometimes gives rise to unnecessary hospital admissions
with expensive laboratory and radiologic evaluations
and, at times, hazardous therapy. The most important
point in management is prophylaxis through the use
of adequate, loose, insulating clothing and appropriate
warm housing and workplace. Maintaining the blood
circulation by avoiding immobility is also helpful. A
short course of ultraviolet light therapy at the beginning of winter was a recommendation but has been
challenged.77 Once chilblains occur, treatment is symptomatic with rest, warmth, and topical antipruritics.
Calcium channel-inhibiting drugs may be effective in
the treatment of severe recurrent perniosis,78 although
they may cause headache and flushing that are troubling to some patients. In cases of crippling severity,
thyrocalcitonin and hemodilution may be helpful.
1087
17
erythematous patches often accompanied by influenzalike symptoms and leukocytosis after generalized exposure to cold. Results of the ice cube test are negative. The
pathogenesis remains unknown. The disease frequently
has been referred to as familial cold urticaria, although the
skin lesions are not urticarial.89
Avoiding cold wind exposure and swimming in cold
water are important preventive measures. Antihistamines reduce clinical signs and symptoms. Desensitization to cold is possible by immersing one arm into
water at 15C (59F) for 5 minutes daily.
Section 17
COLD PANNICULITIS AND

RELATED ENTITIES
::
Cold injuries may affect the subcutaneous tissue in

different ways. The freezing injury in deep frostbite
results in tissue gangrene. Nonfreezing injuries also can
alter the hypodermis. Among them, cold panniculitis is
more common in children than in adults. It affects the
cheeks and legs most commonly. Tender erythematous
subcutaneous nodules appear 1 to 3 days after exposure and subside spontaneously within 2 to 3 weeks.
Ice cube challenge to the childs skin for 10 minutes
results in the development of an erythematous plaque
12 to 18 hours later.
A perivascular mixed infiltrate with neutrophils,
lymphocytes, and histiocytes is present at the dermal
subcutaneous junction after 24 hours, followed by a
well-developed panniculitis at 48 to 72 hours. Some
adipocytes are necrotic and rupture to form cystic
spaces. The reaction subsides completely in 2 weeks.
Infants have a higher content of saturated fatty acids
in adipose tissue than do adults, and this may result
in solidification at higher (less cold) temperatures.90,91
Cold panniculitis should be distinguished from other
related disorders, including erythrocyanosis with
nodules, sclerema neonatorum, and subcutaneous fat
necrosis of the newborn.
SCLEREMA NEONATORUM AND

SUBCUTANEOUS FAT NECROSIS
OF THE NEWBORN
1088

Sclerema neonatorum and subcutaneous fat necrosis of the newborn are distinct disorders involving
the subcutaneous fat of the newborn. As noted in the
prior paragraph, infant fat differs from adult fat in that
it has a higher saturatedunsaturated fatty acid ratio,
which results in solidification at a higher temperature.
Prematurity and immaturity of enzyme systems may
result in a relative inability to desaturate fatty acids,
which alters the ratio further. Sepsis, dehydration,
chilling, infection, and other stresses also may inhibit
the enzyme system. Thus, infants in general, and premature or otherwise compromised newborns in particular, are susceptible to such disorders.
Sclerema neonatorum is a rare disorder characterized by diffuse, rapidly spreading hardening of the
skin and subcutaneous tissue in infants.92 It starts on
the buttocks and trunk, usually in the first week of life.
Palms, soles, and scrotum are spared. Fifty percent of
affected infants are premature. They have difficulty
feeding and are lethargic, and many are otherwise
debilitated. Septicemia is frequent, and the prognosis
is poor. Cold exposure does not seem to be important
in the etiology of sclerema neonatorum; however, similar clinical findings have been seen in cases of primary
cold injury.93 Histologically, the subcutaneous layer
is greatly thickened by enlarged fat cells and wide,
fibrous bands. There is no fat necrosis, and many of the
fat cells contain fine needle-like clefts.94
Treatment of sclerema neonatorum involves correcting dehydration and electrolyte imbalance and
treating septicemia if present. The value of systemic
glucocorticoids is controversial. Successful treatment
with exchange transfusions has been reported.95
Subcutaneous fat necrosis of the newborn is characterized by discrete red to violaceous mobile plaques
and nodules that usually appear within a few days
of birth. The back, thighs, and cheeks are most commonly affected. Fat necrosis and crystallization are the
hallmarks of the disease. There may be a granulomatous inflammatory response with foci of calcification.
In most cases, the condition is benign and self-limited,
although it has been associated with hypercalcemia
and death.96
As in sclerema neonatorum, there is no clear etiologic
relationship to cold, and the cause is likely multifactorial. It has been postulated that an underlying defect
in fat composition, poor nutrition, and various physical
stresses such as hypothermia may be important.
ERYTHROMELALGIA
Erythromelalgia or erythermalgia is a rare chronic
cutaneous disorder characterized by erythema, burning discomfort, and warmth of the extremities.97,98
Primary erythromelalgia is an autosomal dominant
neuropathic disorder involving a mutation in a voltage-gated sodium channel subunit.99106 Vasoconstriction apparently precedes reactive hyperemia, similar
to that seen in Raynaud phenomenon. An early-onset
type and an adult-onset type have been recognized.
When the extremity is lowered or heat is applied, the
pain is intensified. The application of cold or elevation
of the extremity has the opposite effect of decreasing the pain. Idiopathic erythromelalgia may involve
increased thermoregulatory arteriovenous shunt flow.
Secondary erythromelalgia is associated commonly
with myeloproliferative syndrome-related thrombocythemia and is mostly evident in the adult-onset type.
Treatment for adults with erythromelalgia includes
a single daily dose of acetylsalicylic acid (aspirin), but
children who have no associated underlying disorder
obtain little to no relief from the drug. Other drugs
including mexiletine107 and venlafaxine108 may also
help. Pain may be decreased by topical amitriptyline
combined with ketamine.109 Lidocaine in patches110 or
administered intravenously in combination with oral

mexiletine111 may also alleviate pain. Sympathectomy
in the upper extremities is another option for treating
refractory primary erythromelalgia.112
RAYNAUD PHENOMENON
(See Chapter 170)
CRYOGLOBULINEMIA
LIVEDO RETICULARIS

22. Long WB 3rd et al: Cold injuries. J Long Term Eff Med Implants 15:67, 2005
32. Middleton JB, Allen BM: The influence of temperature
and humidity on stratum corneum and its relation to skin
chapping. J Soc Cosmet Chem 24:239, 1974
33. Pirard-Franchimont C, Pirard GE: Beyond a glimpse at
seasonal dry skin: A review. Exog Dermatol 1:3, 2002
46. Daanen HA, van der Struijs NR: Resistance index of frostbite as a predictor of cold injury in arctic operations. Aviat
Space Environ Med 76:1119, 2005
83. Buss YL, Sticherling M: Cold urticaria; disease course and
outcome An investigation of 85 patients before and after
therapy. Br J Dermatol 153:440, 2005
91. Quesada-Corts A et al: Cold panniculitis. Dermatol Clin
26:485, 2008
98. Davis MD, Rooke T: Erythromelalgia. Curr Treat Options
Cardiovasc Med 8:153, 2006
Serious burns require inpatient care, ideally

in a verified burn center.
jobs are at modest increased risk. In developed countries, about 70% of pediatric burns are caused by hot
liquid. Flame injuries are more common in older children and young working adults. Scalding and flame
injuries each account for approximately half of burn
injuries in the elderly, with kitchen and bathing accidents being predominant. Approximately 20% of
burns in younger children involve abuse or neglect.
Large burns are managed in four general

phases:
THERMAL INJURIES AT A GLANCE

Burns are common; most are small and
managed in the outpatient setting.
Initial evaluation and resuscitation.

Wound excision and biologic closure.
Definitive wound closure.
Rehabilitation and reconstruction.
Styles of outpatient burn care are variable,
but proper patient selection and monitored
wound healing are essential.
Long-term outcome quality tends to be very
good in patients surviving large burns.
EPIDEMIOLOGY
The very young and very old are at increased risk of
domestic burns.1,2 Active young adults in industrial
The development of an envelope of cornified skin was

a crucial component of the adaptation of aquatic sea
animals to the land environment. The vapor and fluid
barrier created by the epidermal layer facilitates the
maintenance of fluid and electrolyte homeostasis within
very narrow limits. The dermis provides strength and
flexibility, and the reactive dermal vasculature facilitates control of internal body temperature within very
narrow limits. The appendages provide lubrication and
prevent desiccation. All of these critical functions are
lost when substantial areas of the skin are burned.
There is both a local and a systemic response to the
burn wound.3,4 The local response consists of coagulation of tissue with progressive thrombosis of surrounding vessels in the zone of stasis over the first 1248
postinjury hours. An ability to truncate this secondary
microvascular injury and its associated tissue loss is a
major area of ongoing investigation. In larger burns, a
systemic response develops that is driven initially by
release of mediators from the injured tissue, with a secondary diffuse loss of capillary integrity and accelerated
Thermal Injuries
Chapter 95 :: Thermal Injuries

:: Robert L. Sheridan
::
(See Chapter 173)
17
Chapter 95
(See Chapter 169)
KEY REFERENCES
1089
17
Section 17
::
1090
transeschar fluid losses. This systemic response is

subsequently fueled by by-products of bacterial overgrowth within the devitalized eschar.
Burn wounds are initially clean but are rapidly
colonized by endogenous and exogenous bacteria.5
As bacteria multiply within the eschar over the days
following injury, proteases result in eschar liquefaction and separation. This leaves a bed of granulation
tissue or healing burn, depending on the depth of the
original injury. In patients with large wounds involving 40% or more of the body surface, the infectious
challenge generally cannot be localized by the immune
system, leading to systemic infection. This explains the
rare survival of patients managed in an expectant fashion with burns of this size.
The systemic response to injury is characterized clinically by fever, a hyperdynamic circulatory
state, increased metabolic rate, and muscle catabolism.6 This stereotypical response to injury has been
retained by all mammalian species. It is effected by
a complex cascade of mediators, including changes
in hypothalamic function resulting in increases in
glucagon, cortisol, and catecholamine secretions;
deficient gastrointestinal barrier function with translocation of bacteria and their by-products into the
systemic circulation; bacterial contamination of the
burn wound with systemic release of bacteria and
bacterial by-products; and some element of enhanced
heat loss via transeschar evaporation. It is likely that
this response has significant survival value, but control of some of the adverse aspects of this response,
particularly muscle catabolism, is an active area of
ongoing investigation.7,8
Box 95-1 Essentials of Burn

Management
Burn size, extent, depth, and circumferential components influence decisions regarding outpatient
care, hospitalization or transfer.
Burn extent is best estimated using the Lund
Browder diagram that compensates for the changes
in body proportions with age (see eFig. 95-4.1 in
online edition). An alternative is a rule-of-nines for
adults and children (see eFig 95-5.1 in online edition).
In the adult rule-of-nines, the head and neck is
given 9%, each lower extremity is given 18%, each
upper extremity is given 9%, and the anterior and
posterior torso are each given 18%.
In the pediatric rule-of-nines, the head and neck is
given 18%, each lower extremity is given 15%, each
upper extremity is given 10%, and the anterior and
posterior torso are each given 16%.
For scattered or irregular burns, the entire palmar
surface of the patients hand represents approximately 1% of the body surface over all ages.
CLINICAL FINDINGS
(See Box 95-1)
Burns are classified by depth:

First degree: Red, dry, and painful and are often

deeper than they appear, sloughing the next day
(Fig. 95-1A).
Second degree: Red, wet, and very painful with
enormous variability in their depth, ability to heal,
and propensity to hypertrophic scar formation (see
Fig. 95-1B).
Figure 95-1 Burn depth is classified as first, second, third,

or fourth degree. A. First-degree burns are red, dry and
painful and are often deeper than they appear, sloughing the next day. B. Second-degree burns are red, wet
and very painful. There is an enormous variability in their
depth, ability to heal, and propensity to hypertrophic scar
formation. C. Third-degree burns are leathery, dry, insensate, and waxy. D. Fourth-degree burns involve underlying
bone and/or muscle.
Third degree: Leathery, dry, insensate, and waxy

(see Fig. 95-1C).
Fourth degree: Involve underlying subcutaneous
tissue, tendon, or bone (see Fig. 95-1D).
Circumferential burns require special monitoring

and possible surgical decompression. If across the torso,
they will interfere with ventilation. If they involve an
extremity, limb-threatening ischemia may occur during
resuscitation.
LIGHTNING STRIKES
17
Burn Wound Complications

Common Outpatient Burn Complications
Wound sepsis, usually streptococcal cellulitis
Excessive pain and anxiety
Underestimation of burn depth
Thermal Injuries
unusual. Serious injury is more often the result of

associated blunt trauma or occasional cardiac arrest.
In most survivors, lingering symptoms are nonfocal,
neurologic in nature, often preceded by an immediate
but transient loss of consciousness.9 The most common
physical finding in those injured by side flash is an
evanescent serpiginous cutaneous erythema, as noted
in Figure 95-2.
::
Common Inpatient Burn Complications

Wound sepsis, often invasive
Septic shock and organ failures
Inadequately controlled pain and anxiety
Compartment syndromes
Ocular exposure
Respiratory failure
Gut failure
Pancreatitis
Cholecystitis
Urosepsis
Donor site infection
Soft-tissue contractures
Chapter 95
Although lightning strikes carry large amounts of

energy, measured in millions of volts, human injuries
are rare, with only about 50 people so injured annually
in the United States and a fatality rate of only about
10%. Injury can rarely occur from direct strike, and is
usually fatal. More commonly, people are injured by
current flow around the skin envelope, or side flash,
when a nearby object is struck. Destructive burns are
TABLE 95-1
COMPLICATIONS
Figure 95-2 (A and B) An evanescent serpiginous cutaneous erythema is characteristic of lightning injury.
In the outpatient setting, patient selection should ensure

that major complications are few (Table 95-1). The most
common issues that arise are wound sepsis, excessive
pain and anxiety, and underestimation of burn depth.10
The most common wound infection in this setting is
streptococcal cellulitis, which presents initially with
surrounding erythema that progresses to lymphangitis and systemic toxicity (Fig. 95-3). These patients
often need admission for antibiotics, observation, and
sometimes surgery. In some situations, adequate pain
and anxiety management is very difficult in the outpatient setting, especially around dressing changes. This
can be addressed with judicious medication and sometimes carefully monitored membrane dressings. Some
patients will require admission. It is common for burn
depth to be underestimated initially, with areas of fullthickness injury not appreciated for several days. These
patients may require admission for surgery.
As burns increase in size and depth, the local injury
is accompanied by an increasing degree of systemic
derangement. Classically, this response has two phases.
An initial ebb phase of reduced perfusion and metabolic rate, which lasts 2448 hours, is followed by a
flow phase of protein catabolism and a hyperdynamic circulation.11 This later phase lasts until well after
wound closure. Management of this physiology is an
essential part of inpatient burn care. Those with large
burns are susceptible to a host of other complications
1091
17
Section 17
::
1092
Figure 95-3 The most common wound infection in this

setting is streptococcal cellulitis, which presents initially
with surrounding erythema that progresses to lymphangitis and systemic toxicity.
related to sepsis and organ failure. Careful monitoring
and early intervention are essential to successful outcomes (Table 95-1).

COURSE
PATIENT EVALUATION AND
TREATMENT PLANNING
In both outpatient and inpatient settings, a careful
evaluation of the patient is essential for treatment planning. Patient evaluation is organized into a primary
and a secondary survey, following the guidelines of the
American College of Surgeons Committee on Trauma
and the Advanced Burn Life Support Course of the
American Burn Association. As in trauma, the primary
survey begins with an assessment, and control if necessary, of the airway. Deeper burns of the face and neck
can result in progressive airway edema. Occasionally, a
child will aspirate hot liquids resulting in very severe
upper airway edema mandating urgent intubation.
A burn-specific survey evaluates the issues uniquely
associated with burn injury (eTable 95-1.1 in online edition). This may take just a few seconds if the burn is
small, but will be much more time consuming in the
more seriously injured.12 In those with small injuries,
essentials include a detailed determination of the
mechanism of injury, a screen for associated trauma,
consideration of the possibility of abuse (Fig. 95-4),
and a detailed assessment of the burn wound. Delayed
presentation for care, confusing stories, sharply demarcated margins, immersion patterns, and contact injuries
are physical findings suggesting for abuse or neglect.13
All such children should be admitted for evaluation.
After the patient has been evaluated, the burn wound
should be examined for size, extent, depth, and circumferential components.14 Burn extent is best estimated
using a chart based on the LundBrowder diagram that
Figure 95-4 Some burn patterns are very suggestive of

possible abuse. Here is illustrated flexor sparing in an immersion injury.
compensates for the changes in body proportions with
age (eFig. 95-4.1 in online edition). An alternative is a
modified rule-of-nines, in which the head and neck is
given 18% (instead of the adult 9%), each lower extremity is given 15% (instead of the adult 18%), each upper
extremity is given 10% (instead of the adult 9%), and the
anterior and posterior torso are each given 16% (instead
of the adult 18%). For scattered or irregular burns, the
entire palmar surface of the patients hand represents
approximately 1% of the body surface over all ages.
Burn depth is classified as first, second, third, or
fourth degree (Fig. 95-1AD). First-degree burns are red,
dry and painful and are often deeper than they appear,
sloughing the next day. Second-degree burns are red,
wet and very painful. There is an enormous variability
in their depth, ability to heal, and propensity to hypertrophic scar formation. Third-degree burns are leathery,
dry, insensate, and waxy. Fourth-degree burns involve
underlying subcutaneous tissue, tendon, or bone.
Near or completely circumferential burns should be
identified for special monitoring, as they may need to
be decompressed in the hours following injury to avoid
ischemia (extremities) or failure of ventilation (torso).
The majority of burns can be successfully managed
in the outpatient setting. However, poorly provided
outpatient burn care can be frustrating and painful for
patients and providers. The key is careful patient selection (eTable 95-1.2 in online edition) and a detailed care
plan, especially an inpatient care plan (eTable 95-1.3 in
online edition).
PATIENT OUTCOMES
Burn wounds and grafts typically develop some degree
of hypertrophic scarring.15 This involves a gradual
increase in vascularity and collagen deposition in the
months following healing. Some wounds will demonstrate significant contracture formation, with important
functional and esthetic consequences (Fig. 95-5). Many
patients will have bothersome pruritus and sometimes temporary neuropathic pain if burns are deep. A
17
Chapter 95
::
Figure 95-5 Hypertrophic scarring and contracture formation can become difficult problems
after serious burns (A), but are often amenable to surgical improvement (B).
long-term follow-up plan, consisting of scar management strategies, rehabilitation, reconstructive surgery,
and emotional support will facilitate optimal outcomes.
This care is best provided in a multidisciplinary burn
clinic, ideally part of a comprehensive burn program.
With such supports in place, the long-term outcome for
most patients is surprisingly good. When managed in
a comprehensive follow-up program, even those who
have suffered devastating burns tend to become happy
and productive again.16,17
TREATMENT
OUTPATIENT BURNS
Practice patterns vary widely, but certain characteristics are universal.18 The wound should be kept
generally clean and regularly inspected for infection.
Desiccated exudates and topical medications should
be periodically cleansed. Burns selected for outpatient
management tend to be small and superficial with a
corresponding low risk of infection, so clean rather
than sterile technique is reasonable. If topical agents
rather than membrane dressings are used, wounds
may be cleansed with lukewarm tap water and a bland
soap. Soaking adherent dressings prior to removal will
decrease the pain associated with daily wound care.
The wound is gently cleansed with a gauze or clean
washcloth, inspected for any sign of infection, patted
dry with a clean towel and redressed. It is important to
instruct each patient to return promptly if they notice
Thermal Injuries
erythema, swelling, increased tenderness, lymphangitis, odor, or drainage so that infectious complications
can be addressed early. Most small burns are adequately managed with a daily cleansing and dressing
change. In some cases, a membrane dressing is applied
once it is clear that early surgery is not needed, early
infection is unlikely, and wounds are superficial. Pain
and anxiety can be an issue for many. Some will benefit from an oral narcotic given 3060 minutes prior to
a planned dressing change. If dressings are occlusive,
pain between dressing changes tends to be modest.
Increasing pain and anxiety associated with dressing changes; inability to keep scheduled follow-up
appointments; delayed healing; signs of infection or a
wound, which appears deeper than appreciated at the
time of the initial examination, should prompt early
return and specialty evaluation. Wounds selected for
outpatient management are usually fairly superficial
and heal within two weeks, but patients with mid and
deep dermal injuries may have a deeper component
with resulting scarring that may benefit from specialty
evaluation. Finally, wounds of the face, ears, hands,
genitals, and feet have functional and cosmetic importance out of proportion to their wound size. In some
cases, early specialty evaluation may be prudent, as
initial care can have an impact on long-term outcome.19
INPATIENT BURNS
A system of burn center verification has evolved
to ensure that the patients requiring care of more
1093
17
serious injuries receive coordinated efforts by experienced providers. Burn center referral criteria can be
found at www.ameriburn.org (eTable 95-1.4 in online
edition). Care of severe burns can be divided into phases,
each with important objectives (eTable 95-1.3 in online
edition).20 Critical care is an important component, especially in the first three phases. Verified burn programs
are required to have embedded burn intensive care units.
TOPICAL MEDICATIONS AND

MEMBRANES
Section 17
::
1094
There is an increasingly confusing array of wound

medications and membranes available for burn
wounds. Wound medications and membranes provide
three benefits: (1) pain control, (2) prevention of wound
desiccation, and (3) reduction of wound colonization.
Topical wound medications range from aqueous
solutions through antibiotic-containing ointments and
debriding enzymes. Most topical agents in outpatient
use have a viscous carrier that prevents wound desiccation and a more or less broad antibacterial spectrum that
reduces wound colonization. A gauze wrap minimizes
soiling of clothing and protects the wound from trauma.
Silver sulfadiazine is in common use because it is painless on application and has a broad spectrum of antibacterial activity. Superficial burns are commonly treated
with a clear, viscous antibacterial ointment containing low concentrations of various antibiotics. Wounds
around the eyes can be treated with topical ophthalmic
antibiotic ointments. Significant ear burns should be
treated with mafenide acetate, as it is the only agent that
will penetrate the relatively avascular cartilage.
Wound membranes provide transient physiologic
wound closure while the underlying wound heals.21
Physiologic closure implies a degree of protection from
mechanical trauma, vapor transmission characteristics
similar to skin, and a physical barrier to bacteria. The
major benefit of wound membranes is that, when successful, they minimize wound manipulations. These
membranes help create a moist wound environment
with a low bacterial density and are generally intended
for use on selected clean superficial wounds and donor
sites. Occlusive synthetic membranes must be used
with caution if wounds are not clearly clean and superficial, as submembrane infection can occur, deepening
underlying wounds and causing systemic infection
and toxicity.
PREVENTION
There have been a plethora of burn prevention efforts,
which have met with mixed success. They can be
based on (1) public education, (2) legislation, or (3)
engineering.22 Public education campaigns depend for
their success on an educated literate community. The
stop, drop, and roll campaign in elementary schools
is an excellent example. Legislation is often more effective. Examples include safe factory set points for home
water-heaters and flammability standards for childrens bedclothes. Engineering solutions are perhaps
the most effective. Examples are common in industry,
and include physical isolation of high-power lines
and child-proof cigarette lighters. Often all the three
are combined, a current example being the fire-safe
cigarette. A self-extinguishing cigarette has been engineered and, in some places, its sale is mandated after
public education influenced the legislative process.
KEY REFERENCES
1. Fagenholz PJ et al: National study of Emergency Department visits for burn injuries, 1993 to 2004. J Burn Care Res
28(5):681-690, 2007
10. Sheridan R: Outpatient burn care in the emergency department. Pediatr Emerg Care 21(7):449-656, 2005
12. Sheridan RL: Comprehensive management of burns. Curr
Probl Surg 38(9):641-756, 2001
13. Chester DL et al: Non-accidental burns in childrenAre
we neglecting neglect? Burns 32(2):222-228, 2006
14. Sheridan RL: Evaluating and managing burn wounds.
Dermatol Nurs 12(1):17-31, 2000
16. Sheridan RL et al: Longterm outcome of children surviving massive burns. JAMA 283(1):69-73, 2000
20. Sheridan RL: Burn care: Results of technical and organizational progress. JAMA 290(6):719-722, 2003
17
Chapter 96 :: Skin Problems in Amputees

:: Calum C. Lyon & Michael H. Beck
SKIN PROBLEMS OF AMPUTEES
AT A GLANCE
Skin problems under limb prosthesis result
from:
Trauma.
Pressure.
Occlusion and maceration.
Irritant and allergic contact dermatitis occurs

due to materials applied to skin, worn, or
used in construction of the prosthesis.
Koebner phenomenon may occur in skin
under prosthesis.
Management: most important are basic
hygiene measures.
Early medical intervention and collaboration
with prosthetist are essential to address
problems.
The skin of an amputation stump is not designed to

withstand the physical insults it encounters within a
prosthetic limb. For example, although some adaptation to friction or pressure occurs, some skin problems
are inevitable. If these dermatoses cannot be prevented
or rapidly resolved by prosthesis adjustment or medical
intervention, they can incapacitate the patient, particularly those who have lower limb, weight-bearing prostheses. As a result, patients may suffer social isolation,
Skin Problems in Amputees
Microclimate under prosthesis promotes

bacterial and fungal infections.
DERMATOLOGIC PROBLEMS IN
AMPUTEES
::
Physical trauma, disturbances of tissue fluid

dynamics may cause other distinctive skin
changes.
Chapter 96
Heat.
either a butyl rubber sleeve or corset to hold the appliance firmly onto the thigh (Fig. 96-2). Many patients
with above-knee amputations now use a suction socket
device that provides sufficient suspension by holding
the prosthesis in place through negative pressure without the need for additional belts (see Fig. 96-1).
Limb prostheses are the subject of continual technological development particularly in the field of bionics.
Myoelectric devices, for example, rely on skin contact
with electrodes to detect neuromuscular signals that
can be converted to artificial limb movement. Neuroprosthetic devices involve implantation of electrodes
into neural tissue usually through the skin, for example, cochlear implants. Such devices are under development for prosthetic limbs. These devices thus have
the potential for causing skin problems.
Above-knee prosthesis
TECHNICAL BACKGROUND:
LIMB PROSTHESES
In most centers, artificial limbs are constructed in a
modular fashion.1 The stump is placed in a thermoplastic socket that is then fitted into the main body of
the limb. The bulk of the prosthesis comprises a metal
frame with articulations and an outer casing of acrylic
resin or carbon composite material. Before fitting
the limb, many patients place their stump in a liner
designed to reduce friction on the skin. This may be
an expanded plastic cup, a silicon/mineral oil sleeve,
or a cotton or nylon sock. The prosthetic limb, once fitted, is held in position by one of a range of suspension
elements. In above-knee (Fig. 96-1) or proximal arm
amputations, this is usually a fabric belt arrangement
worn around the waist or shoulders, respectively.
Below-knee amputees require a different system using
Figure 96-1 Above-knee

prosthesis.
prosthesis.
Suction-socket
1095
17
Below-knee prosthesis
used, and peripheral vascular disease.4 A more recent

questionnaire-based study of 805 lower limb amputees5 suggests that the factors more likely to be associated with skin problems are, smoking, younger age,
female sex, washing the stump frequently and the use
of antibacterial soaps. Overall one-third of amputees,
either upper or lower limb, experiences a skin problem
that significantly interferes with the normal use of the
artificial limb.6
DERMATOSES RELATED TO THE

REASONS FOR AMPUTATION
Section 17
::
Figure 96-2 Below-knee prosthesis. Patellar tendonbearing cuff suspension.

emotional distress, or even financial deprivation if they
are unable to work.
Skin problems may occur because of allergy or
chemical irritation to materials in contact with the
skin, as well as from trauma and occlusion. Examples
of physical stresses on the skin include shearing and
friction from elements in the socket and pressure on
load-bearing areas, especially on the tibial tuberosity
in below-knee amputations and the ischial tuberosity,
adductor region, or groin in above-knee amputations.
In all cases, the occlusion results in increased humidity
from trapped perspiration, increasing the likelihood of
irritation, allergy, and infection.
The common skin disorders in amputation stumps
can be classified into diseases related to the reasons for
the amputation, physical effects of a prosthesis, infection, contact dermatitis, and other cutaneous disorders.
EPIDEMIOLOGY
1096
The great majority of artificial limb wearers are amputees, although a small proportion are people with congenital limb malformations. Lower limb amputees are
the most numerous and are also the group at greatest
risk of skin problems. Traumatic amputations are possibly more likely to be associated with a dermatosis2
although the commonest problems encountered are
the same as for all amputees.3 Modern limb prostheses
allow many of todays amputees to lead an active life
with good mobility. Nevertheless, as many as 73% of
one cohort of lower limb amputees reported at least
one skin disorder.2 In a further group of 745 lower leg
amputees, 40.7% had at least one skin problem. Further
analysis identified four factors independently associated with dermatologic disorders, namely transtibial
amputation, employment status, type of walking aid
Several disorders resulting in the need for amputation

can have a significant impact on skin integrity. In general, younger patients require artificial limbs because
of traumatic amputations, congenital abnormalities, or
malignancy, whereas in the older age group, arterial
disease and vascular complications of diabetes mellitus predominate. Amputations after trauma or severe
vasculitis may be associated with scarring that makes
for a suboptimal prosthesis fit (Fig. 96-3). Stump dermatoses appear to be more likely in patients following
traumatic amputations. Koc et al2 found a skin problem
in nearly three quarters of amputees most of whom
had lost a limb as a consequence of mine explosions.
The nature of current conflicts means that, presently,
such amputations are unfortunately common amongst
both service personnel and civilians. Vasculitis resulting in amputation may be ongoing and cause problems
in the skin of amputation stumps (Fig. 96-4). However,
it is diabetes mellitus that is particularly associated
with protracted skin problems (Chapter 151) as a result
of impaired wound healing, susceptibility to infection,
abnormal sensory nerve function, and disruption of
normal tissue fluid balance.7 Diabetic amputees as a
group require more frequent clinical review to prevent complications. Treatment of the diabetic amputee
not only requires good control of the blood glucose
level but possibly a change of the stump environment
through adjustment or redesign of the artificial limb.
The diabetic amputee highlights the need for close
links with a prosthetics department, which allow rapid
referral of patients for assessment.
Figure 96-3 Scarring of the stump after amputation for

severe postinfective vasculitis.
17
Chapter 96
::
Figure 96-4 Patient with vasculitis resulting in ischemia (A) that required amputation (BC). This recurred on the amputation stump (D) but fortunately responded to systemic therapy.
PHYSICAL DERMATOSES
The physical effects of wearing a prosthesis are the
most common causes of skin problems.6,8 These can
be divided into those resulting from repeated direct
trauma and those secondary to disturbance of tissue
fluid dynamics.
DIRECT PHYSICAL TRAUMA

Ulceration. Ulceration and callus
formation are
seen where there is chronic pressure or repeated frictional forces on stump skin. Ulceration may also be
caused by infection or poor cutaneous nutrition, particularly secondary to diabetes mellitus (Figs. 96-5 and
96-6). Stump ulcers should be treated early as malignancy may develop in long-standing ulceration.9 With
repeated infection and ulceration, an amputation scar

on the distal stump skin can erode further. In some
cases, the skin may become completely adherent to
bone and develop thick, callus-like hyperkeratosis
(Fig. 96-7), which may necessitate revision of the distal bony surface. Ulceration or other injuries incurred
while putting on artificial limb components may be
particularly associated with poor manual dexterity consequent on neurological disorders or arthritic
changes.10,11 Incorrect use of some appliance components can also result in injury.12 Patient selection and
access to follow-up advice is therefore important in
reducing such injuries. Apparently spontaneous ulceration at unexpected sites is occasionally seen (Fig.
96-8). In every instance, the cause of the ulceration
must be determined to resolve a chronic process that
can become totally disabling. However, a recent study
1097
17
Section 17
::
1098
Figure 96-5 Chronic ulcer of stump skin.

examining 102 patients over 4 years suggests that the
majority of patients with delayed wound healing or
secondary ulcers will experience healing despite continuing to use their prosthesis, provided they are carefully monitored.13
Figure 96-7 Chronic ulceration resulting in thick hyperkeratosis and scab formation adherent to the underlying
bone.
Epidermoid Cysts and Follicular Keratoses.
invagination of keratin around hair follicles, which

then results in a foreign-body reaction. Follicular keratoses are therefore the earliest changes.14 These are
very common, often multiple, and distributed at sites
of weight bearing such as the anterior tibial area, popliteal fossa, and the adductor or inguinal areas of the
thigh (Fig. 96-9A). Fortunately, they cause little trouble
in many cases, but they can become inflamed and painful particularly if the patient picks at them to extract
Figure 96-6 Ulceration associated with infection in a diabetic man with an amputation for ischemia.
Figure 96-8 Ulceration in a patient receiving nicorandil

for angina. The ulcer appeared spontaneously and not at a
site of friction. It resolved slowly over 3 months after nicorandil was stopped suggesting the drug may have been
involved.
Physical Dermatitis. In some patients, eczema

may be caused by a poorly fitted or misaligned prosthesis or by edema and congestion of the terminal
portion of the stump; only with alleviation of these
problems does the condition clear.
Epidermoid cysts and follicular keratoses are two ends
of a spectrum of the same disorder. Repeated pressure and friction from the prosthesis appears to cause
17
Chapter 96
::
the keratin plug or if they become infected. Inflamed

follicular keratoses can have an acneiform appearance,
leading some to suggest that they represent a form of
acne mechanica. When the continued pressure and
friction causes the keratin to extend deeper into the
dermis, larger cystic lesions, 13 cm in diameter, form;
these are commonly termed posttraumatic epidermoid
cysts. Meulenbelt et al15 described a case of follicular
keratoses of a transfemoral amputation stump in a
patient who did wear an appliance at all. These lesions
recurred after resection and were associated with
retention of vellus hairs. This raises the possibility that,
in some individuals, mechanisms other than just friction may be involved. Deeper cysts can be very tender
when compressed by the prosthesis. Some cysts have
an obvious punctum and patients may express keratinous material from them. Large cysts can be so painful
that the patient can no longer wear a weight-bearing
prosthesis each day (see Fig. 96-9B and 96-9C). Distention of the overlying epidermis can occur, followed by
spontaneous rupture. A serous, purulent, or hemorrhagic fluid is then discharged. The resulting sinus is
difficult to occlude and the discharge continues as long
as the prosthesis is worn. Intercommunicating sinuses
can appear and spontaneous ruptures may occur.

In advanced cases, a granulomatous reaction occurs
around the cyst with considerable capillary dilation,
vascularization, and a heavy inflammatory infiltrate
progressing to abscess formation (see Fig. 96-9B).
Management of this condition can be difficult.
Clearly, prevention is the ideal but is not always possible despite regular prosthetic assessments. The fit of
the prosthesis is the single most important method of
preventing cyst formation. The problem can sometimes
be improved or successfully eliminated by proper fitting and aligning of the prosthesis and continued
adjustment by the prosthetist. Rough surfaces in areas
of increased contact pressure in the socket, particularly
the suction socket, tend to catch the skin, increasing the
shearing forces. For this reason, the lining of the socket
should be kept smooth. With the idea of inserting a buffer between the skin and the socket, protective devices
such as liners and stump socks are used. Various synthetic films and adhesives, such as Teflon, have been
found satisfactory as liners. They allow for a smooth,
gliding action of the prosthetic socket wall or brim
against the skin. Applying a vapor-permeable adhesive
membrane to the skin before fitting the appliance can
Figure 96-9 Epidermoid cysts in different stages. A. Early follicular keratoses in the popliteal fossa of a man with belowknee amputation. B. Hemorrhagic and inflamed large epidermoid abscess in a man with an above-knee prosthesis. Note
the follicular hyperkeratosis. C. Inflamed epidermoid cysts in
the groin of a man with an above-knee prosthesis.
1099
17
Section 17
::
also help reduce frictional trauma. Topical glucocorticoids can be used at night to reduce inflammation and
provide symptomatic relief. Intralesional injection of
glucocorticoids into the cysts and their channels also
results in temporary improvement.
Surgical intervention is useful in cases with a few
lesions that are not infected. Lesions can be surgically
incised and drained. In other instances, removal of the
prosthesis is sufficient to cause the lesion to involute,
provided that the cyst has not become too large. However, spontaneous rupture, incision, and drainage, and
even spontaneous resorption of the lesion are of only
temporary benefit. When the prosthesis is worn again,
these cysts can recur so that surgical excision is not
always the treatment of choice, especially in continually rubbed areas.
In selected cases, systemic retinoid therapy may be
appropriate to minimize hyperkeratosis. One author
found oral isotretinoin to be effective in a patient
described as having acne mechanica.16
DISTURBANCES OF TISSUE FLUID

DYNAMICS
Edema. Amputation of a lower extremity greatly dis-
turbs the normal pattern of blood and lymph channels,

as well as the relationship of pressure both inside the
vessels and in the surrounding tissues of the stump. An
important feature of care during convalescence after
amputation is the reduction of edema and stabilization
of new circulatory patterns in the stump. Swelling can
be partially prevented by gradual compression of the
stump tissues with an elastic bandage or shrinker
sock before fitting the prosthesis and socket.
When an amputee begins to wear a suction-socket
prosthesis, the skin must adapt to an entirely new environment. The patient can expect edema, reactive hyperemia for days or weeks, a reddish-brown pigmentation
resulting from capillary hemorrhage, and, occasionally,
serous exudation and crusting of the skin of the distal portion of the stump. These changes are relatively
innocuous, usually short lived, and do not usually
require therapy.
The extent to which edema may persist or recur in
the healed stump depends on many factors.17 Edematous portions of the skin of the distal part of the stump
may become pinched and strangulated within the
socket (Fig. 96-10). Such areas may ulcerate if they
catch in the spring-valve opening and become gangrenous as a result of the impaired blood supply. Therapy
includes eliminating all mechanical factors contributing to the edema, such as choking by the socket, poor
fitting, and misalignment. Excessive negative pressure in a suction-socket prosthesis also contributes to
circulatory congestion and edema. Treatment should
be directed toward better support of the distal soft
tissues. Occasional use of an oral diuretic sometimes
allows the edema to resolve.
Verrucous Hyperplasia.
1100
Verrucous hyperplasia
refers to a reactive hyperplastic condition, characterized morphologically by numerous, coalescent
warty papules (Fig. 96-11). It occurs when the chronic
Figure 96-10 Dependent edema/early verrucous hyperplasia in a man with multiple amputations after severe peripheral vasculitis and necrosis.
pressure effects of a poor prosthetic fit disrupt vascular and lymphatic channels, resulting in chronic
tissue edema. The same appearance is seen around
longstanding leg ulcers where there is an element of
lymphedema (see Chapter 174). Histologic examination can show evidence of pseudoepitheliomatous
hyperplasia, although the condition itself is benign
and potentially reversible. However, in neglected
cases, malignant change can occasionally occur (see
Fig. 96-11C). Bacterial infection may play a role in the
development of pseudoverrucous hyperplasia, as secondary mixed flora infections are common because of
the poor superficial blood flow and the convoluted
surface (Fig. 96-12). External compression is the best
method of treatment, in combination with topical control of bacterial infection. In below-knee amputees,
the distal part of the stump is edematous; the stump
dangles freely in the socket or has no distal support or
partial end-bearing. When the stump end is supported
in the socket by a temporary cushion or platform,
compression gradually reduces and slowly clears the
verrucous condition. The greater the compression on
the distal stump, the more immediate and lasting is
the improvement. The use of compression bandaging, shrinker socks and other pads, and partial endbearing all have a definite place in therapy and can be
skillfully applied by the prosthetist. Short courses of
oral diuretics may be indicated to reduce edema of the
stump. The medication can be gradually decreased
when the stump and its skin return to normal.
Acroangiodermatitis. Acroangiodermatitis
occurs when the chronic pressure changes result in vessel proliferation in the upper- and middermis. There is
also extravasation of red blood cells and these features
combine to give a purplish hue to the papules and
plaques that appear on a background of edematous
skin. The appearance may mimic Kaposi sarcoma.18
Some authors suggest that acroangiodermatitis occurs
in above-knee amputees who use a suction socket prosthesis that exerts negative pressure.19 However, there
are reports of acroangiodermatitis in below-knee amputees,20 and the same condition is seen in chronic venous
insufficiency and in the patients with arteriovenous
17
Chapter 96
::
shunts (acroangiodermatitis of Mali). Management of

this condition is the same as for stump edema and verrucous hyperplasia.
BACTERIAL AND FUNGAL INFECTIONS

The bacterial flora of amputation stumps have been
examined in small groups of patients,21,22 and the most
common species encountered are Staphylococcus epidermidis, S. aureus, and Streptococcus sp. (see Chapter 176).
The moist, occluded environment under a prosthesis
is ideal for fungal and bacterial growth so that minor
skin infections occur fairly frequently. In one study, S.
aureus folliculitis or Trichophyton rubrum infection was
identified in 3% of the study population.6 Infections
are more common during hot weather and in those
amputees who pay insufficient attention to stump
hygiene, partly because in these situations the skin
becomes macerated more readily and follicular infec-
Figure 96-11 Verrucous hyperplasia of the distal stump

skin. A. Before compression therapy. B. Total resolution
after compression therapy. C. Malignant degeneration into
squamous cell carcinoma.
tions become more likely. Although folliculitis (Fig.
96-13) and furuncles are more common, superficial
infections of the skin itself may also occur (see Chapter
176). Superficial dermatophyte and candidal infection
(see Chapters 188 and 189) are also common and may
be difficult to eradicate because of the ideal environment for fungal growth within a prosthesis.
The diagnosis of infection is usually obvious when
the rash extends onto skin not covered by the prosthesis. Underneath the prosthesis, any superficial infection may present as a nonspecific scaling erythema
indistinguishable from that caused, for example, by
chronic irritation. All stump rashes should be swabbed
and scraped for bacterial and fungal culture.
In the management of bacterial infections, oral
antibacterial therapy should be directed by bacterial
culture and sensitivity. Topical antiseptics or antibacterials can be used but some antiseptic preparations
can cause irritation and there is also the potential for
sensitization.
1101
17
Section 17
::
1102
Figure 96-12 This man developed postinfectious purpura

fulminans after varicella-zoster infection as a child in the
1960s and lost both legs as a consequence. He presented
with infected verrucous hyperplasia having lived a reclusive life in a cabin in the woods wearing an old-fashioned
unadjusted aluminum prosthesis for many years. The infection was treated with new hygiene measures, and he
was fitted with a modern modular prosthesis. The skin
rapidly resolved, although some of the verrucous hyperplasia changes persisted.
Superficial fungal infections respond to appropriate
topical therapy (see Chapters 188 and 189) but can be
hard to completely eradicate because of the favorable
conditions for fungal growth. In this situation, systemic antifungal therapy is useful.
Figure 96-13 Folliculitis of stump skin showing the

typical distribution in the occluded area.
contain allergens such as fragrances or preservatives.

Colored stump socks may contain potentially allergenic nylon dyes.
Knowledge of the materials used in prosthesis manufacture is also necessary when considering potential
sensitizers and irritants. This is best achieved by liaison with the local prosthetist, as different construction
techniques may be used in different areas. In general,
CONTACT DERMATITIS
The clinical presentations of irritant and allergic
contact dermatitis affecting amputation stumps are
indistinguishable (Fig. 96-14), ranging from dry, scaling erythema to weeping dermatitis.6 Indeed, the
morphologic features may be the same as nonspecific
eczematization where no irritant, allergic, or infectious
cause is found, and where there is no history of eczema
or atopy. Consequently, a careful history and examination is essential if one is to identify irritant or allergic causes (Table 96-1). This includes accurate timing
of the onset of dermatitis in relation to changes in the
patients appliance routine or the composition of the
prosthesis. The distribution of rash typically matches
the site of the contactant. To identify a primary irritant
or allergen, it is particularly important for the dermatologist to observe the patient removing and refitting
their limb, making note of its construction and any
medicaments or other agents such as cleansers, talcs,
and creams that the patient uses. These products may
Figure 96-14 Allergic contact dermatitis to formaldehyde-releasing biocides in a lubricating baby oil. Note
the nonspecific, dry, eczematous appearance.
TABLE 96-1
Causes of Dermatitis on Amputation Stump
OTHER CUTANEOUS DISORDERS
::
modern modular prostheses are fabricated with sockets, liners, and casings that may contain acrylic resins,
carbon composites, and thermoplastics. Epoxy and,
occasionally, polyester resins are still used by some
manufacturers. Acrylate-based thread sealants are
commonly used in socket bolts and metalwork. Butyl
or black rubber material may be used to conceal access
points to the metal frame. Rubber materials can also
be found in some suction socket valves (Fig. 96-15).
Accelerators used in the manufacture of natural or
synthetic rubbers are potential allergens, for example,
dialkyl thiourea used in chloroprene rubber.23 Suspension elements often include chrome-tanned leather
and sometimes have metal fastenings, rivets, or screws
17
Chapter 96
Traumatic
Irritant
Soaps and washing materials
Topical applications, including medicaments
Solvents in glues and resins used to make prosthesis
Allergic
Active ingredients, perfume, and excipients of topically
applied materials (e.g., deodorizers, cleansers, topical
medicaments, and moisturizers)
Acrylic, epoxy, polyester, and formaldehyde resins
Resin hardeners
Other plastic additives (e.g., para-tertiary butylphenol
catechol)
Nickel
Rubber accelerators and antioxidants
Chromate (leather)
Nylon dyes
containing nickel. Glues containing para-tertiary butylphenol formaldehyde resins are often used.
Repairs or adjustments to prostheses can introduce
new irritants and allergens. For example, sockets
sometimes have additional leather linings cemented to
points of friction or pressure.
Irritant dermatitis (see eFig. 96-15.1 in online edition)
can be due to occluded contact with volatile solvents
in glues or resins and from fragrances and detergents
in topical medicaments or lubricants. Soaps and other
washing materials used to clean appliances can cause
irritation if they are not removed by proper washing (see
Table 96-1). Burns from a malfunctioning electrode
used in a myoelectric prosthesis have been reported.24
Contact allergy should always be considered as a
cause of inflammatory and dermatitic disorders affecting the stump, especially if there is secondary spread (see
Table 96-1). In addition to standard series patch testing,
the authors recommend an extra series of allergens to
include components of plastic, including acrylic, epoxy,
and polyester resin systems, as well as an azo dye series.
It is important to test with pieces of the prostheses and
all materials applied to the stump skin including emollients, cleansers, powders, medicaments, and cosmetics.
In our experience, the most common relevant allergens
are nickel, acrylates, rubber, chromate (in leather), paratertiary butylphenol formaldehyde resin, and components of topical applications.6
Common skin diseases, for example, eczema (see eFig.

96-15.2 in online edition) and psoriasis (see eFig. 96-15.3
in online edition), may affect amputation stumps. Those
Figure 96-15 Allergic contact dermatitis to rubber materials in a suction socket from
an arm prosthesis. A. The prosthesis fitted. B. The dermatitis is worst around the areas
where the pressure is released on removing the limb.
1103
17
Section 17
::
diseases that exhibit the Koebner phenomenon, especially psoriasis or lichen planus, have been reported
on amputation stumps with little involvement of
other areas of skin. Treatment should always take into
account the implications of an occluded environment.
Hyperhidrosis can be a problem in some patients
resulting in maceration of the skin increasing the risk of
erosions and even ulceration. Standard topical antiperspirants can be irritating under occlusion and one novel
approach is to use intradermal botulinum toxin A.25
Benign keratoses, warts, nevi, and a variety of cutaneous papillomas may occur on stump skin and occasionally cause discomfort when a prosthesis is worn.
Malignancies have also been described and squamous
cell carcinoma (Marjolins ulcer)9 may develop in nonhealing chronic stump ulcers or verrucous hyperplasia
(see Fig. 96-11). The patients who have amputations for
lymphangiomas may develop the StewartTreves syndrome and metastatic lymphangiosarcoma (see Chapter
128). There is a risk that such malignancies may not be
recognized as an ulcer might be wrongly blamed entirely
on trauma from a poorly fitting prosthesis. A biopsy of
persistently ulcerated areas should be undertaken.
Treatment of these benign and malignant tumors is
the same as when they occur elsewhere on the skin.
Healing after tumor excision may take weeks, during
which time the artificial limb may not be worn.
General Management
Considerations
Many of the more common skin problems can be prevented or controlled by adherence to an appropriate
hygiene and skin-care regimen in conjunction with
regular prosthetics reviews, which ensure that the
prosthesis remains appropriate and correctly adjusted.

To this end, it is important that good communication
exists between the dermatologist and prosthetist, which
permits rapid referral of patients before skin disorders
become established.
As a general routine, the stump skin should be washed
at night rather than in the morning because newly
washed skin is hydrated and swollen, thereby increasing the likelihood of friction and shearing trauma. Nonperfumed soap should be used to minimize contact
with potential sensitizers and fully removed with tepid
water and gentle rubbing with a nonabrasive towel.
Antibacterial soaps and washes can reduce the possibility of infection in addition to their cleansing action.
However, these antiseptic preparations can cause irritation or allergy in a small number of cases and patients
should be warned about this. If a stump sock is worn, it
should be changed daily and washed and rinsed fully
as soon as it is taken off, before perspiration is allowed
to dry within it. Silicone liners should be washed every
day.
KEY REFERENCES
1. Marks LJ, Michael JW: Science, medicine, and the future:
Artificial limbs. BMJ 323(7315):732-735, 2001
4. Dudek NL et al: Dermatologic conditions associated with
use of a lower-extremity prosthesis. Arch Phys Med Rehabil
86(4):659-663, 2005
6. Lyon CC et al: Skin disorders in amputees. J Am Acad Dermatol 42(3):501-507, 2000
8. Levy SW: Skin problems of the leg amputee. Prosthet
Orthot Int 4(1):37-44, 1980
Chapter 97 :: Skin Problems in Ostomates

:: Calum C. Lyon & Michael H. Beck
SKIN PROBLEMS IN STOMA PATIENTS AT A GLANCE
Peristomal skin is chronically occluded and
subject to pressure, shearing forces, and
fecal/urine soiling. Some skin problems are
therefore inevitable.
Two-thirds of ostomates develop dermatological
problems. Irritant reactions, common skin
diseases, and infections are the most common.
1104
The occlusion under a stoma appliance can

result in unusual clinical appearances of
common dermatoses. All rashes should be
swabbed to exclude primary or secondary
infection.
Allergic contact dermatitis is relatively

uncommon. Nonetheless patients should
be advised to minimize exposure to
potential allergens especially fragrances and
preservatives.
Some dermatoses are commoner than expected
around stomas, particularly psoriasis,
pyoderma gangrenosum, and lichen sclerosus.
Liaison with stoma nurses (ET therapists)
and surgeons is essential to provide an
effective service for patients with peristomal
dermatoses.
17
SKIN PROBLEMS IN PATIENTS

WITH ABDOMINAL STOMAS
(OSTOMATES)
EPIDEMIOLOGY
Skin Problems in Ostomates
Figure 97-1 A typical drainable stoma bag with a convex

barrier.
convex appliance that apply less pressure on the skin

and collars or sleeves that fit snugly around the stoma
before applying the bag thereby reducing the chance of
leaks of effluent or intestinal mucus under the barrier.
As many as two-thirds of ostomates experience
skin problems that interfere with the normal use of
their stoma appliance,2,3 and such dermatoses are the
commonest reasons for a visit to outpatient stoma
services.4,5 The majority of these problems are irritant
reactions, usually dermatitis secondary to leaks from
the stoma; however, there are also a number of other
well-defined irritant reactions. Common coincidental
dermatoses, particularly psoriasis and constitutional
eczema, account for around 15% of the diseases seen.2,6
An approach to diagnosing peristomal dermatoses is
given in eFigure 97-1.1 in online edition.
::
There are estimated to be more than 1.4 million ostomates in the United States and 100,000 in the United
Kingdom and Ireland. Some stomas are temporary,
with surgical anastomosis delayed, pending resolution of the acute disorder. Temporary stomas are often
loop stomas where a loop of bowel is brought to the
skin surface and part of the wall removed to allow
preferential drainage into a stoma pouch in order to
relieve a distal problem, for example, perianal ulceration. Such stomas are more frequently associated
with skin problems secondary to leaks.1 Many stomas
formed for malignant indications can be seen as palliative procedures.
A stoma appliance is essentially a device for collecting stoma effluent with a high degree of comfort
and security until it can be disposed of. There continues to be promising advances in the design of stoma
bags. Essentially, the device is a pouch or bag held in
place over the stoma by an adhesive skin barrier made
solely or partly from hydrocolloid. Many ileostomists
and urostomists use two-piece appliances where the
barrier remains on the skin for 24 days and is detachable; disposable bags are changed as necessary. Appliances with convexity on the surface next to the skin
are available for patients with short or buried stomas
(Fig. 97-1). Useful recent innovations include softer
Figure 97-2 Peristomal dermatitis due to fecal irritation.

The skin beneath the stoma was chronically exposed to
feces because a bag with too large an aperture was used.
Chapter 97
A stoma is a surgically created opening onto the skin of

part of the gastrointestinal or urinary tract in order to
drain the effluent from that viscus. The most frequently
performed stomas are ileostomies, colostomies, and
ileal conduits (urostomies or urinary diversion). The
commonest indications for stoma surgery are inflammatory bowel disease, malignancy and neurological
problems. A patient with a stoma is usually termed an
ostomist or ostomate.
IRRITANT REACTIONS
DERMATITIS. Dermatitis most frequently results from
the chronic leakage of effluent onto the skin because
the patient is using an inappropriately shaped appliance or one with too large a hole for their stoma. The
most common cause is the remodeling of the stoma and
abdominal wall that occurs in the months after surgery,
whereby a stoma usually becomes a little shorter and
thinner, resulting in leaks unless a correctly fitting appliance is selected (Figs. 97-297-6). Leaks will also occur
when patients gain a lot of weight after surgery and
the effective length of their stoma diminishes because
it becomes buried by subcutaneous fat.7 Irregular scarring after surgery or retraction of the stoma, may also be
associated with chronic leakage. Such irregularities can
be corrected with topically applied pastes. One effective
alternative is to use collagen fillers (Porcine collagen
Permacol)8 to recontour the skin surface. Short stomas (<2 cm long), loop ileostomies and stomas formed
as emergency procedures are more likely to be associated with skin problems.1,9 Chronically irritated skin
can become markedly hyperkeratotic and acanthotic
1105
17
::
(Fig. 97-7). These problems can be prevented and

resolved by careful postsurgical follow-up by the enterostomal therapist (ET; stoma nurse specialist) to ensure
that the correct appliance is being used. Severe, acute
irritant dermatitis can be effectively treated with a short
course of topical corticosteroid while longer term appliance modifications are being undertaken (Table 97-1).
Anxieties about possible leaks and odors can lead to
excessively frequent bag changing, which may cause
an irritant dermatitis by stripping the skin. Patients
may, for the same reasons, wear waist belts too tightly
thereby causing pressure damage even ulcers (eFig.
97-7.1 in online edition) and occasionally necrosis.
Section 17
Figure 97-3 Irritant contact dermatitis circumferentially

around an ileostomy because the bag aperture was cut
too big thereby allowing soiling of the skin around this
short stoma.
1106
Figure 97-5 A short ileostomy where recurrent soiling

has led to irritation and hypertrophic changes due to
massive hyperkeratosis and acanthosis similar to chronic
papillomatous dermatitis.
Whatever the cause of skin inflammation, a vicious
cycle can develop when the damaged skin prevents
proper bag adhesion necessitating more frequent bag
changes.12 Careful counseling is usually necessary in
order to reassure the patient regarding leaks.
Approximately 15% of ostomates with skin problems suffer from a chronic or recurrent dermatitis for
which no irritant, allergic, or infective cause can be
found, and where primary skin disease is ruled out.2 In
the absence of a primary treatable cause, the use of topical corticosteroid lotions is appropriate. Most patients
Figure 97-4 A. Eroded irritant dermatitis in two places

around an ileostomy. B and C. show the release film from
the bag in the two positions that the patient was accustomed to place the appliance, accounting for the fecal
soiling and the dermatitis seen.
TABLE 97-1
17
Topical Corticosteroid Treatment of

Inflammatory Peristomal conditions
::
require only occasional short courses for a maximum

of 4 weeks duration (Table 97-1). A small number of
patients require intermittent applications longer term.
Provided that the frequency of application is no more
than once every 10 days, steroid atrophy of the skin
appears to be unusual.
In ileostomy patients with short bowel, the output
may be very high and corrosive due to the enzyme
and bile salt content. In this situation, some leaks are
inevitable, despite the use of proprietary barrier preparations or soothing lotions. Where the irritation has
resulted in an eroded dermatitis, sucralfate powder
applied at every stoma bag change can be very effective. In addition to forming a sticky barrier, the preparation is thought to promote healing.13 Surgical scars
and even large striae (eFig. 97-7.2 in online edition)
can lead to ulcerations and bag failures, which may
respond to topical carmellose sodium or sucralfate
powders. Wound dehiscence can cause severe difficulties for bag adhesion (eFig. 97-7.3 in online edition) and
Chapter 97
Figure 97-6 Irritant contact dermatitis from leaks occurring when reclining at night resulting in a cycle of poor
bag adhesion and further leaks. Patient was unable to
sleep sitting up and the rash did not respond to barriers or
steroid tape. It eventually responded to applications of beclomethasone via a metered dose inhaler allowing proper
bag adhesion and less leakage.
1. Good adhesion between the appliance and the skin is

essential. Ointments, creams, and greasy lotions will cause
a bag to lift so that most patients will not use them.
2. One approach tolerated by some patients is to use
dressings such as thin hydrocolloid or vapor-permeable
membranes placed over the cream preparation and before
applying a stoma bag.
3. Another approach is to apply a cream preparation for
13 hours per day before wiping off and applying a stoma
bag. While the cream is in place, a nonadhesive bag can
be worn, held in place with a waist belt, provided that the
patient is sedentary during this time.
4. A number of alternative vehicles for delivering topical
corticosteroid are available although none is ideal nor
designed for stoma use.
a. Adhesive tapes impregnated with fludroxycortide
4 mcg/cm2.
b. Scalp lotions (oil-free; 40% isopropyl alcohol)
betamethasone valerate 0.1%, clobetasol propionate
0.05%. These will sting on broken skin and can be
applied to the bag adhesive and allowed to dry before
applying to the stoma.10
c. Scalp gels flucinolone acetonide 0.025%. This
preparation contains propylene glycol that may impair
bag adhesion a little.
d. Steroid asthma inhalers beclomethasone dipropionate
250-g/metered dose. Several activations are used to
the affected area (Fig. 97-6)
e. Carmellose sodium oral pastes are especially useful
in ulcerative conditions such as mild pyoderma
gangrenosum, e.g., triamcinolone acetonide 0.1% in
carmellose sodium paste (this product needs to be
compounded).
f. Alternative nongreasy steroid sprays are available in
some regions.11
5. With each of these preparations, the steroid is under
occlusion and, therefore, effectively more potent. Skin
atrophy and absorption, particularly in children must be
considered. The authors limit initial courses to a maximum
of 4 weeks and thereafter one to two times per week if
needed.
Figure 97-7 A. Ulcerated hyperkeratotic dermatitis due to leaks. B. Three weeks after leakage was reduced using a combination of convex barrier and filler pastes around the stoma.
1107
17
presents particular challenges for nursing management where the dermatologist may be called upon for
advice as part of the multidisciplinary team.14
CHRONIC PAPILLOMATOUS DERMATITIS.
Section 17
::
1108
This term refers to clinical appearance of warty excrescences around urostomies resulting from leaks and
pooling of urine on the peristomal skin (eFig. 97-7.4
in online edition). Recurrent urinary tract infections
appear to increase the likelihood of chronic papillomatous dermatitis (CPD) probably due to the presence of
ammonia from urea-splitting bacteria. Histologically,
there is massive hyperkeratosis and acanthosis. Pseudoepitheliomatous hyperplasia may also be a feature
but is not universal. The histology is therefore not
specific and comparable to that of other irritant reactions. Verrucous lesions with similar appearances are
occasionally seen affecting ileostomies15 (Fig. 97-5). In
severe cases, the lesions can encroach on the stoma and
cause stenosis (Fig. 97-8). When the leaking of urine is
caused by a receding stoma, CPD will resolve rapidly
if a convex-backed appliance is used to increase the
effective length of the urostomy and thereby stop leaks.
Acetic acid soaks (10% domestic vinegar in water)16
at each bag change are effective in some cases (eFig.
97-8.1 in online edition). Larger excrescences may be
shaved off under local anesthetic to allow a bag with
a smaller aperture to be used. In severe cases, surgical
revision of the stoma may be required.
GRANULOMAS. The term granuloma is commonly

used for a range of papular lesions, which are almost
all secondary to irritation. The authors have only seen
the condition affecting ileostomies or colostomies
and not urostomies. They may affect the stoma itself
(inflammatory colonic or ileal polyps) or the mucocutaneous junction, or may be found more widely,
Figure 97-8 Chronic papillomatous dermatitis affecting a

urostomy in a patient who is using a bag with too large
an aperture. The red area is stoma and is becoming stenosed by the warty papules. The brown pigmentation is
a typical finding in long-standing urostomies in all races.
(Courtesy of Anita Eriksson, Karolinska Institute, Stockholm, Sweden.)
Figure 97-9 Granulomas around a colostomy. The patient

has cut the bag aperture larger to accommodate the original lesion, and the area thus exposed is seen as a ring of
postinflammatory hyperpigmentation in which new
lesions developed.
extending onto the peristomal skin (Fig. 97-9). The
latter is more frequent in patients with colostomies,
and in this situation, the papules may become very
extensive. This occurs when the patient enlarges the
stoma bag aperture to accommodate a papule, thereby
exposing normal skin to fecal irritation, which precipitates further lesions and prompts the patient to
enlarge the aperture still further (eFig. 97-9.1 in online
edition). Histologically, the lesions contain a chronic
inflammatory infiltrate, granulation tissue, and sometimes metaplastic bowel mucosa where the metaplasia
is probably a response to fecal irritation. Comparable
lesions occur around ileostomies (eFig. 97-9.2 in online
edition) but are generally flatter and may even present as sheets of cherry-red granulation tissue. These
lesions are sometimes caused by seeding mucosa at
the time of surgery.17 The majority, however, probably
represent mucosal metaplasia as a consequence of persistent fecal contact with the skin. In long-standing
ileostomies (greater than 10 years), there is a small
risk of malignant change analogous to Barrett esophagus.18 A biopsy to rule out malignant change should be
considered for unusual lesions particularly ulcerative
changes in existing granulomas around ileostomies.
Asymptomatic, solitary lesions can be left. Where
they are painful19 or bleed easily leading to poor stoma
bag adhesion, they can be destroyed by cautery (thermal or silver nitrate) or by cryotherapy, using a liquid
nitrogen spray. Larger and proliferating lesions especially around colostomies are best removed by shave
and cautery under local anesthetic and an appliance
with a correctly sized aperture fitted in order to prevent massive proliferation. Laser ablation is increasingly regarded as a first-line treatment being less
painful and possibly more effective.20
PSORIASIS. Psoriasis is a common cause of peristomal skin disease because it may appear in irritated
PYODERMA GANGRENOSUM. This rare, inflammatory, ulcerative neutrophilic dermatosis (see Chapter 33) is more common in peristomal skin than would
be expected from its frequency in the general popula-
17
::
INFECTIONS. The most frequent peristomal skin

infection is staphylococcal folliculitis, usually, but not
exclusively, in those individuals with hairy abdomens
who shave regularly to help the bags stick (eFig. 97-9.5
in online edition). It responds to oral antibiotics and to
a reduction in shaving frequency to no more than once
per week. Although antiseptic washes can be a useful
additional therapeutic measure, they can cause irritant
reactions if the skin is not correctly rinsed before being
occluded by the stoma bag. Localized skin infections,
usually staphylococcal or streptococcal, can produce
a rash indistinguishable from irritant dermatitis or
primary skin disease such as psoriasis or eczema. Furthermore, preexisting psoriasis or eczema can become
secondarily infected under occlusion (eFig. 97-9.6 in
online edition). Therefore, all peristomal rashes should
be swabbed for microbiological investigation and
appropriate antibiotics prescribed based on microbiological sensitivities. In tropical climates, cutaneous
fungal infections are common, whereas in more temperate regions, Candida albicans is an occasional problem and dermatophyte infection is rare. Viral warts are
occasionally seen and can present as verrucous lesions
solely affecting the stoma itself (eFig. 97-9.7 in online
edition). Despite the body site and the presence of
skin trauma herpes zoster is surprisingly uncommon
around stomas. Nonetheless viral infections should
be considered in the differential diagnosis of vesicular eruptions and where there are peristomal erosions
because vesicles and bullae are typically deroofed by
removing stoma bags and, therefore, are not commonly observed (eFig. 97-9.8 in online edition).
tion.23,24 Clearly, this is partly due to its strong association with inflammatory bowel disease. There is some
evidence, however, that the increased use of convexbacked appliances may contribute to the incidence via
the pathergic effect of increased pressure on the skin.
We have seen a decline in incidence of peristomal PG in
the last 5 years associated with reduced use of deeply
convex appliances and the introduction of softer convex
materials. Although some cases of pyoderma gangrenosum (PG) are associated with active inflammatory bowel
disease,25 the association is not universal; indeed, peristomal PG occurs in ostomates who have no history of
inflammatory bowel disease.26 Peristomal PG presents as
a painful papule or pustule, often hemorrhagic, which
then ulcerates and is usually very painful (eFigs. 97-9.8
and 97-9.9 in online edition). The pain and the ulceration
can have profound effects on the patients ability to wear
a bag and, therefore, on their quality of life. The ulcers
heal with cribriform scarring (eFigs. 97-9.10 and 97-9.11
in online edition) that can itself impair bag adhesion so
that rapid, effective treatment of PG is essential.
Management is similar to that for PG elsewhere
(Chapter 33) although small, superficial, and solitary
ulcers respond very rapidly to topical therapy alone
(eFig. 97-9.12 in online edition). Because of the problems with greasy preparations causing lifting of stoma
bags, alternative vehicles are usually necessary (Table
97-1). There are no randomized controlled trials of
treatment for this rare condition and some current
evidence has recently been reviewed.27 The authors
approach is detailed in Table 97-2.
Chapter 97
or traumatized skin (Koebners phenomenon) and

because it is associated with inflammatory bowel disease (Chapter 18). Peristomal psoriasis presents as
a glazed erythema similar to flexural psoriasis (eFig.
97-9.3 in online edition) and can be treated in the same
way with topical corticosteroids although, at the peristomal site, a nongreasy base should be selected (Table
97-1). The diagnosis is usually unmistakable being
part of more generalized involvement (eFig. 97-9.4 in
online edition) but localized peristomal involvement is
described.21 Resolution of psoriasis under hydrocolloid
occlusion has been described,22 which is of relevance
to stoma patients because 50% of cases of peristomal
psoriasis will resolve if a bag is selected with a thicker,
hydrocolloid-only barrier. Where the patient can tolerate the stoma being temporarily unprotected from
leaks, ultraviolet (UV) phototherapy is effective as for
psoriasis elsewhere. The mucous membranes of the
stoma should be protected from UV light. Although
irritating topical psoriasis treatments are not usually tolerated, some patients have had success with
creams containing hydrocortisone 1% and coal tar 3%,
the application being left on the skin for 1 hour each
day (Table 97-1, Point 3). Superficial X-ray (Grenz-ray)
therapy has been used in recalcitrant cases.
CONTACT ALLERGY
Modern stoma bags are made largely from food-grade
materials and those with a low potential for sensitization. Nonetheless, there are case reports of sensitivities
to individual ingredients including Gantrez (GAF
TABLE 97-2
Management of Peristomal Pyoderma

Gangrenosum
The majority of smaller and superficial PG ulcers respond
to potent or superpotent topical corticosteroid in a suitable
base (Table 97-1).23,28
Larger, deeper, or multiple lesions and those not
responding to steroid alone may require topical tacrolimus
0.3% in carmellose sodium paste.29,30 Fludroxycortide
impregnated tape used in conjunction with topical
tacrolimus may hasten improvement; it also serves to
reduce the overgranulation typically seen when topical
tacrolimus is associated with rapid healing of a PG ulcer.30
Systemic treatment may be indicated from the outset for
very multiple, circumferential or rapidly progressing PG as
well as for where topical therapy has failed. These agents
are as described for PG elsewhere (Chapter 33). Those
specifically reported for peristomal PG include cyclosporin,
mycophenolate mofetil,31 infliximab,32 and adalimumab.33
With all treatments the first sign of improvement is
reduction of pain and tenderness usually seen within
48 hours with effective therapies.
1109
17
Section 17
::
1110
Corporation. Wayne NJ) resins and acrylate adhesive

systems (eFig. 97-9.13 in online edition). Furthermore,
there is a potential for contact allergy from deodorizers
and topically applied preparations. These case reports
of peristomal allergic contact dermatitis have recently
been the subject of a literature review.34 Despite the fact
that contact allergy is a relatively uncommon cause of
peristomal dermatitis most patients and many health
professionals regard contact hypersensitivity to their
appliance as the likely cause of a peristomal rash.
Patch testing is indicated in patients with persisting
problems where infection, irritation, and constitutional
skin disease has been ruled out.35 We have patch tested
well over 100 such patients and relevant positive allergic reactions were found in only three cases of topically
applied materials including fragrance in a deodorizer
and biocides in wet wipes.
OTHER CONDITIONS
In theory, almost any of the multitude of skin disorders
might affect a stoma. In clinical practice, the common
disorders (e.g., psoriasis predominate and others) are
more common than expected (e.g., PG). Some less common peristomal dermatoses are worthy of note either
because they present practical difficulties such as pemphigoid and nicorandil ulceration, or in the case of lichen
sclerosus because they have an unusual predilection for
this site. The authors have managed five patients with
pemphigoid affecting the skin around stomas (eFig.
97-9.14 in online edition); in all cases, the principal
problems are pain and the failure of stoma bag adhesion (eFig. 97-9.15 in online edition). This necessitates
a low threshold for rapidly effective systemic therapy
(Chapter 56) otherwise the patient is rendered immobile
in order to reduce the effect of a leaking stoma. Cecchi et
al have summarized the clinical features and therapy of
their own plus five previously published cases.36
Nicorandil, a potassium channel activator with nitrate
activity is used in the management of angina. It has
been associated with mouth ulceration as well as perianal,37 peristomal and even small bowel ulceration.38 It
presents as rather indolent ulcers with minimal inflammation clinically or histologically. In a patient with
pericolostomy ulcers that has had the stoma formed
because of intractable perianal ulcers, for example, the
diagnosis is usually straightforward. There are, however, a range of differential diagnoses for nonspecific
ulceration including simple trauma such as one sees in
patients with parastomal hernias that cause stretching

and tearing of the skin. The diagnosis should be considered in patients receiving nicorandil with otherwise
unexplained ulceration around a stoma. In most cases,
the ulceration resolves within a month or two of stopping the drug (eFig. 97-9.16 in online edition).
Lichen sclerosus affecting peristomal skin is an enigmatic condition as it can present in the absence of genital involvement and affect any type of stoma.3941 In the
authors experience of six cases (eFig. 97-9.17 in online
edition), the condition is painful and readily ulcerates.
Topical corticosteroid therapy may be ineffective and
intralesional steroid may be required (eFig. 97-9.17 in
online edition). Stoma surgery is avoided if at all possible
in patients with inherited conditions that are associated
with skin fragility or blistering. These conditions together
with the more severe congenital ichthyoses can cause significant difficulties with proper stoma bag adhesion.
Benign tumours, particularly seborrheic keratoses,
sometimes cause problems if they become inflamed
or infected under the occlusion of a stoma appliance.
In these circumstances, ablative treatment with simple
curettage and cautery is effective.
Other conditions occasionally seen around stomas
include Crohn disease, metstatic ulcerative colitis,42
basal cell carcinoma,43 squamous carcinoma,44 and
metastatic adenocarcinoma.45
KEY REFERENCES
2. Lyon CC et al: The spectrum of skin disorders in abdominal stoma patients. Br J Dermatol 143(6):1248-1260, 2000
7. Nybaek H et al: Skin problems in ostomy patients: A casecontrol study of risk factors. Acta Derm Venereol 89(1):64-67,
2009
14. Braun K: Managing a highly exudative wound adjacent to
an ileostomy. J Wound Ostomy Continence Nurs 30(3):159164, 2003
18. Al-Niaimi F, Lyon CC: Primary adenocarcinoma in peristomal skin: A case study. Ostomy Wound Manage 56(1):
45-47, 2010
21. Moriyasu A, Katoh N, Kishimoto S: Psoriasis localized exclusively to peristomal skin. J Am Acad Dermatol 54(Suppl.
2):S55-S56, 2006
24. Hughes AP, Jackson JM, Callen JP: Clinical features and
treatment of peristomal pyoderma gangrenosum. JAMA
284(12):1546-1548, 2000
33. Fonder MA et al: Adalimumab therapy for recalcitrant
pyoderma gangrenosum. J Burns Wounds 5:e8, 2006
Chapter 98 :: Corns and Calluses

:: Thomas M. DeLauro & Nicole M. DeLauro
CORNS AND CALLUSES AT A GLANCE
Corns and calluses result from prolonged
application of forces to the skin and produce
painful symptoms.
Every weight-bearing human being is
vulnerable.
Corns and calluses show changes within the

epidermis, dermis, and adipose layer.
EPIDEMIOLOGY
Every human being, with the exception of the nonweight-bearing infant, is vulnerable to the development of corns and calluses, because the skin is subjected
to regular mechanical stress. The prevalence of corns
and calluses can be readily appreciated by the number
of nonprescription products aimed at reducing or preventing thema billion-dollar market annually.
The earliest known discussion of these lesions can
be found in the writings of Cleopatra, who authored
a textbook on cosmetics.1 Corns and calluses have
plagued humankind since antiquity, affecting those at
all socioeconomic levels.
Certain foot types and regions are prone to mechanically induced skin thickening, regardless of race, gender, or age.
HISTORY
Corns and calluses produce painful symptoms often
described as burning, especially when the affected area
is weight bearing and/or shoes are worn. This discomfort is thought to result from microtearing of the thickened, inflexible skin.
CUTANEOUS LESIONS
Corns [clavi or helomata (singular: clavus or heloma)]
and calluses [tylomata (singular: tyloma)] are, respectively, keratotic papules and plaques that occur in
areas that are subject to sustained excessive mechanical shear or friction forces.
Corns and Calluses
Treatments are available and vary in

aggressiveness.
CLINICAL FINDINGS
::
There are no associated systemic

abnormalities.
individuals skeletal architecture. A family history of

bony abnormality or ligamentous laxity predisposes
the person to the presence of sites of increased cutaneous friction or shear. The prevalence of these lesions
has also proven to be significantly higher in females,
certain ethnic groups, and mentally ill patients.2,3
Chapter 98
Lesions occur in predictable pedal locations.
17

The lesions occur in predictable pedal locations, corresponding to a structural deformity or biomechanical
fault. Crookedness of the lesser toes leads to prominence of the proximal and/or distal interphalangeal
joints. Keratoses can therefore form either dorsal
to those joints, between the toes, at the distal end of
the toe, or on the lateral aspect of the fifth toe and/or

Corns and calluses result from the prolonged application of excessive mechanical shear or friction forces to
the skin. In theory, these forces induce hyperkeratinization, which leads to a thickening of the stratum corneum, although the precise mechanism by which this
occurs remains unknown. If the abnormal forces are
distributed over a broad area (i.e., more than 1 cm2),
a callus develops. In contrast, a corn will form if the
same forces are applied to a focused location, with the
lamellae of the stratum corneum becoming impacted
to form a hard central core known as the radix or
nucleus (Fig. 98-1).
Mechanical keratoses are not determined genetically.
Heredity does play a role, however, in configuring the
Figure 98-1 A simple corn beneath the fifth metatarsal

head. Note the white central radix or nucleus, which has
been partially pared. This radix must be pared to provide
comfort.
1111
17
Section 17
::
Figure 98-2 A soft corn (also known as a heloma molle)

located deep within the fourth interdigital space.
Figure 98-3 A large callus beneath the fifth metatarsal

head in a postpoliomyelitis patient whose foot is now in
rigid adductovarus.
toenail (lateral toenail corn, also known as Durlachers

corn; see eFig. 98-1.1 in online edition). Interdigital
corns can be hard when they are adjacent to the interphalangeal joint(s) (see eFig. 98-1.2 in online edition)
or soft when deep within the fourth interdigital space.
The softness of latter last corn results from trapped
perspiration, which leads to maceration of the keratotic tissue (Fig. 98-2).
In patients with bunions (hallux valgus), a callus
usually forms at the medioplantar aspect of the hallux. During gait, the individual rolls off that portion
of the great toe because of its incorrect position. The
skin is subsequently pinched to form a pinch callus
(see eFig. 98-2.1 in online edition). In addition, the
first metatarsal often does not bear its fair share of the
weight-bearing load. Weight is therefore transferred
laterally to the second metatarsal head, which usually
leads to the development of an additional corn or callus beneath that bone.
Other favored locations for lesser metatarsal head
keratosis include the following:
Another variant of corn is that referred to as heloma

miliare or seed corn. This title is derived from the clinical appearance of these corns: multiple guttate keratoses that are easily pared. When seamed nylon hosiery
was fashionable, this garment was considered the
causative factor. However, patients still present with
seed corns even though they have never worn seamed
stockings.
1112
Beneath the first and fifth metatarsal heads in cavus

foot types
Beneath the fifth metatarsal head alone in persons
with tailors bunions (bunionette)
Erratic locations (e.g., beneath the third and fifth
metatarsal heads, isolated third or fourth metatarsal head, second and fourth metatarsal heads) in
individuals with structural abnormalities such as
brachymetatarsia or dislocated metatarsophalangeal
joints, as in rheumatoid arthritis or neuroarthropathy (Fig. 98-3)
Beneath the second through fourth metatarsal heads
when multiple hammertoes, hallux valgus, or an
equinus deformity coexists (Fig. 98-4)
Figure 98-4 A large callus beneath the second metatarsal

head in a patient with concomitant hallux valgus. Usually,
the hallux valgus segment causes a lateral shift in weight
bearing to the second metatarsal.
HISTOPATHOLOGY
(See Box 98-1)

COURSE
If left untreated, corns and calluses result in painful
ambulation and also in subhelomal bursitis and blistering that can rupture to the surface. Because of the
close proximity of some corns to joints and bone, septic
arthritis and/or osteomyelitis can ensue. The mechanical forces that cause corns and calluses can also rupture
portions of the subcutaneous vascular plexus, which
leads to hemorrhage into keratotic tissue. In healthy
patients, such findings are of minor significance, but in
other cases (e.g., in diabetic patients and patients with
connective tissue disease), they may herald extensive
skin ulceration or vasculitis.
The need for lower extremity amputation is a dominant fear in most diabetic patients. Such amputations
are most often preceded by a history of foot ulceration
(see Chapter 151). Although a number of comorbidities contribute to the development of ulceration (e.g.,
peripheral vascular disease, neuropathy, and limited
joint mobility), minor trauma via repetitive pressure is
the pivotal precipitating event. As markers of repetitive friction and shear, corns and calluses in the diabetic
foot are of special significance. Simple dbridement of
these hyperkeratotic lesions decreases peak plantar
pressures by as much as 26%.5 In a retrospective review
of more than 200 diabetic foot ulcerations, patients
who had their corns and calluses pared frequently
experienced a statistically significant decrease in the
incidence of foot ulceration, hospitalization, and surgical intervention.6 Hemorrhage within a corn or callus
is an especially ominous sign, indicating subcutaneous breakdown with a strong potential for ulceration.
Therefore, ulcer care should include paring of calluses.
The use of proper footwear by the diabetic as well as
the nondiabetic patient may also play a role in not only
preventing but also reducing the development of callosities. Shoes should be correctly sized to accommodate the width and length of the patients foot, and the
heel should be elevated minimally, if at all, to prevent
pathology and pain.7,8
Corns and Calluses
Most Likely (Secondary to Structural Deformity)

Corn or Callus
Deformity
Location
Pronation
Medioplantar heel
Pes planus foot type
Medioplantar heel
Charcot
Midsole
neuroarthropathy
Cavus foot type
Submetatarsal
heads 1 and 5
Tailors bunion
Submetatarsal
head 5
Hallux valgus
Submetatarsal
head 2
Medioplantar
hallux
Brachymetatarsia
Submetatarsal
heads 3, 5
Dislocations as in
Submetatarsal
heads 3, 4
and other structural
Submetatarsal
abnormalities
heads 2, 4
Transmetatarsal amputa Stump of
tion without tendo-Achilamputation
les lengthening
Consider
Multiple guttate keratoses
Heloma miliare
Painful corns
Intractable plantar keratoses
Neurofibrous or neurovascular corn
Porokeratosis plantaris discreta
Always Rule Out
Lesions not associated with bony prominences
Verruca
Genokeratoses
Cutaneous neoplasms
Neuroborreliosis
DIAGNOSIS AND
::

of Corns and Calluses
17
Chapter 98
In contrast to nonmechanically induced keratoses, corns

and calluses exhibit changes within the epidermis,
dermis, and adipose layer. Corns demonstrate a parakeratotic plug within the stratum corneum, with a pressure-related loss of the stratum granulosum as well as
atrophy of the stratum malpighii. The dermis displays
significant fibrosis, dilated eccrine ducts and blood vessels, hypertrophied nerves, and scar tissue replacement
of subcutaneous fat. Overall, the histologic changes in
calluses are less pronounced, and include a thickened
stratum corneum but intact stratum granulosum.4
Because corns and calluses are the result of mechanical friction and shear alone, there are no associated
hematologic, chemical, serologic, or immunohistochemical abnormalities.
TREATMENT
(See Box 98-2)
PREVENTION
Corns and calluses can be prevented only by reducing or eliminating the mechanical forces that created
1113
17
Box 98-2 Treatment
Section 17
PHYSICAL
Paring
Padding
Second line
Injectionsb
4% alcohol
mixed with local
anesthetic
Under
investigation
Injectionse
Botulinum toxin
to reduce digital
contractures and
thereby reduce
the increased
local skin pressures that lead to
hyperkeratosis13
::
First line
Central radix of
corn requires
dbridement
Lipid extract with

garlicc
SURGICAL
40% salicylic
acid or 40% urea
cream used as
directed
Osseous and/
or soft-tissue
proceduresd
Keratolytics are to be used with caution. Their use is contraindicated in patients with comorbid peripheral neuropathy or arterial disease.
Injections are useful for soft corns and intractable plantar keratoses. Typically up to seven injections may be required, with darkening and
thrombosis of the lesion heralding a cure.9,10
c
Newer modality under research. Side effects include blistering, redness, burning, and hyperpigmentation.11
d
Osseous procedures are designed to redistribute weight-bearing pressures, whereas soft-tissue procedures (i.e., adipofasciocutaneous
flaps12) are used to eliminate cicatrix (fifth digit) secondary to the use of medicated padding.
e
Newer modality under research. Efficacy undetermined.
b
them. Usually, this is a daunting, if not impossible, task.

Repetitive occupational motions are often unavoidable,
patients are commonly reluctant to alter shoe styles, and
osseous architecture is predetermined through heredity.
KEY REFERENCES
2. Dunn JE et al: Prevalence of foot and ankle conditions in a
multiethnic community sample of older adults. Am J Epidemiol 159:491, 2004
1114
TOPICAL
Keratolyticsa
4. Lemont H: Histologic differentiation of mechanical and

non-mechanical keratoses of the sole. Clin Dermatol 1:44,
1983
6. Sage RA, Webster JK, Fisher SG: Outpatient care and morbidity reduction in diabetic foot ulcers associated with
chronic pressure callus. J Am Podiatr Med Assoc 91:275,
2001
9. Costello MJ, Gibbs RC: The Palms and Soles in Medicine.
Springfield, IL, Charles C Thomas, 1967
10. Dockery GL, Nilson RZ: Intralesional injections. Clin Podiatr Med Surg 3:473, 1986
13. Radovic PA, Shah E: Nonsurgical treatment of hallux
abductovalgus with botulinum toxin A. J Am Podiatr Med
Assoc 98:61, 2008
Chapter 99 :: Sports Dermatology

:: Dirk M. Elston
SPORTS DERMATOLOGY AT A GLANCE
17
PYOGENIC SKIN INFECTIONS

EPIDEMIOLOGY
Forty percent of all athletes develop skin

problems.
Infections are highly prevalent.
Control of MRSA outbreaks requires

treatment of fomites and skin
colonization.
TABLE 99-1
Sports-Associated Skin Conditions

Bikini bottom: bacterial folliculitis on the buttocks of
swimmers
Infections with Pseudomonas, Vibrio, and

atypical mycobacteria are frequently
associated with water sports.
Sports Dermatology
The most important intervention for a

CAMRSA abscess is drainage.
::
MRSA typically presents as an abscess or

folliculitis.
Chapter 99
Community-acquired methicillin-resistant
Staphylococcus aureus (CAMRSA) has
emerged as the most important pathogen
among athletes.
Cutaneous community-acquired methicillin-resistant

Staphylococcus aureus (MRSA) has emerged as the most
important pathogen among athletes.1013 Athletes at
risk include weight lifters, wrestlers, and members of
competitive sports teams.1416 During an outbreak of
MRSA in a college football team, linemen had the highest attack rate (18%). Preexisting cuts or abrasions and
sharing bars of soap were important risk factors associated with infection. Nasal carriage was associated with
sharing towels, living on campus, having a locker near
a teammate.17 Cosmetic body shaving has also been
identified as a risk factor for MRSA infection.18 Data
Jazz ballet bottom: buttock cleft abscess

Joggers nipples: painful, swollen, eroded or hyperkeratotic
nipples
Heat and cold injury remain important

problems in athletes.
Karate cicatrices: linear scars on the dorsal aspects of the

hands
Mogul skiers palm: traumatic hypothenar ecchymosis
Painful piezogenic pedal papules: transdermal fat herniations
EPIDEMIOLOGY
Ping-pong patches: traumatic ecchymotic patches

1,2
Skin problems are common among athletes. During an 8-week survey of university athletes, 40%
reported skin problems.3 In a study of mountain
biking injuries, skin lesions accounted for 75% of all
injuries.4 Skin lesions account for 35% of all in-line
skating injuries.5 Skin infections are more prevalent
in athletes than in the general population.6 Skinrelated complaints are especially common in warm,
humid climates. During the 1993 Central American
and Caribbean Games, held in Puerto Rico, one out of
every hundred athletes had a skin-related complaint
severe enough to require medical care.7 Similarly,
sports that involve repeated immersion in water are
associated with an increased incidence of skin injury
and infection.8 Winter sports often involve short periods of repetitive injury resulting in a high frequency
of injuries.9
Table 99-1 lists some unique sports-associated
skin conditions that are worthy of mention but are
not discussed further in this chapter (Figs. 99-1 and
99-2).
Pool palms: smooth, shiny, tender palms secondary to rough

pool surfaces
Pulling-boat hands: pernio-like condition produced by friction
and damp cold
Rowers rump: lichenification
Runners nail: multiple Beaus lines or periodic shedding of the
nail plate (see Fig. 99-1)
Runners rump: ecchymoses of the superior gluteal cleft
Stingray hickey: bite ecchymosis
Stretchers scrotum: scrotal hematoma
Swimmers shine: facial oiliness seen in swimmers
Swimmers shoulder: abrasion of the shoulder by the beard
during crawl stroke
Talon noir (black heel): intradermal hemorrhage
Tennis toe: subungual hematoma with or without subungual
hyperkeratosis or nail dystrophy (joggers toe, hikers toe,
skiers toe are similar) (see Fig. 99-2)
Turf toe: metatarsophalangeal joint sprain
1115
17
nose, external ear canal, necks, back, extremities, and

buttocks.20
Section 17
MRSA isolates usually contain the type IV staphylococcal chromosomal cassette (SCC)mec coding for
methicillin resistance, as well as the Panton-Valentine
leukocidin virulence factor. There is a high risk of colonization in close contacts of individuals with MRSA,
and those who are colonized commonly progress to
clinical infection.21,22 Sharing of towels and higher
body mass index are independent risk factors for
MRSA infection.23
CLINICAL FINDINGS
::
1116
Figure 99-1 Runners nail. In this case there are multiple

Beaus lines with onychoschizia.
from an outbreak of MRSA abscesses among members
of a professional football team (St. Louis Rams) indicates that most infections developed at turf-abrasion
sites. Infection was significantly associated with the
lineman or linebacker position as well as a higher body
mass index. MRSA was cultured from whirlpools and
taping gel as well as from 35 of the 84 nasal swabs
from players and staff.19 In competitive male athletes,
abscesses generally occur at sites of minor abrasions.
In weightlifters, abscesses favor the axillae. Abscesses
among female athletes favor the thighs and buttocks.
Folliculitis and abscesses noted during an outbreak
of MRSA in a saturation diving facility involved the
Figure 99-2 Tennis toe. Subungual hemorrhage seen in

runners and basketball and tennis players that produces
anxiety because of fear of melanoma. It can be easily differentiated from melanoma by dermoscopy.
MRSA infection in athletes typically presents as folliculitis or spontaneous abscess (see Chapters 176 and
177). Abscesses may begin as furuncles but rapidly
evolve to fluctuance with surrounding cellulitis.
TREATMENT
Like other abscesses, MRSA abscesses respond to drainage. Surveillance data from Baltimore, Atlanta, and
Minnesota including 1,647 cases of CAMRSA infection
show that therapy to which the strain was resistant
was not associated with adverse patient-reported outcomes if the abscess was incised and drained.24 Other
data also suggest that many MRSA abscesses respond
to drainage alone.25,26 Failure to drain MRSA abscesses
may have catastrophic results, even if effective antibiotic therapy is prescribed. In one report, bilateral
blindness resulted.27
Although the SCCmec type IV gene cassette present
in most MRSA strains codes only for methicillin resistance, an isolate from a Japanese athlete also contained
a transmissible plasmid coding for multiple-drug
resistance.28 Other MRSA isolates have emerged that
are resistant to multiple antibiotics. Some MRSA isolates from Taipei carry a distinct SCCmec cassette (type
VT) that codes for resistance to multiple antibiotics.29
While drainage will cure many MRSA abscesses, some
athletes will require antibiotic therapy. Of the inexpensive oral agents available to treat MRSA infections,
sulfa drugs consistently show the best mean inhibitory concentrations. Tetracyclines are good alternative agents, although only about 80% of MRSA will be
sensitive in many locations. Lincosamide resistance is
increasing.3032 Inducible resistance, related to the erm
gene, results in strains that test clindamycin-susceptible in vitro, but may be resistant in vivo. A D-test can
be used to determine the presence of inducible resistance. In the D-test, clindaymcin and erythromycin
disks are placed close together on a culture plate. If
inducible lincosamide resistance is present, the zone
of inhibition around the clindamycin disk is flattened
on the side towards the erythromycin disk, resembling a capital letter D. Rates of inducible lincosamide
OTHER PYOGENIC SKIN INFECTIONS

AMONG ATHLETES
Group A streptococcal infections may also spread rapidly among athletes. Pyoderma with a nephritogenic
Streptococcus can cause epidermic glomerulonephritis.
Streptococci also produce erysipelas and lymphangitis
(see Chapters 177 and 178).
Pseudomonas infections are commonly associated
with water. Pseudomonas folliculitis, green nails, and
VIRAL SKIN INFECTIONS

Herpes simplex virus (see Chapter 193) can be transmitted by skin-to-skin contact during any contact sport.
Herpes gladiatorum is recognized as a major problem
among wrestlers. Attack rates as high as 34% have been
reported. Ocular involvement is a serious complication. Wrestlers with active infections are barred from
participation. The use of abrasive shirts may contribute
to the spread of herpes simplex virus infection among
wrestlers. They should be avoided. Oral antiviral drugs
such as acyclovir, valacyclovir, and famciclovir can be
used to shorten the course of an outbreak. It is likely
that all three of these drugs can prevent outbreaks of
herpes gladiatorum when given as long-term or periodic prophylaxis.
FUNGAL INFECTIONS
(See Chapter 188)
Cutaneous fungal infections are more common among
athletes than in the general population, and are particularly common among swimmers and soccer players.58,59
Tinea facei and tinea capitis are particularly common
among wrestlers and others who engage in close contact
sports.60,61 During an outbreak of Trichophyton tonsurans
tinea in Japan, 52% of the patients were Judo participants and 39% were wrestlers.62 Asymptomatic carriage and poor compliance with eradication regimens
is common in this setting and contributes to the spread
of the disease.6365 Many of the implicated strains were
recently imported to Japan, spread first through martial
arts, then to the community at large.66 Tinea pedis may
be spread by floors around swimming pools. Prevalence
among runners increases with age, and asymptomatic
carriers are common. Periodic prophylactic treatment of
carriers with topical agents to prevent clinical disease
may be possible, and oral prophylaxis with 100 mg of
fluconazole daily for 3 days twice during the season has
been shown to be effective in reducing the incidence of
fungal infections among high-school wrestlers. In one
study, the incidence rate of tinea gladiatorum dropped
from 67.4% to 3.5% as a result of intervention.67
Sports Dermatology
Nasal colonization correlates poorly with cutaneous

MRSA infection, suggesting that other sites of carriage
and close physical contact with carriers are important in
disease transmission.46 Cutaneous carriage and fomites
are important in the spread of MRSA infection among
athletes, and preventive measures directed only at nasal
decolonization are frequently ineffective.47,48 Topical
antiseptics such as chlorhexidine, povidone iodine, quaternary ammonium compounds, triclosan, and Dakins
solution play an important role in management.49
Chlorhexidine gluconate is widely used and generally
has good activity against staphylococci. Some MRSA
isolates are less sensitive to chlorhexidine than methicillin-sensitive Staphylococcus aureus (MSSA) isolates.50,51
Some chlorhexidine-resistant isolates also exhibit resistance to quaternary ammonium compounds. Resistance
can be overcome by using disinfectants containing both
alcohol and chlorhexidine.52 Seventy percent ethanol
alone is an effective agent for fomite sterilization if contact can be maintained for 3 minutes.53 Povidone iodine
has shown good activity against both MRSA and MSSA
isolates.81 Triclosan-based products are readily available
as no-wash hand sterilizers. Some triclosan resistance
has been documented, and some MRSA isolates are
less sensitive than MSSA isolates.54,55 Mupirocin is commonly used to treat staphylococcal nasal carriage, but
resistant strains have emerged.56 In one double-blind,
placebo-controlled trial, successful nasal eradication
was only 44%.57
17
::
PREVENTION
Pseudomonas webspace infection are the most common

(see Chapter 180 and online edition).
Chapter 99
resistance vary from 8% in Houston to 94% in Chicago.3337 In some areas in the United States, MRSA
strains were less likely than methicillin-sensitive
strains to demonstrate inducible resistance.38 In contrast, some locations in Asia report that 100% of tested
MRSA strains demonstrate the ermB gene.39
Some serious MRSA infections will require the use of
linezolid, vancomycin, fluoroquinolones, daptomycin,
quinupristin/dalfopristin, or newer generation carbapenems. Fluoroquinolones and linezolid, have the
advantage of oral administration. In some groups of
severely ill patients, linezolid has proved superior to
vancomycin.4042 Daptomycin has been used effectively
in serious MRSA infections, but resistance has been
reported, and disk diffusion testing may not predict
clinical outcome.43,44 A new cephalosporin, ceftobiprole
medocaril appears to offer a good balance of efficacy
and tolerability.45
TRANSMISSION OF BLOOD-BORNE
PATHOGENS
There is growing concern about possible transmission
of blood-borne pathogens during contact sports. Minor
cuts and abrasions are both a source of contamination
and a portal of entry for human immunodeficiency
virus and hepatitis viruses. Lacerations can be covered
with self-adherent biosynthetic dressings to prevent
blood transmission from minor wounds during contact
sports.
1117
17
HEAT AND COLD INJURY
Section 17
::
Heat injury is a common cause of morbidity during

sports. The skin serves as the major organ of thermal
regulation. Regular exercise modifies the responsiveness of cutaneous vessels, increasing cutaneous perfusion during periods of activity.68 The duration of
exercise can be safely increased in hot environments if
a volume of fluid at least equal to that lost in sweat is
ingested within 60 minutes prior to and during exercise.69 Uniforms promote heat retention, and adequate
skin surface must be exposed during exercise in order to
reduce the risk of heat stress injury. Evaporative cooling
from forearm skin is more efficient than that from the
upper trunk; therefore, short sleeve uniforms are helpful in hot climates.70 Clothing should be lightweight
and have high water permeability in order to facilitate
evaporative cooling. At high humidity, evaporative
cooling from skin is inefficient and the risk of heat stress
increases. Spraying of water on the skin during exercise
can reduce skin temperature, but results in vasoconstriction and does not reduce core body temperature.71
Cooling vests can improve athletic performance in hot
weather.72,73 Harlequin syndrome is a disorder of the
sympathetic nervous system with diminished sweating
and flushing in response to exercise.74
Younger athletes have a greater skin surface area,
which places them at greater risk for hypothermia in
cold environments. Skin injury, such as frostbite and
perniosis, are seen in sports enthusiasts who engage
in cold weather sports. Frostbite is a common problem among joggers, and may involve the face, hands,
feet and penis. The decreased oxygen tension at high
altitudes contributes to peripheral vasoconstriction,
decreasing peripheral blood flow and increasing the
risk of frostbite.75 Clothing must remain dry in order
to retain its insulating properties. Frequent changes of
socks and periodic breaks in a warm environment are
important safeguards. If frostbite occurs, rapid rewarming should be accomplished as soon as the individual is
in a safe environment with no risk of refreezing.
SKIN INJURIES
Skin and soft tissue injuries are common among
athletes.76,77 New treatments, including hydroactive wound dressings, have advanced the treatment
of superficial wounds. Application of a hydroactive
dressing can provide a protective barrier that can
allow an athlete to return to training. Cold gel application has been shown to provide effective symptomatic
relief for sports-related soft tissue injuries.
FRICTION BLISTERS
1118
Friction blisters occur as a result of midepidermal

necrosis (Fig. 99-3). Proper fitting of footwear and the
use of gloves and chalk can reduce the incidence of
blistering. Heat, sweating, and maceration increase
the risk of blistering. Antiperspirants have been used
Figure 99-3 Friction blisters are a manifestation of intraepidermal necrosis.
in an attempt to reduce the incidence of blistering,

but results have been mixed, and they may cause irritant dermatitis. Attempts to reduce the incidence of
irritant dermatitis through the addition of emollients
reduce the efficacy of the antiperspirant. In a study
of cross-country hikers, use of a 20% solution of aluminum chloride hexahydrate in anhydrous alcohol
reduced the rate of blister formation from 48%21%,
but the incidence of irritant dermatitis was high and
noncompliance with the treatment regimen was common. The use of closed-cell neoprene insoles, acrylic
socks, or thin polyester socks combined with thick
wool or polypropylene socks that maintain their bulk
can reduce the incidence of blisters. The use of meshtop footwear can decrease the risk of blistering by providing a cooler, dryer environment without the use of
antiperspirants. A unique form of friction dermatitis
occurs in Sumo wrestlers.78
LIME BURNS
The use of calcium oxide (quicklime) or calcium
hydroxide (slaked lime) instead of calcium carbonate (chalk) to line sports fields may result in chemical
burns, especially in wet weather. Second- and thirddegree burns may occur. Lime use may also result in
severe inhalation and ocular injury.
ATHLETES NODULES
Collagenous surfers nodules are a well-described
complication of surfboarding. Boxers, marbles players,
and football players are also prone to collagenous nodules. Surgical excision may be required.
ACTINIC DAMAGE
BITES AND STINGS

Actinic irradiation can cause burns and a risk of skin
cancer in later life. Even relatively short periods of exposure during sports are associated with an increased risk
of basal cell carcinoma. Sweating alters hydration of
the stratum corneum and lowers the minimal erythema
dose of ultraviolet (UVB) light by as much as 40.9%
after just 15 minutes of jogging. Actinic exposures are
particularly high during nautical and mountain sports
and participation in water sports and marathons are
independent risk factors for both melanoma and nonmelanoma skin cancer.7982 Athletes should be advised
to reduce UV exposure by choosing training schedules
with lower sun exposure, wearing UV-protective clothing, and using water-resistant sunscreens.
Unexpected bites and stings are frequent while playing sports and may result in both local injury and anaphylaxis (see Chapter 210).
SKIN PROBLEMS RELATED TO

WATER SPORTS
::
Sports Dermatology
Figure 99-4 Athletic shoe allergic contact dermatitis.
Figure 99-5 Finger dermatitis in this diver paralleled the

intensity of her training. It resolved during breaks from
training.
Chapter 99
(See Chapter 13)

Rubber allergens are the most common cause of
sports-associated allergic contact dermatitis (Fig. 99-4).83
Rubber adhesives and rubber chemicals in the box toe
and cushioning materials can cause dermatitis from
footwear. Contact dermatitis can also result from equipment, swimming-pool chemicals, athletic tape, epoxy
resins associated with golf clubs or bowling balls, and
topical creams and sprays.8486 Wetsuit dermatitis is
usually related to thioureas but may also be caused by
p-tert-butylphenol formaldehyde resin and zinc diethyldithiocarbamate.87 Clothing dermatitis in athletes may
relate to fabric softener, textile finishes, dyes, or designs
applied to the fabric. Textile dye penetration of skin is
more closely related to the degree of sweating rather
than the duration of contact between fabric and skin.88
Dermatitis under soccer shin guards more commonly
represents irritant dermatitis related to sweating and
friction rather than allergic contact dermatitis.89
Skin eruptions account for almost half of all illnesses

related to recreational water. Monitoring of water for
fecal coliforms has been practiced for years and has
proved to be a better predictor of the risk of skin disease than of the risk of gastrointestinal disease. Contamination by storm runoff results in a predominance
of organisms linked to skin infections. Water and activity can rapidly reduce the effect of many sunscreens,
although some newer formulations retain their efficacy
better under these conditions.90
Exposure to the rough surfaces of diving boards
can result in a chronic plantar dermatosis. The fingers
can also be affected. Some individuals with this disorder have a history of atopic dermatitis, psoriasis,
or juvenile plantar dermatosis. The rough interior of
swimming pools can result in pool palms. The skin
appears taut, shiny, and erythematous with loss of
dermatoglyphics (Fig. 99-5). Green hair is related to
the presence of copper in pool water. Copper pipes or
algicides may be the source of the high copper levels.
Acidic pH, fluoridation of water, and swimming pool
chlorination all contribute to the release of copper into
pool water. Green hair has been treated with penicillamine shampoo, hot vegetable oil, hydrogen peroxide,
edetic acid, and 1-hydroxyethyl diphosphonic acid.
Swimming pool water may be treated with chlorine,
bromine, or ozone ionization. All three methods are
acceptable, although the use of bromine with ozone
may be associated with a slightly lower risk of cutaneous reactions.
ALLERGIC CONTACT DERMATITIS
17
1119
17
Section 17
::
1120
SWIMMERS ITCH
(See Chapter 209)
Swimmers itch is related to avian schistosome
cercariae.91 Newly created bodies of water, such as
recently abandoned quarries, are associated with a
lower incidence of swimmers itch. Administration
of praziquantel to ducks inhabiting a lake can reduce
the incidence of swimmers itch. Chemical control or
mechanical removal of snails can also be effective. The
rash heals spontaneously in 23 weeks. Topical steroids and antihistamines may be beneficial. Topical
antipenetrants have been evaluated, but an ointment
based on IR3535 (ethyl butylacetylaminopropionate)
failed to prevent an outbreak of cercarial dermatitis
during swimming races across Lake Annecy in France.
SEA BATHERS ERUPTION

(See Chapter 209 and online edition)
OTHER SKIN PROBLEMS RELATED

TO OCEAN SPORTS
Jellyfish stings result in immediate pain and may
produce delayed immune-mediated reactions. Cyanea
and Chrysaora sea nettles are the most common causes
of jellyfish dermatitis. Chrysaora jellies are especially
common off Atlantic beaches. Physalia physalis, the Portuguese man-of-war, is common in the southeastern
United States and the Gulf of Mexico. Physalia utriculus,
the blue bottle jellyfish, is native to the Pacific. Stings
of Chironex fleckeri, the Pacific box jellyfish or sea wasp,
may result in shock or death. Victims of any marine
envenomation should immediately be removed from
the water. Administration of antivenin can prevent
cardiovascular collapse. Verapamil shows little effect
in experimental animals and may negate some of the
beneficial effect of antivenin. Unlike verapamil, MgSO4
has been shown to prevent cardiovascular collapse in
test animals. First aid includes mechanical removal
of tentacles by seawater and sand. Most northern sea
nettle nematocysts are inactivated in alkaline conditions, and most man-of-war nematocysts are inactivated in acidic conditions; however, the use of either
acid or alkaline solutions can be complicated by the
release of venom in some species. Application of ice
can provide analgesia. Most marine venoms are inactivated by heat, and hot water immersion [40C41C
(104F105.8F)] generally results in better pain relief.
Jellyfish sting inhibitors can be added to sunscreen
lotions. Haloclava producta, the ghost anemone, is
responsible for summer outbreaks of dermatitis off the
coast of Long Island, New York.
Stingray injury usually occurs when a swimmer
accidentally steps on a ray. Roughly 750 stingray stings
are reported each year off the US coast. Stings are associated with severe pain, hyperhidrosis, hypotension,
muscle cramps, and dysrhythmia. Tissue necrosis can
be extensive, and surgical exploration is commonly

required. Hot water immersion is effective in the control of acute pain but may not prevent skin necrosis.
Lionfish are most common in the subtropical waters of
the Pacific but are increasingly being reported off the
coast of the United States. Stings cause pain, swelling,
redness, bleeding, and mild systemic symptoms. Hot
water immersion generally produces pain relief. Surgical exploration may be prudent for injuries involving
the hands.
Corals, especially fire coral, can produce contact dermatitis in divers. Their stinging cells produce a powerful
irritant that can produce severe local reactions, including reactions that resemble full-thickness burns. Contact
with seaweed has been implicated in vesiculobullous
reactions. Algal organisms in seaweed can cause stinging seaweed dermatitis and pustular folliculitis.
Mycobacterium marinum can cause epidemics of
swimming pool granuloma (see Chapter 184). Mycobacterial infections are also commonly acquired in
brackish coastal waters. Marine Vibrio infections (see
Chapter 180) also occur with exposure to brackish
coastal waters. Necrotizing fasciitis and sepsis may
occur. Culture of specimens from wounds contaminated with seawater has a greater yield if thiosulfatecitrate-bile-sucrose agar is used, and the cultures are
incubated both at room temperature and at 30C (86F).
Decompression injury may affect the skin of divers. Livedo reticularis is commonly noted. In a porcine
model of decompression injury, vascular congestion
and vasculitis were common findings in skin biopsy
specimens.
HISTAMINE-MEDIATED REACTIONS
Exercise-associated urticarial reactions include cholinergic urticaria, solar urticaria, symptomatic dermatographism, pressure-induced urticaria, cold urticaria,
aquagenic urticaria, latex-induced contact urticaria,
and exercise-induced anaphylaxis. These entities are
ACNEIFORM LESIONS
Acne mechanica is common among athletes, occurring
under chinstraps, helmets, and shoulder pads. The
lesions may respond better to keratolytics than to antibacterial agents. Severe acne may be a sign of anabolic
steroid use.92 The use of these drugs is widespread
among athletes of all ages. Some studies suggest that
healthcare providers provide illegal androgens to up
to 48.1% of abusers, and physicians are involved in
illegal prescription of anabolic steroids in 32.1% of
cases.93 There is an alarming trend to combine anabolic
steroids with human growth hormone, insulin, and
insulinotropic milk protein-fortified drinks to potentiate the effect of each agent.94 Although the standard
in drug testing is immunoassay screening followed by
gas chromatographymass spectrometry of urine samples to provide confirmation, newer technology may
allow reliable detection of anabolic steroids in hair.
DERMATOLOGIC PROBLEMS
OF SPECIAL ATHLETES

1. Cordoro KM, Ganz JE: Training room management of
medical conditions: Sports dermatology. Clin Sports Med
24(3):565-599, 2005
Decubitus (Pressure) Ulcers
::
KEY REFERENCES
17
Chapter 100
Patients with preexisting dermatoses may experience

koebnerization or pathergy following cutaneous injuries related to sports.95 Athletes with atopic eczema
may experience bouts of pruritus with exercise. However, there is evidence that the sweating and vascular
response improve with athletic training and that athletics may not interfere with treatment of atopic dermatitis.96,97 Application of an emollient after showering and
short periods of rest can inhibit sweat-induced itching
in atopic athletes, and regular moderate exercise does
not cause deterioration in the condition of their skin.98
The athlete treated with oral retinoids also faces special problems. Arthralgia, staphylococcal colonization,
photosensitization, and fatigue may result in lost training time or lost seasons. Retinoids cause disruption of
epidermal integrity and skin fragility. Greater trochanter enthesopathy (pain at the site of tendon insertion)
may be a complication of short-term oral retinoid therapy in athletes.99 When possible, retinoid treatment
should be planned between seasons.
2. Pecci M, Comeau D, Chawla V: Skin conditions in the athlete. Am J Sports Med 37(2):406-418, 2009
10. Redziniak DE et al: Methicillin-resistant Staphylococcus aureus (MRSA) in the Athlete. Int J Sports Med 30(8):557-562,
2009
14. Cohen PR: Cutaneous community-acquired methicillinresistant Staphylococcus aureus infection in participants of
athletic activities. South Med J 99(6):596-602, 2005
16. Centers for Disease Control and Prevention (CDC):
Methicillin-resistant Staphylococcus aureus infections
among competitive sports participantsColorado, Indiana, Pennsylvania, and Los Angeles County, 2000-2003.
MMWR 52(33):793-795, 2003
19. Kazakova SV et al: A clone of methicillin-resistant Staphylococcus aureus among professional football players. N
Engl J Med 352(5):468-475, 2005
23. Centers for Disease Control and Prevention (CDC):
Methicillin-resistant Staphylococcus aureus among players on a high school football teamNew York City, 2007.
MMWR Mortal 58(3):52-55, 2009
24. Fridkin SK et al: Active Bacterial Core Surveillance Program of the Emerging Infections Program Network.
Methicillin-resistant Staphylococcus aureus disease in three
communities. N Engl J Med 352(14):1436-1444, 2005
41. Sharpe JN, Shively EH, Polk HC Jr: Clinical and economic
outcomes of oral linezolid versus intravenous vancomycin in the treatment of MRSA-complicated, lower-extremity skin and soft-tissue infections caused by methicillinresistant Staphylococcus aureus. Am J Surg 189(4):425-428,
2005
47. Garza D et al: Ineffectiveness of surveillance to control
community-acquired methicillin-resistant Staphylococcus
aureus in a professional football team. Clin J Sport Med
19(6):499-501, 2009
49. Elston DM: Handling a community-acquired methicillinresistant Staphylococcus aureus outbreak: Emerging data.
Cutis 82(2 Suppl. 2):13-17, 2008
67. Brickman K et al: Fluconazole as a prophylactic measure
for tinea gladiatorum in high school wrestlers. Clin J Sport
Med 19(5):412-414, 2009
Chapter 100 :: Decubitus (Pressure) Ulcers

:: Jennifer G. Powers, Lillian Odo, &
Tania J. Phillips
PRESSURE ULCERS1,2 AT A GLANCE
Commonly known as decubitus ulcers,
pressure sores, and bedsores.
Affect approximately 0.5% to 2.2% of the
population.
Related risk factors are prolonged

immobilization, sensory deficit, impaired
consciousness, circulatory disturbance, poor
nutrition, and chronic diseases.
Tend to occur over bony prominences, more

common from the waist down.
Staged according to the degree of tissue

damage observed (I to IV); pathologic
findings depend on the stage of evolution.
Etiologic factors include pressure, shearing,

frictional forces, and moisture.
No specific laboratory findings. The

diagnosis is made clinically.
1121
17
Section 17
::
1122
EPIDEMIOLOGY
Estimates are that between 1.5 and 3 million people in
the United States have pressure ulcers. Hospital stays
with pressure ulcers listed as a diagnosis increased
by nearly 80% in the United States between 1993 and
2006. These chronic wounds cost approximately $5 billion annually to treat, and Center for Medicaid and
Medicare Services (CMS) no longer reimburses for
additional costs arising from nosocomial stage III or IV
pressure ulcers.16
The prevalence and incidence of pressure ulcers varies with the clinical setting. In acute care, the incidence
ranges from 0.4% to 38%; in long-term care, from 2.2%
to 23.9%; and in home care, from 0% to 17%. Most pressure ulcers develop during the first few weeks of hospitalization. The prevalence of pressure ulcers in acute
care settings is approximately 15%, in long-term care
settings from 2.3% to 28%, and in home care from 0%
to 29%.14
Pressure ulcers are more common in the elderly,
especially those over the age of 70, in patients who
have had surgery for hip fracture, and in patients with
spinal cord injury. A multicenter study of 3,233 elderly
admitted from the emergency demonstrated a pressure-ulcer incidence (mostly stage II) of 6.2% on hospital day 3, with significant associations to advanced
age, male gender, dry skin, urinary and fecal incontinence, difficulty turning in bed, and poor nutritional
status.7
The majority of pressure ulcers occur on the lower
part of the body, 65% in the pelvic area and 30% on the
lower limbs, though other locations include the scalp
in infants with neurological injury or the face from
endotracheal tubes during long surgeries or intensive
care unit (ICU) stays.14

The main etiologic factors contributing to pressure
ulcer development include pressure, shearing forces,
friction, and moisture.
Pressure or force per unit area is considered to be the
most important factor in pressure ulcer formation. Normal
tissue pressure is between 12 and 32 mm Hg. Pressures
higher than this upper limit can compromise tissue circulation and oxygenation. When a patient lies immobile on a
hospital bed, pressures as high as 150 mm Hg can be generated, especially over bony prominences. At pressures
of 70 mm Hg or more, there is an inverse timepressure
curve with rapid pressure ulcer formation.2 Sitting positions can also generate elevated pressure over precise
body surfaces. The duration as well as degree of pressure is important. If pressure is relieved regularly, tissue
recovery can occur, whereas constant pressure can lead
to tissue death (Fig. 100-1). Often, damage occurs deep
at the bonemuscle interface, in which the limited cutaneous injuries may be only the tip of the iceberg of
deeper, more extensive damage (eFig. 100-1.1 in online
edition). Patients who are immobile should therefore
be turned regularly to prevent pressure ulceration. The
Figure 100-1 Pressure ulcer, stage IV. (From Wolff K and

Johnson RA. Fitzpatricks Color Atlas, 2009.)
pathophysiology of pressure ulcer formation is summarized in eFigure 100-1.2 in online edition, and common
sites of pressure ulcers are shown in Figure 100-2.
Shear force results from the motion of bone and subcutaneous tissues relative to the skin when the skin is
fixed (e.g., when the upper body of a supine patient is
raised to an angle above 30 and the skin remains in
contact with the bed). Shearing forces are parallel to the
tissue surface, and the subsequent sliding pressure is
transmitted to deeper tissues, which can become angulated and occlude the blood vessels (Fig. 100-3A). Spinal cord injury patients develop such shearing forces
with muscle spasms, which may be controlled with
muscle relaxants.8
Friction is the force that resists the relative motion
between two surfaces that are in contact. This causes
damage to the superficial layers of the skin (e.g., when
a patient is dragged across the bedsheets) (Fig. 100-3B).
A moist environment from urinary or fecal incontinence, perspiration, or excessive wound drainage can
cause maceration of the skin, which increases the risk
of pressure ulcer formation fivefold (Fig. 100-4). Other
risk factors for pressure ulcer development include
prolonged immobilization, sensory deficit, circulatory
disturbances, poor nutrition, acute illness, advanced
age, and a previous history of pressure ulcers as well as
fecal and urinary incontinence, hip fractures, smoking,
and dry skin. Concomitant use of medications such as
corticosteroids, which can impair healing; sedatives
and analgesics, which can impair consciousness; and
drugs that can cause alterations in cutaneous blood
flow, such as antihypertensive medications, can also
increase pressure ulcer risk, and such drugs should be
used with care (Table 100-1).
CLINICAL FINDINGS
(See eFig. 100-4.1 in online edition)
HISTORY
History taking and physical examination for pressure
ulcer patients should incorporate a risk assessment scale.
Common sites of pressure ulcer development
17
Chapter 100
::
Figure 100-2 Common sites of pressure ulcer development. (From Preventing Pressure Ulcers: A Patients Guide. Washington, DC, US Department of Health and Human Services, USGPO 617-025/68298, 1992.)
A number of risk assessment tools have been devised
in an attempt to identify persons at risk for pressure
ulcers. The Braden, Waterlow, and Norton scales have
been extensively tested for reliability and validity and
have been recommended by the Agency for Healthcare
Research and Quality for predicting the risk of developing pressure sores. Currently, best practices in acute
care, long-term care, and home-health care dictate that
such risk assessments be performed initially at admission and at subsequent precise intervals. Components
of these scales assess the following risk factors: mobility,
activity level, nutritional status, mental status, incontinence/moisture conditions, general physical condition,
skin appearance, medication use, friction and shear,
weight, age, predisposing diseases, and prolonged pressure (eTable 100-1.1 in online edition).
1123
17
Shear force generated
Section 17
::
Figure 100-3 Shear force generated when a patient slides

down a bed, for example, in the sacral region (A) or on the
heels (B). (From Grey JE, Harding KG, Enoch S: Pressure
ulcers. BMJ 332:472, 2006, with permission of Blackwell
Publishing.)
CUTANEOUS LESIONS
Staging is an assessment system that classifies pressure
ulcers based on anatomic depth of soft-tissue damage.
Pressure ulcers often progress from lower to higher
TABLE 100-1
Major Risk Factors for Developing Pressure Ulcers

Alteration in sensation or response to discomfort
Degenerative neurologic disease
Cerebrovascular disease
Central nervous system injury
Depression
Drugs that adversely affect alertness
Alteration in mobility
Neurologic disease or injury
Fractures
Pain
Use of restraints
Significant changes in weight (5% in 30 days or 10% in
previous 180 days)
Proteincalorie undernutrition
Edema
Incontinence
Bowel and bladder
1124
Excerpted from American Medical Directors Association: Clinical

Practice Guideline: Pressure Ulcers. Columbia, MD, American Medical Directors Association, 2008. 2008 American Medical Directors
Association.
Figure 100-4 Pressure ulcer, stage III, complicated by

fecal incontinence.
stages, and any small pressure ulcer should be considered as the possible tip of an iceberg. Table 100-2
shows the clinical appearance of pressure lesions and
ulcers and their histopathologic correlates as defined by
the National Pressure Ulcer Advisory Panel (NPUAP).
Palpation is important to assist visual evaluation. Ulcers
that initially appear superficial can end up being classified as stage III or IV after dbridement reveals their
true depth. The epidermis may be hypertrophic at the
ulcer margin with varying degrees of pigmentation.10
There are several staging systems for classifying
pressure ulcers. The most commonly used include the
NPUAP, Shea, and Yarkony et al systems. In February
2007, the NPUAP redefined the stages of pressure ulcers
established in 1989 by preserving the four original stages
and adding two new stages of deep tissue injury and
unstageable pressure ulcers. The unstageable category
was created to avoid unnecessary removal of slough or
eschar simply for the purpose of staging, which might
hinder ulcer healing (Fig. 100-5). eTable 100-2.1 in online
edition compares these four classification systems.2,1013

All pressure ulcer patients should undergo a full physical examination to identify systemic disease contributing to wound development, such as anemia, chronic
cardiac or respiratory disease, and neurologic disorders.
Tenderness, erythema, edema and warmth of surrounding skin, exudate, and foul odor are symptoms
and signs of infection. Fever and declining mental or
physical status should raise suspicion of bacteremia or
osteomyelitis.
Spasticity secondary to inflammation and infection
may trigger muscle contractures and joint deformity
17
TABLE 100-2
Comparison of Clinical and Histologic Findings by Ulcer Stage

Clinical Findings
Histopathologic Description
Stage I
Nonblanchable
erythema of intact skin
Epidermis appears normal.

Striking red blood cell engorgement of capillaries
and venules, mainly in papillary dermis with platelet
thrombi and hemorrhage. Degeneration of sweat
glands and subcutaneous fat is often seen.
Stage II
Partial-thickness skin
loss involving epidermis,
dermis, or both
Epidermis is lost.
Dermal papillae are often identifiable. Acute
inflammation of papillary and reticular dermis is
found. In addition to a perivascular lymphocytic
infiltrate, neutrophils are seen.
Necrotic changes in the appendages and fat are
more pronounced.
Stage III
Full-thickness skin
loss involving damage
to or necrosis of
subcutaneous tissue that
may extend down to, but
not through, underlying
fascia.
Hemorrhagic crust containing acute inflammatory

cells or a thin zone of coagulation necrosis on the
surface.
Diffusely fibrotic dermis.
Loss of appendageal structures.
Stage IV
Full-thickness skin loss

with extensive necrosis
of or damage to muscle,
bone, or supporting
structures.
Full-thickness destruction of skin.

The tissue appears basophilic with obliteration
of cellular detail, although the general dermal
architecture is preserved.
Inflammatory infiltrate is often not seen.
Chapter 100
Classification/Stage9
::
NPUAP = National Pressure Ulcer Advisory Panel.
1125
17
Section 17
Figure 100-5 Unstageable pressure ulcer covered with

slough. (Used with permission from Mary Gloeckner, RN,
MS, CWOCN.)
assessing large, complicated lesions with associated

sinus tracts or extensive undermined margins. Computed tomography is the only radiographic modality
that can define the external margin of the lesion.
Magnetic resonance imaging (MRI) is helpful in
determining the depth and extent of soft-tissue involvement underlying decubitus ulcers. It can also be a useful tool for identifying osteomyelitis, fluid collections,
abscesses, and sinus tracts.15,16 The gold standard for
the diagnosis of osteomyelitis is histologic/microbiologic analysis of surgical biopsy specimens, but MRI is
accurate in the diagnosis of osteomyelitis (sensitivity,
98%; specificity 89%) and associated soft-tissue abnormalities. It also can delineate the extent of infection to
assist in guiding limited surgical resection and preserving viable tissue.14
TREATMENT
::
1126
that can limit motion, which complicates positioning.

Weakness and signs of anemia and dehydration can be
found secondary to profound loss of fluid and protein
from these open, draining wounds.
LABORATORY TESTS
The diagnosis is made clinically. However, anemia,
leukocytosis, hypoproteinemia, hypoalbuminemia,
elevated ESR, or reduced serum iron levels may be
present. It is important to exclude other diseases that
can cause skin ulcers, including calciphylaxis, vasculitis, and connective tissue diseases.
SPECIAL TESTS
BIOPSY. Histologic analysis may be helpful to diagnose the pressure ulcer stage when clinical findings
are insufficient to determine depth and exclude other
diseases that can present with skin ulcers such as collagen vascular diseases. In long-standing pressure
ulcers, squamous cell carcinoma can develop (Marjolins ulcer). Histologic findings in pressure ulcers are
described in Table 100-2.
IMAGING STUDIES. Radiology is most useful to
identify complications, particularly of deep pressure
sores. Plain radiographs can identify ectopic bone, air
in the ulcer cavity, and sclerotic or destructive changes
in the underlying bony prominence. Ectopic bone can
cause a pressure sore by altering the patients posture
and locally increasing pressure over soft tissue.14 When
there is clinical uncertainty about the size or extent of
a pressure ulcer, sinography can be performed. Direct
magnification radiography of sacral areas is useful
when plain radiographs leave doubt about the condition of the bony cortex adjacent to a pressure sore. If
the cortex is intact, osteomyelitis is unlikely.
Computed tomographic scanning is useful to determine the extent of a pressure ulcer and its anatomic
relation to surrounding structures. It is helpful in
Therapy should be individualized for each patient and

involves more than simple wound management. Pressure ulcers are frequently a clinical sign of underlying
medical conditions which should be treated to facilitate
healing. Treatment takes great coordination by inpatient facilities such as nursing homes, where caretakers
often use the NPUAP-designed PUSH (Pressure Ulcer
Scale for Healing) tool or the BatesJensen Wound
Assessment Tool (BWAT) to document wound healing.23,24 Photography can also be an important means of
documenting improvement and should include dimensions, date, and wound location.25 Few controlled trials have evaluated specific treatment modalities for
pressure ulcers, but reasonable interventions include
use of basic support surfaces, repositioning the patient,
optimizing nutritional status, and moisturizing sacral
skin with expectations of some improvement within
2 weeks.26 The general principles of therapy for pressure ulcers are as follows.
TABLE 100-3
Complications of Pressure Ulcers

Local infections
Bacteremia
Osteomyelitis
Sinus tracts
Malignancies
Myonecrosis
Metabolic alterations
Hypercalcemia
Hypoproteinemia
Anemia
Postsurgical complications
Hematoma
Seroma
Wound dehiscence
Abscess
Amyloidosis and others
Death
RELIEF OF PRESSURE, SHEAR, AND

FRICTIONAL FORCES
::
SUPPORT SURFACES. Support surfaces can

be used on top of or instead of standard mattresses.
They distribute pressure over a large surface area, and
the type of support surface used will depend on the
patients needs and abilities. Support surfaces are typically divided into static and dynamic, the latter powered by electricity (eTable 100-3.1 in online edition).
Static support surfaces are recommended for patients
who can assume several positions without bearing
weight on an ulcer. These include specialized foam
mattresses and mattresses with various fillings. They
may also be overlays used atop of a base mattress.
Low-tech foam mattresses are the most commonly used material for pressure reduction, given
their ease of use, affordability, and evidence base.
A Cochrane Systematic Review examined five trials
comparing foam alternatives with standard hospital
mattresses, demonstrating a relative risk reduction of
60% in pressure ulcer incidence with the use of foam
mattresses.28 Foam slabs should be 34 inches thick to
effectively reduce pressure. A trial with 70 intensive
care unit patients in France showed 85% risk reduction in heel ulcers in patients using a total foam body
support system compared to control groups receiving
17
Chapter 100
POSITIONING. Positioning techniques are critical

in the management of tissue loads.
While in bed, patients should be positioned to avoid
pressure over existing ulcers or over bony prominences, especially the trochanter. Pillows or foam
wedges can be used to raise a pressure ulcer off its support surface or to prevent direct contact between bony
prominences, such as knees or ankles. It is important
to limit the amount of time the head of the bed is elevated and to maintain the head of the bed at the lowest
possible level of elevation tolerable to reduce shearing
forces at sacral tissues. Immobilized patients are usually placed in a 30 oblique position to the left or right,
which should be alternated every 2 hours at a minimum. International best practices have validated this
approach though controlled studies are still needed.
The patient and caregivers must learn appropriate
transfer or mobilization techniques to avoid friction.
The patient should be lifted rather than dragged across
the bedsheets, using lifting devices such as a trapeze
or bed linen.27 Repositioning should be done as frequently as warranted by the patients condition.
Moisture from urinary or fecal incontinence, perspiration, or wound drainage should be minimized, and
the skin should be kept clean. Absorbing underpads
or briefs, diapers, and occasionally urinary catheters
or rectal tubes may be required to help manage incontinence. Skin barrier creams can help protect the skin
from maceration.
Patients, who are sitting, may select a pressurerelieving cushion based on specific needs. Donut-type
devices should be avoided because they result in venous
congestion and may worsen ulcers. Patients should be
encouraged to reposition themselves frequently.
standard pressure ulcer protocol including a water

mattress.29
Other low-tech pressure supports include static
supports filled with air, water, gel, silicone, polyvinyl,
heel elevators, and sheepskins. Most of them permit a
high degree of immersion, allowing the body to sink
into the surface as it conforms to the bony prominences. This increases the surface pressure distribution
area and lowers the interface pressure by transferring
the pressure to adjacent areas. Unfortunately, many of
the water-filled and bead-filled mattresses that demonstrated success in clinical trials are no longer available.
A Cochrane Systematic Review of two trials examining
the effects of sheepskins showed relative risk of 0.42
for pressure ulcer development compared to standard
low-tech support surfaces.28
Patients who cannot tolerate frequent turning, immobile patients, those with large or multiple ulcers, and
patients with unresponsive ulcers may require dynamic
support surfaces, which are electrically powered. These
provide cyclical, alternating pressure relief, and include
air-fluidized, low-air-loss, and/or alternating-air beds.
Air-fluidized beds contain microspheric silicon-coated
beads encased in an air-permeable fabric (polyester or
Gore-Tex). The beads are suspended by pressurized
streams of warmed air, which allows patients to float
and decreases pressure through the principle of immersion while simultaneously reducing shear. Feces and
body fluids flow freely through the sheet; thus, the skin
is kept dry.
Low-air-loss systems use a series of connected, airfilled cushions that are inflated to specific pressures.
Some have alternating and pulsating pressure features.
A prospective, randomized trial demonstrated that the
use of low-air-loss beds resulted in threefold faster
wound healing than use of a foam mattress.30 Unlike
with air-fluidized beds, urine and feces do not pass
through the fabric of low-air-loss beds.
Alternating-pressure systems distribute pressure by
shifting the body weight to different surface contact
areas. The air is pumped into the chambers at periodic intervals to inflate and deflate them in opposite
phases, which thereby changes the location of contact
pressure. Though alternating-pressure systems have
not been proven more efficacious than low-tech supports, a cost effectiveness analysis by the UK National
Health Service associated them with 80% probability
of being cost saving due to shorter hospital stays and
delay in ulceration.28,31
Other pressure supports that may be of modest
benefit include kinetic turning beds, operating table
overlays, and seat cushions. Kinetic turning beds are
primary used in ICU settings for pulmonary concerns.
Operating table overlays may decrease postoperative
pressure ulcer incidence and should be employed with
high-risk patients undergoing long procedures.
WOUND MANAGEMENT
CLEANSING. Cleansing should be performed gently to minimize mechanical and chemical trauma to
healing tissues. Normal saline is preferred because it
1127
17
Section 17
::
1128
is most physiologic in relation to the wound. Safe and

effective irrigation pressures for ulcers range from 4 to
15 psi; higher pressures than this may cause trauma
and drive bacteria into the wound tissue. Certain skin
cleansers and antiseptics such as povidone iodine,
sodium hypochlorite solution, hydrogen peroxide,
acetic acid, and liquid detergents should be avoided,
because these agents are cytotoxic and may retard epithelialization.
DBRIDEMENT. Ulcers with devitalized, necrotic

tissue should be dbrided, because necrotic tissue supports the growth of pathogenic organisms. Mechanical
dbridement techniques include application of moistened saline or wet-to-moist dressings, hydrotherapy
(whirlpool), wound irrigation, and application of dextranomers. Wet-to-dry dressings changed every 4 to
6 hours are painful and are nonselective for necrotic
tissue. Whirlpool devices can be considered for pressure ulcers with thick exudate, slough, or necrotic tissue. For wound irrigation, a large 35-mL syringe and
19-gauge angiocatheter can be used to provide adequate pressure.1
Sharp dbridement involves the use of a scalpel,
scissors, or other sharp instrument to remove devitalized tissue and is generally indicated in cases in which
there is eschar. For smaller ulcers, local anesthesia
can be used, whereas larger stage III or IV ulcers may
require extensive surgical dbridement under general
anesthesia. Enzymatic dbridement can be used in
patients who cannot tolerate surgery. Topical agents
such as sutilains, collagenase, fibrinolysin, and deoxyribonuclease can be used. Papain was removed from
the market due to hypersensitivity reactions.32 Dressings should be changed once to several times daily.
Contact dermatitis can sometimes occur, and these
agents should not be used if tendon is exposed.2
Autolytic dbridement involves the use of synthetic
dressings to cover the wound, which allows digestion of necrotic tissue by enzymes normally present in
wound fluids.
In addition to traditional dbridement methods, the
use of sterile fly larvae (maggots) to clean necrotic tissue is gaining popularity and appears to be safe and
effective.
DRESSING PRODUCTS. Dressings can help
protect the wound from the environment, reduce or
prevent wound infection, stimulate autolytic dbridement, reduce wound pain, and stimulate the development of granulation tissue. It has been demonstrated
experimentally that wounds maintained in a moist
environment heal 40% faster than air-exposed wounds.
Control of moisture and drainage from the wound
helps provide an optimum wound environment for
healing. There are several types of dressings, each one
of which has specific properties, advantages, and disadvantages (eTable 100-3.2 in online edition). Higher
stage ulcers usually require more absorptive dressings
to maintain a moist environment. A variety of specialized dressings may be helpful for pressure ulcer management, including a bilayer matrix wound dressing,
pig-derived acellular small intestine submucosa, and
natural latex biomembrane. Both the NPUAP and the

EPUAP (European Pressure Ulcer Advisory Panel)
state in their international pressure ulcer guidelines
that gauze dressings should be avoided in clean, open
pressure ulcers since they may stick to wounds, causing pain with dressing changes.24 In fact, a systematic
review of 29 studies demonstrated hydrocolloid dressings to be superior to gauze in terms of pressure ulcer
healing, pain associated with dressing change, absorption capacity, side effects, and cost.33
Intact skin surrounding the ulcer should always be
assessed for signs of inflammation and infection. Irritation of surrounding skin may result from epidermal
skin stripping during dressing changes or maceration
secondary to contact with feces, urine, or wound drainage. Periwound skin must be adequately moisturized
but neither macerated nor eroded.28 A randomized
clinical trial of 331 patients over a 30-day period demonstrated pressure ulcer incidence was 7.32% in a group
of patients treated twice daily over high-risk sites with
Mepentol, a hyperoxygenated fatty acid preparation,
compared with 17.37% in the placebo group treated
with a generic greasy product. In addition, Mepentol,
comprised of such compounds as oleic acid, linoleic
acid, arachidonic acid, and eicosenoic acid was found to
be cost effective.34 Creams or gels containing metronidazole, balsam of Peru, trypsin, and recombinant human
platelet-derived growth factor are also available.
BACTERIAL COLONIZATION AND

INFECTION MANAGEMENT
Ulcer cleansing and dbridement are important to control microbial burden in pressure sores. Systemic antibiotic therapy is not recommended for contamination
or minor localized infections but is indicated when
bacteremia, cellulitis, or osteomyelitis is present.
Topical antibiotics are used to prevent or treat
wound infection, reduce bacterial load, or reduce odor
and signs of inflammation. Topical antibiotics such as
neomycin and bacitracin are common allergens and
can cause contact dermatitis and, rarely, anaphylaxis.
Topical formulations of antibiotics that are used systemically (e.g., gentamicin) should be avoided because
bacterial resistance may develop. However, the Agency
for Healthcare Research and Quality guideline recommends a short 2-week course of topical antibiotics for
a clean ulcer that is not healing or that is producing
a moderate amount of exudate despite appropriate
care.35 The use of topical metronidazole 1% solution or
0.75% or 0.80% gel has gained popularity in reduction
of wound odor, though randomized controlled trials
are still needed to prove efficacy.36
PAIN MANAGEMENT
Pain management requires a combination of conservative measures, medications, and appropriate wound
care. Muscle relaxants and physical and occupational
therapy may be helpful to decrease muscle spasm in
the area of ulceration. Transcutaneous electrical nerve
TABLE 100-4
Preventive Measures
Maintain personal hygiene. Consider topical lotions
containing fatty acids.
Try to assure adequate nutrition and hydration.
Evaluate and manage urinary and fecal incontinence.
Position to alleviate pressure over bony prominences and
shearing forces over heels and elbows, base of head, and ears.
Try to reposition every 2 h when in bed and every hour when
in a chair; if alert and capable, the patient should be taught to
shift his or her weight every 15 min while in a chair.
Try to avoid placing the patient on his or her trochanters or

directly on the wound.
Try to prevent contractures.

Do not massage reddened areas over bony prominences.
Modified from American Medical Directors Association: Clinical Practice
Guideline: Pressure Ulcers. Columbia, MD, American Medical Directors
Association, 2008. 2008 American Medical Directors Association.
stimulation may help relieve acute and chronic pain.

The use of topical anesthetics such as lidocaine-prilocaine cream on wounds 30 minutes before dbridement
significantly reduces pain associated with wound care
procedures. An opiate diamorphine gel was also shown
KEY REFERENCES
Body Art
Use lifting devices such as draw sheets or a trapeze.
Preventive actions can decrease the patients risk of

developing pressure ulcers. These steps can also keep
pressure ulcers from getting worse. Preventive measures are listed in Table 100-4.
::
Maintain the lowest head elevation possible (no greater than

30)
PREVENTION
17
Chapter 101
Use appropriate positioning devices and foam padding; do

not use donut-shaped devices. Consider dynamic supports in
high-risk patients.
to significantly reduce pain with dressing changes in a

small randomized controlled trial of patients with stage
II and III ulcers.37
Nonopioid analgesics (aspirin, other nonsteroidal
anti-inflammatory drugs) are first-line systemic therapy, followed by stronger medications such as opioids.
Adjuvant medications such as tricyclic antidepressants can be used to enhance analgesia.37 They can also
improve depression in some chronic pain states and
have sedative, sleep-enhancing qualities.

2. Kanj LF, Wilking SVB, and Phillips TJ: Pressure ulcers. J
9. Shea JD: Pressure sores: Classification and management.
Clin Orthop Relat Res 112:89, 1975
26. Reddy M, Gill SS, Rochon PA: Preventing pressure ulcers:
A systematic review. JAMA 296:974, 2006
28. McInnes E et al: Support surfaces for pressure ulcer prevention. Cochrane Database Syst Rev 4:CD001735, 2008
38. Langer G et al: Nutritional interventions for preventing
and treating pressure ulcers. Cochrane Database Syst Rev
4:CD003216, 2003
Chapter 101 :: Body Art

:: Anne Laumann
BODY ART AT A GLANCE
Tattoos are common: 24% of the US 18- to
50-year-olds in 2004, equal numbers of men
and women.
Tattooing medical complications are rare:
mainly related to pigment ingredients,
but include viral, bacterial, fungal, and
transfusion-transmitted diseases.
Tattoo social associations and difficulties are
significant.
Piercing: soft earlobes 37% and body

piercing excluding the soft earlobe 14% of
the US 18- to 50-year-olds in 2004, mainly
women; 46% of women aged 1624 in the
United Kingdom in 2005. Body piercing
fashion started in the late 1980s.
Piercing medical complications are common:
metal-induced contact allergic dermatitis,
broken teeth, anesthetic risks, and infections
of all types.
The relationship of body art to hepatitis is
unclear.
1129
17
Section 17
::
1130
DEFINITIONS
Body art is art made on, with, or consisting of, the
human body. The most common forms of body art are
tattoos, body piercings, and body painting, but other
types include scarification, branding, tongue splitting, subdermal and extraocular implants. Tattooing is
the practice of producing an indelible mark or figure
on the human body by inserting pigment under the
skin using needles or other sharp instruments.1 Body
piercing refers to the cosmetic piercing of body parts
for the implantation of objects such as rings, studs, or
pins.2 Body painting is the application of paint on to
the skin and includes face painting, the application of
mehndi and temporary tattoos. Scarification is a means
of permanently marking the skin by cutting alone,
without the use of pigments. This includes the deliberate formation of keloids. When purposeful thirddegree burns are used to induce a scar, the procedure
is called branding.3 Tongue splitting is the bisection
of the tongue from the tip toward the back for about
35 cm leading to an appearance similar to the tongue
of a lizard.4,5 Subdermal implantation is the placing of a
foreign body under the skin so that none of the object
remains outside of the body. A three-dimensional
effect is seen on the surface. Materials used are silicone, Teflon, or metal.6
Extraocular implantation is the placing of sterile nonpyrogenic platinum jewelry inside the interpalpebral
conjunctiva of the eye.7
TATTOOING
EPIDEMIOLOGY AND BACKGROUND
The word tattoo is said to come from Captain Cook
after he saw markings on the bodies of the Polynesian
people during his 1769 South Pacific voyage. Ta-Tu
means to mark in Tahitian and is associated with
the sound made by the Tahitian tattoo instrument.8
However, tattoos have probably been performed since
the beginning of humanity. The famous Ice Man dating from 3300 BC found in the mountains of Europe
was covered in tattoos, and they are seen on Egyptian
mummies dating from 2000 BC. Tattoos were a sign
of nobility, bravery and beauty. They are forbidden in
the Old Testament in both Leviticus and Deuteronomy
and in the Koran. Despite this, the practice has persisted and has been popular in Europe and America.
During the Depression, the prevalence of tattooing
declined as incomes shrank. Nondecorative tattoos
were used to identify slaves, criminals and internees
in prisoner of war and concentration camps during the
Second World War. Military personnel often had tattoos with patriotic designs, together with hearts and
the names of loved ones. With the advent of peace,
the popularity of tattoos decreased, although they
were still seen in close-knit group situations. They
became associated with marginalized groups, signaling time spent in jail, punk status, membership in a
motorcycle gang or a traveling circus. In recent times,
images have become increasingly eclectic and the practice has become mainstream.9
Studies performed in 2008,10 2006,11 and 200412 found
that 14% of 18- to 64-year-olds in the United States
have tattoos, including approximately 30% of those
under the age of 40. They are equally common among
men and women and are seen in all ethnic groups.
They are still found more commonly in those with a
military association and in those of low educational
and socioeconomic backgrounds. They are associated
with the abuse of alcohol, the taking of illicit drugs
and having spent significant time in prison.13 They are
inversely associated with having a religious affiliation
and having never drunk alcohol. Most tattoos are done
in a dedicated studio, but approximately a quarter of
people with tattoos have had at least one tattoo done
elsewhere.
PROCESS
A handheld device, powered by low-voltage direct
current, holds solid needles placed singly or in groups
of up to fourteen on an oscillating bar (Fig. 101-1). The
needles are dipped into colored inks and then moved
across the skin in the desired pattern, penetrating rapidly and vertically 0.52.0 mm into the skin, depositing
the pigment into the dermis. A thin layer of petroleum
jelly is applied to the skin prior to and during the procedure to minimize blood loss and prevent spatter. After
the tattoo is finished, the area is cleaned with a mixture
of alcohol and water, and more ointment is applied.
Sometimes, the ink is spread over an area of skin and
the needles made to penetrate through it to carry the
particles into the skin. Amateur tattooers often do it
this way using handheld needles wound round with
thread to prevent too deep penetration. Other instruments used may be pencils, pens, and straight pins.
Figure 101-1 Tattooing with a handheld electric tattoo

machine.
17
Chapter 101
::
Much of the pigment is extruded through the epidermis during the first 10 days (Fig. 101-2). The final location of the pigment is in the mid-to-lower dermis (Fig.
101-3), but the pigment in amateur tattoos tends to be
more superficially and more variably placed. The particles are membrane bound (in secondary lysosomes)
within fibroblasts, macrophages and occasionally mast
cells around blood vessels. They may also be seen
around hair follicles and sebaceous glands. Many of
the pigment conglomerations are too large to traverse
the vessel walls and leave the area of original deposition, but with time pigment diffusion from the site may
lead to blurring of the visible design as well as pigment
deposition in the draining lymph nodes (Fig. 101-4).14,15
Figure 101-4 This Tattoo is 35 years old and the image

has blurred. From the top down: Mom in heart, a wreath,
an eagle, a peace arrow, God Bless America.
Body Art
Figure 101-2 Four days after the application of this

tattoo, much of the inserted pigment is extruding.
PIGMENTS
Tattoo pigment composition, as obtained from the
manufacturer, and possibly further mixed by the artist, is complex, usually nonsterile, unregulated, variable and changing. In recent times, industrial organic
pigments, including azo and polycyclic compounds,
sandalwood and brazilwood, as well as aluminum,
cadmium, calcium, copper, iron, phosphorus, silica,
and sulfur have been identified.16 In addition, titanium
dioxide and barium sulfate are often used to lighten
the color. The 1976 Food, Drug and Cosmetic Act limited the content of lead and mercury in cosmetics for
application to the skin so that now these two elements
are rarely found.1719 The pigment in amateur tattoos is
usually black and carbon based, often deriving from
India ink, charcoal, soot, or mascara20 (Table 101-1).
COMPLICATIONS
Figure 101-3 Tattoo pigment is seen in the reticular

dermis. The particles are within fibroblasts, macrophages,
and occasional mast cells around blood vessels.
Medical complications are unusual in developed

countries. Clearly, there is a real risk of contracting a
contagious disease, but most recent reports are anecdotal. These include reports of verrucae, molluscum
contagiosum, and atypical mycobacterial infections
in the area of the tattoo, methicillin-resistant staphylococcal infections spreading from the area of the tattoo and bacterial endocarditis within a week of tattoo
application.2126 There has been more than one report
of cutaneous leishmaniasis in a tattoo site among HIVinfected individuals with visceral leishmaniasis.27
Inoculation leprosy is common in parts of the world
where leprosy is endemic.28,29 (See Table 101-2.)
There have been outbreaks of hepatitis B traced
to tattoo parlors in the past, but currently there is a
1131
17
TABLE 101-1
Tattoo Pigments
Red
Mercuric sulfide (cinnabar); cadmium selenide; ferric hydrate
(sienna); sandalwood; brazilwood; aromatic azo compounds
including naphthol-AS; quinacridone
Green
Chromium oxide; lead chromate; copper or aluminum
phthalocyanine; malachite (contains copper); ferrocyanides
and ferricyanides
Section 17
Purple
Manganese ammonium pyrophosphate; aluminum salts;
quinacridone; dioxazine/carbazole
Blue
Cobalt aluminum oxide; chromium oxide; copper
phthalocyanine
::
Yellow
Cadmium sulfide; curcuma (from the ginger plant family);
chrome yellow (lead chromate mixed with lead sulfide)
Black
India ink; ferrous oxide; magnetite (Fe3O4); carbon; logwood
(a heartwood extract from Haematoxylum campechianum
found in Central America and the West Indies)
Brown
Iron oxides
White
Zinc oxide; titanium dioxide; lead carbonate; barium sulfate
controversy as to how often hepatitis C in the United

States is transmitted this way. During the same time
that the prevalence of tattoos has increased, the absolute numbers of reported acute hepatitis B and C
cases have fallen. The numbers were at a nadir for
hepatitis B in 2007 (1.5/100,000), in contrast to a high
of 11.5/100,000 in 1985; for hepatitis C, the numbers
are stable at 0.3/100,000 since 2003, from a high of
2.4/100,000 in 1992.30 Most hepatitis C infection is
asymptomatic. The sources of approximately 65% of
the cases of hepatitis C are unidentified. Cross-sectional data from a number of population groups, for
example, veterans,31 attendees in an orthopedic practice,32 hospital outpatients,33 have been inconsistent
in identifying tattoos as an independent risk factor

for the presence of Hepatitis C. Variables such as getting the procedure in a dedicated studio or in a penitentiary34,35 may be relevant and the confusion may
relate to the fact that, in some people, tattoos are a
marker for other unconventional or socially disapproved behaviors.36,37 The American Association of
Blood Banks recommends that blood for donation
not be taken from anyone within a year of a tattoo
or a body piercing, unless applied by a state-regulated entity with sterile needles and ink that have not
been reused.38 In 2005, the Canadian Blood Services
decreased the deferral period from 12 to 6 months.
Donor deferral rates were assessed before and after
the change. Remote tattooing was associated with
increased hepatitis C risk, but this did not hold true
for recent tattooing nor piercing. There was no measurable adverse effect on safety and a positive but less
than expected effect on blood availability.39
Many, but not all, of the pigment-based reactions are
in the red areas of tattoos (Fig. 101-5). Now that cinnabar,
vermilion or other pigments containing mercuric sulfide, are rarely used, other culprits have been identified.
These include cadmium selenide and quinacridone.40
Reactions may be photosensitive and histology may be
pseudolymphomatous, lichenoid,41 or granulomatous,
either (1) foreign body type with numerous giant cells
containing pigment or (2) hypersensitivity type with
dense aggregates of epithelioid cells, a thin peripheral
ring of lymphocytes and few giant cells.42 Hypersensitivity reactions may be localized or generalized,43 but
standard epicutaneous patch testing is not often helpful, presumably related to the dermal placement or the
rapid decomposition of the tattoo antigen.44 The social
implications of tattooing are protean and may alert the
onlooker to other risk-taking behaviors.45
TATTOO REMOVAL
Most people are proud of their tattoos, but approximately 17% desire removal. In addition, 5% opt for
and 8% are considering further tattooing to cover
a disliked or faded image. Often these people have
obtained their tattoos at a young age and want them
TABLE 101-2
Known Infectious Complications of Tattooing
1132
Bacterial
Impetigo
Ecthyma
Furunculosis
Erysipelas
Tuberculosis cutis
Atypical mycobacterial
infection
Syphilis
Leprosy
Endocarditis (rare)
Viral
Warts
Herpes simplex
Herpes zoster
Vaccinia
Rubella
Viral hepatitis
HIV possible but no case
reports
Figure 101-5 Red tattoo reaction.
17
TABLE 101-3
Tattoo Removal Methods
May use a handheld mechanical unit or sterile sandpaper to abrade the skin to the
reticular dermis. Rotating (up to thousands of rpm) wire brushes, diamond fraises, or
serrated wheels attached to compact electric machines are available.
Salabrasion
First described by Aetius, a Greek physician in 543ad, tap water dipped in salt is rubbed
vigorously to abrade the skin overlying the tattoo.
Chemical extraction using a remover

paste
The remover paste, made with deionized water, zinc oxide, magnesium oxide, calcium
oxide, triethanolamine, isopropanol, and benzoic acid49 is applied. A superficial
microtattoo process is used to puncture the skin over the tattoo and the paste is
reapplied. Inflammation ensues and the pigment is extruded.50
Cryosurgery
Salt/ice (-20C) or dimethyl ether/propane (-50C) mixtures, solid carbon dioxide

(-79C), nitrous oxide (-70C), or liquid nitrogen (-196C) may be used.
Application of caustic chemicals
These include phenol, trichloroacetic acid, tannic acid, or oxalic acid with silver nitrate.51
Argon and carbon dioxide lasers
These were the early tattoo removal lasers but nowadays mainly used for the removal
of tattoo granulomas as healing times are prolonged. Significant thermal damage and
hypertrophic scarring often ensue.
Q-switched lasers
These produce nanosecond pulses similar to the Tra of the target pigment. Each pulse
has a very high peak power. Surface cooling may be used to prevent epidermal damage.
Body Art
Mechanical dermabrasion
::
For grafting, to avoid donor site scars, techniques may be used that enzymatically
separate the excised epidermis from the underlying, excised, pigment-containing
dermis and grafting this epidermis to the original tattoo site.48
Chapter 101
Excision with primary closure or grafting
Tr is the thermal relaxation time, the time it takes for the target chromophore to lose 50% of its incident heat without conducting heat to the
surrounding tissue.
removed or changed to enhance self-esteem, or for

social, domestic, and family reasons.46,47 Many tattoo removal methods have been documented (Table
101-3), but most are only partially effective, and leave
scarring and pigmentary changes (Fig. 101-6). With
the advent of the theory of thermal relaxation, lasers
with very short (nanosecond) high-energy pulses
have been designed, which are less likely to heat the
surrounding tissue leaving scars (Table 101-4). On the
horizon, are lasers (titanium:sapphire) with picosecond pulse durations which may be even more effective but potentially more destructive to surrounding
tissue. The laser energy photoacoustically explodes
the pigment particles. Some of these may be allergenic
or carcinogenic. Macrophages engulf the fragments

so that they are removed via the draining lymphatics, and some may be extruded through the epidermis.
Lightening may take several weeks. In general, proximally placed and old tattoos are easier to remove than
distally placed and more recent ones.20
Removal of tattoos in dark-skinned individuals is difficult. A long wavelength laser (Q-switched
Nd:YAG) may be used together with skin freezing to
cause lightening of the epidermis so that the laser light
not only penetrates deeply enough but also bypasses
the melanin in the epidermis to avoid a permanent
pigment change. Red, white, and flesh-tone tattoos,
which often contain ferric and/or titanium oxides,
may darken with laser treatment related to chemical
reduction by the laser beam (See Chapter 239).
TEMPORARY TATTOOS
Figure 101-6 Scarring related to tattoo removal by acid

50 years previously.
Traditional henna tattooing, practiced throughout

Africa, the Middle East, and India (mehndi) for thousands of years, very rarely causes hypersensitivity
reactions. Henna is made from the leaves of the plant
Lawsonia inermis, a member of the Loosestrife family,
and is a reddish brown color. Recently, the application of temporary tattoos has become popular in the
developed world. Some of these are made with black
henna, which contains up to 16% para-phenylenediamine (PPD) used as a darkening agent. Concentrations
of PPD as high as this commonly cause sensitization
and lead to contact allergic dermatitis (see Chapter 13).
1133
17
TABLE 101-4
Use of Lasers for Tattoo Removal

Fluence (J/cm2)
Used for This Color
10
612
Black, blue
532
10
212
Red, orange, purple
Ruby
694
25
810
Black, blue, green
Alexandrite
755
50100
4.58
Black, blue, green
Q-Switcheda Laser
Wavelength (nm)
Nd:YAG
1,064
Frequency-doubled
Nd:YAG
Pulse Duration (ns)
A Q-switch is an electro-optical device that concentrates laser energy into a single, intense nanosecond pulse.
Section 17
BODY PIERCING
::
EPIDEMIOLOGY AND BACKGROUND
Body piercing has been practiced in almost every

society and on every continent, not only for beautification but also for ritual, religious and status reasons.
Usually, only the ears, mouth, and nose were pierced,
although penile piercing was described in detail in the
Kama Sutra (4th century bc). More recently there have
been many myths propagated by the promoters of
body art in order to stimulate interest in the practice.52
For instance, it is a myth that a nipple piercing could
support the weight of a Roman centurions toga. In the
United States, piercing of the soft earlobes has been
common in women since the 1960s, but the body piercing fashion appears to have taken off in the late 1980s.
A US cross-sectional study of 18- to 50-year-olds
in 2004 found that 19% of men and 49% of women
had soft earlobe piercings and 8% of men and 21%
of women had body piercings in other parts of the
body. Of 18- to 29-year-olds, 32% had body piercings,
not including the soft earlobe.12 Similarly, a 2005 UK
study found that 46% of 16- to 24-year-old females and
13% of males had body piercings other than the soft
earlobes.53 Other studies in teens and young adults
have shown body piercing outside the earlobe in 27%
51%.54,55 Women are more likely to have body piercings than men, and more than 50% of those with body
piercings have more than one. Most piercings are done
in tattoo or dedicated shops, but soft earlobe piercings are often done in department or specialty stores.
Important behavioral and social associations in the
young include some cultural normative attributes, for
example, being of Hispanic or South Asian heritage,
but they also include the participation in a number of
risk-taking behaviors such as being a drinker, having
used illicit drugs, having spent time in jail, having limited religious affiliation, and having early and multiple
sex partners. It may also be a marker for depression.56,57
TABLE 101-5
Complications Related to Infection of Piercings

Complication
Reported Organisms
Loss of ear cartilage
Endocarditis: usually
superimposed on a
known underlying
cardiac abnormality,
but occasional
reports without
prior cardiac
abnormality
Skin piercing:
Group A -hemolytic Streptococcus
Staphylococcus epidermidis
Mucosal piercing:
Streptococcus viridans
Neisseria mucosa
Haemophilus aphrophilus
Haemophilus parainfluenzae
Septic arthritis
Osteomyelitis
Toxic shock
syndrome
Lymphadenitis
Lactobacillus
Cephalic tetanus
Clostridium tetani
Acute
glomerulonephritis
(may lead to acute
renal failure)
Ludwigs angina
Oral piercing:
Neisseria mucosa
Haemophilus aphrophilus
Haemophilus parainfluenzae
Fournier gangrene
Male genital piercing:

Group A Streptococcus and
mixed Gram-negative bacilli and
anaerobic organisms
Brain abscess
Tongue piercing resulting in a mixed

infection:
Peptostreptococcus micros
Actinomyces species
Eikenella corrodens
Lupus vulgaris
Mycobacterium tuberculosis
inoculation at time of nose piercing
(India)
PROCESS
1134
A hollow 1216 gauge needle is passed through the

body part and body jewelry is inserted in the hole. A
piercing gun is often used for soft earlobe piercings,
but these are difficult to sterilize, can lead to crush injuries, and, if used in a cartilaginous area, to loosening
of the perichondrium. Swelling occurs immediately
so that the jewelry inserted has to be long and fine
enough to allow for this. It should be made of titanium,
niobium, 14-karat yellow gold, or stainless steel in
order to avoid the induction of nickel and/or cobalt
delayed type hypersensitivity. Postoperative healing
times, from 2 weeks for clitoris to 9 months for navel
piercings, vary with the site. There are two types of
bead closures. The captive bead ring is held closed by
pressure. The bead screw is similar to any other screw
mechanism and is often part of hoops, barbells, and
circular barbells.
oral antibiotic. If pseudomonas is suspected a fluoroquinolone, which will also cover most species of
Staphylococcus and Streptococcus, including many
-lactam-resistant strains, is a good choice. Importantly, viral hepatitis may be transmitted through the
piercing needle. This includes hepatitis C and less
often hepatitis B and D, although this uncommonly
occurs in modern America,62 where disposable or sterilized piercing equipment is used.63 Transmission of
HIV is another risk that has not been proven to occur.
Other complications are protean (Table 101-6). In
view of the high and increasing prevalence of nickel
Noninfectious Complications Related to Piercings

Bleeding
Usually at time of or immediately after procedure. This may
lead to significant blood loss.
Scarring
May lead to phimosis or strictures.
Keloid formation.
Cyst related to tract closure.
Body Art
Avulsion Injuries
Earlobe tear, urethral rupture, splitting of urinary stream,
rejection of jewelry near the eyebrow, navel, or nipple.
::
These vary with the site on the body of the piercing as

well as with the place the procedure is done, for example, at home or in a commercial studio. Bleeding may
occur during or immediately following the procedure,
and bacterial, fungal, or viral diseases may be transmitted, especially if nonsterile instruments are used58
(Table 101-5). However, most infection comes from
the subjects own flora often related to poor hygienic
practices during the healing period leading to localized infection (erythema, edema, purulent drainage).
Rates as high as 35% after ear cartilage piercings have
been reported, sometimes leading to loss of ear cartilage and, rarely, endocarditis (Fig. 101-7).59,60 Other
high-risk areas include the navel, with its propensity
for movement, and any intraoral site.61 Jewelry may
be left in place to facilitate drainage and prevent sac
formation. In addition, local hygiene should include
compresses, a topical antibiotic, and, if necessary, an
Chapter 101
TABLE 101-6
COMPLICATIONS
17
Neurological Damage
Loss of taste, increased salivary flow, clitoral numbness.
Anesthetic Risks
Interference with free access to the airwaya, postoperative
laryngospasm, pressure on area during surgery,
electrosurgical burns, problems with catheterization.
Intraoral
Aspiration of jewelry ball.
Broken teeth and gingival recession.
Speech impairment.
Loss of taste.
Increased salivary flow.
Embedding of jewelry in tongue.
Nipples
Galactorrhea related to hyperprolactinemia due to nipple
stimulation.
Penis
Priapism related to entrapment of penis in a scrotalpiercing hole.
Paraphimosis related to inability to replace the prepuce
over jewelry in the glans.
Glanular hypospadias.
Split urinary stream.
Jewelry-induced Contact Allergy
Nickel and cobalt are the most likely allergens (Type IV
delayed hypersensitivity)
In the US
12% jewelry allergy in those without piercings
31% in those with piercings: 48% in those with three
piercings
Gold and palladium rarely cause delayed reactions which
may be of granulomatous (sarcoidal) type.64
Figure 101-7 Early upper ear cartilage infection following

the insertion of metal jewelry.
To avoid problems, remove tongue, lip, or cheek jewelry before anesthesia and insert a nonreactive thread to preserve tract patency.
1135
17
effect in 1992. The European Union (EU) adopted the

EU Nickel Directive in 1994. It went into full effect in
all EU nations in 2001. Nickel content of piercing post
assemblies was initially set at 0.05%. In 2004, this
was changed to 0.2 g/cm2/week of nickel release,
and it appears that the incidence of new sensitization
is falling.65
Piercing tracts are not necessarily permanent as they
may close if the jewelry is removed. This is common
with tongue piercings as the epithelium in the depths
of the tract is thin and possibly missing.66 Replacement
of tongue jewelry prior to anesthesia can be done with
a fine inert flexible catheter.
Section 17
MAGNETIC JEWELRY
::
This is occasionally used to avoid piercing (Fig. 101-8).

Aspiration of the magnetic back of the jewelry is a possible complication.
1136
KEY REFERENCES
Figure 101-8 Magnetic jewelry avoids a piercing but still

can be inhaled accidentally or become embedded in the
tissue.
allergy, European nations implemented legislation to
limit the release of nickel from objects intended to be
in prolonged contact with the skin. This legislation
was first passed in Denmark in 1976 and went into full
1. Sperry K: Tattoos and tattooing. Part I: History and methodology. Am J Forensic Med Pathol 12(4):313-319, 1991
2. Stirn A: Body piercing: Medical consequences and psychological motivations. Lancet 361(9364):1205-1215, 2003
9. De Cuyper C, Prez-Cotapos M, eds: Dermatologic Complications of Body Art. Heidelberg, Springer, 2009
12. Laumann AE, AJ Derick: Tattoos and body piercings in
the United States: A national data set. J Am Acad Dermatol
55(3):413-421, 2006
30. Daniels D et al: Surveillance for acute viral hepatitis
United States, 2007. MMWR Surveill Summ 58(3):1-27,
2009
65. Schram SE et al: Nickel hypersensitivity: A clinical review
and call to action. Int J Dermatol 49(2):115-125, 2010
Neurocutaneous and
Psychocutaneous
Aspects of Skin Disease
PA RT
Neurocutaneous and Psychocutaneous

Skin Disease
Chapter 102 :: Neurobiology of the Skin

:: Martin Steinhoff & Thomas A. Luger
NEUROBIOLOGY OF SKIN AT A GLANCE
In an interactive network, cutaneous nerves
communicate with various skin cells, the
endocrine system, and the immune system.
Neurocutaneous interactions influence
a variety of physiological and
pathophysiological functions such as
thermoregulation, cell growth, inflammation,
host defense, apoptosis, pruritus, pain,
metastasis, and wound healing.
Primary afferent as well as autonomic nerves
release neuromediators and activate specific
receptors on many target skin cells.
Cutaneous cells express a variety of specific
receptors tightly controlled by upregulatory
or downregulatory signals, peptidases, or
neighboring receptors.
THE NERVOUS SYSTEM AND SKIN

This chapter discusses the structural basis and the specific molecules involved in the interactions between
the skin and different portions of the nervous system.
The peripheral nervous system provides essential information to the rest of body during injury of
danger signals such as parasites, UV radiation, tox-
Many mediators (peptides, proteases,

cytokines, kinins, prostanoids, opioids,
cannabinoids, neurotrophins, etc.) are
critically involved in physiological and
pathophysiological conditions in the skin by
activating neuronal receptors.
The spinal cord and CNS modulate
transmitted signals from the peripheral
nerves with respect to the perception of pain
or itch, andvice versamodulate skin
function.
New pathways are being defined for
the treatment of various skin diseases in
which the neuro-immuno-endocrine axis is
implicated.
ins, allergens, pH changes, or stress. This information can be modulated at various levels including the
brain, spinal cord, dorsal root ganglia (DRG), peripheral sensory nerve endings, autonomic nerves and
neurons, etc; and through specialized structures like
Pacini bodies or specialized cells such as Merkel cells.
This closely woven group of structures and their molecules are ultimately and critically involved in normal
18
Section 18
::
Neurocutaneous and Psychocutaneous Skin Disease
1138
cutaneous biology and skin diseases (eTable 102-0.1

in online edition). In conjunction with the spinal cord
and the brain, peripheral sensory nerves have afferent
functions; their endings detect physical stimuli such as
touch, heat or cold, and chemical mediators into the skin
from nerve endings and also have efferent functions in
the skin. (eFig. 102-0.1 in online edition). These sensory
nerves critically contribute to skin development before
birth and to protection and homeostasis after birth. In
addition, autonomic nerves modulate both physiological and pathophysiological functions as part of the stress
response to external or endogenous stimuli, and form a
vital link communicating with the vascular, endocrine,
and immune systems (eTable 102-0.1 in online edition).
PERIPHERAL NERVES
Sensory as well as autonomic (in the skin predominantly cholinergic sympathetic) nerves influence a
variety of physiologic and pathophysiologic functions
of the skin such as embryogenesis, vasoconstriction,
vasodilation, body temperature, erector pili movement, regulation of the function of the pilosebaceous
unit, sensing physical, chemical and biological stimuli
on the skin surface; modulating epidermal barrier
function, cell secretion, cell growth and differentiation,
cell nutrition and apoptosis, nerve growth, inflammation, immune defense, and wound healing, respectively (eTable 102-0.1 in online edition).
In unstimulated cutaneous nerves, neuromediators
are stored in cytoplasmic vesicles. On direct or indirect activation through physical, mechanical, electrical,
chemical or biologic or endogenous inflammatory processes lipids, cytokines or neurotrophins (NT), a significant increase of regulatory neuropeptides, or oxygen
products can be detected at the site of inflammation
within seconds to hours. Thus, mediators derived from
sensory or autonomic nerves may play an important
regulatory role in the skin under many physiologic
and pathophysiologic conditions. However, in addition to neuroimmunomodulation in the periphery,
a subtle and complex communication network also
exists between the spinal cord, the central nervous
system (CNS), and the immunoendocrine system that
also modulates skin function. In addition, neuropeptides and NTs can be upregulated and released by nonneuronal cells under certain circumstances that may
amplify or counterregulate the neurogenic stimulus.
While certain neuropeptides [e.g., substance P (SP)]
exert clear-cut proinflammatory effects during inflammation, others such as calcitonin-gene-related protein
(CGRP) may be acutely released to induce vasodilatation (proinflammatory), but in addition counterregulate inflammatory responses like antigen presentation
and immunosuppression in order to reestablish skin
homeostasis at the later stage of inflammation.
The skin expresses a variety of receptors for these
neuromediators, such as G protein-coupled receptors,
ion channels and certain cytokine receptors (see Tables
102-1 and 102-2). This neuromediatorreceptor interaction is controlled by endopeptidases [neutral endopeptidase (NEP), angiotensin-converting enzyme (ACE),
endothelin-converting enzyme (ECE)], which terminate neuropeptide-induced inflammatory or immune

responses.13 A close multidirectional interaction
between neuromediators, high-affinity receptors, and
regulatory peptidases is critical to maintain or reestablish tissue integrity and regulating pathophysiologic
conditions in the skin. Ion channels are promiscuous
and can be activated by physical stimuli (heat, cold),
chemicals (e.g., capsaicin, menthol, protons) as well as
lipid metabolites like prostaglandins. Activation of ion
channels by cannabinoids (CB) has been also recently
described.
From this background, it is clear that a better cellular and molecular understanding of the complex
skinnervous system interactions opens an avenue for
future therapeutic approaches to skin disease.
Taken as a whole, present information clearly indicates a crucial role for the neuronal skin network in
influencing a variety of physiologic and pathophysiologic functions such as host defense, inflammation,
pruritus, pain, burning, wound healing, and probably
cancer (e.g., by modulating angiogenesis).
BRAINSKIN AXIS
The CNS proper is connected to skin either directly via
efferent nerves or CNS-derived mediators, or indirectly
via the adrenal glands or immune cells.1 Cutaneous
nerves also respond to internal stimuli from the circulation (e.g., pH changes, osmotic changes, bradykinin,
cytokines) or the skin itself and to emotions (internal
trigger factors).2 Under normal circumstances, the
sensory and the autonomic nervous systems modulate important biologic functions such as body temperature, blood flow, and cell growth. Mechanically
induced nerve impulses transmit information such
as pressure to the CNS. Chemical- or heat-responsive
afferent nerve fibers are involved in recognizing dangerous signals. Thus, normally the innervated skin is a
crucial barrier in protecting the body from danger from
the external environment. This is also supported by the
finding that not only the dermis but also the epidermis
is highly innervated.4 Interactions between the central
and peripheral nervous system have been implicated
to play a role in thermoregulation,1,5 the pathophysiology of various skin diseases such as psoriasis,68 atopic
dermatitis,9 acne,10 wound healing,11 as well as hair
loss and regrowth.1214
SPINAL CORD
Our knowledge about the involvement of the spinal
cord in regulating specific chronic pain sensations in
human skin, its role in modulating pruritus, or modulating inflammatory stimuli transduced from the
periphery to the brain is very limited. We know that
-opioids such as morphine can induce pruritus while
being analgesic when injected intrathecally. In contrast, -opioids exert antipruritic effects, probably by
the inhibition of the -opioid receptor. These results
strongly indicate a role of opioids in the regulation of
18
TABLE 102-1
Role of Nerves in Inflammation, Immunomodulation, Pruritus and Pain

Pruritogenic
Stimuli (In
Alphabetic
Order)
Receptors
Sources,
Receptors by
which Expressed
Comments
Mediates itch in atopic dermatitis; mAChR3 is probably
involved in itch.
Calcitonin generelated peptide

(CGRP)
CGRP receptors
Sensory nerve fibers
Expressed on central terminals; sensitizes receptive

endings. Associated with increased pain transmission,
prolongation of itch latency after substance P injection
(inhibitory effect on itching). Involved in itchy skin
diseases. Regulates antigen presentation on Langerhans
cells; involved in drug-induced adverse reactions, atopic
dermatitis and contact dermatitis. Downregulates NF-B
Cannabinoids
CB1, CB2 receptors
Nerves, keratinocytes,
immune cells
Involved in antinociception (peripheral and central),

anti-fibrotic; anti-inflammatory (contact dermatitis);
regulates cell growth, differentiation, apoptosis. Involved
in thermoregulation.
Corticotropinreleasing hormone
(CRH) and
proopiomelanocortin
(POMC)
CRH receptors
(CRHR1, CRH-R2)
CRH-R1:
keratinocytes, mast
cells CRH-R2: bone
marrow mast cells
Induces release of histamine, cytokines, TNF-, VEGF

from mast cells. CRH-like immunoreactivity seen on
sensory nerves (rat).
Cytokines
Cytokine receptors
(e.g., IL-2, IL-31)
Leukocytes,
keratinocytes,
endothelial cells,
nerves
T cells release IL-31 during inflammation and activate

monocytes and keratinocytes via the IL-31 receptor
(IL-31R). IL-31R is upregulated in atopic dermatitis and
prurigo.
Endocannabinoids
Cannabinoid
receptors (CB1, CB2)
Nerves, immune cells,

keratinocytes, hair
follicles
Antipruritic in the periphery.
Endothelins (ETs)
Endothelin receptors
(ETA, ETB)
Endothelium, mast
cells
Induces burning itch. Degraded by chymase via ETAreceptor activation.
TRP channels and

agonists (heat, cold,
acidosis, osmolar
changes, capsaicin,
menthol, camphor,
eicosanoids,
bradykinin,
prostaglandins,
various
neurotrophins;
aldehydes, formalin,
nicotine, etc.)
Activation of transient
receptor potential
vanilloid 1 (TRPV1)
sensitization of TRPV1
via activation of
specific receptors (see
in this table)
TRPV1 is expressed
on sensory neurons,
mast cells, epidermal
and hair follicle
keratinocytes,
Langerhans cells,
smooth muscle, and
sebocytes
TRPV2 expressed by
sensory nerves and
murine macrophages
TRPV3 and TRPV4:
expressed by
sensory nerves
and keratinocytes.
TRPV6: keratinocytes.
TRPA1: expressed by
sensory nerves and
keratinocytes
Short-term TRPV1 activation: induces pain and itch,

depletes neuropeptides from sensory neurons. Longterm antipruritic effect of TRPV1 agonists (e.g., capsaicin):
Suspend interplay between sensory neurons and mast
cells. Affects epidermal and hair follicle proliferation,
differentiation, apoptosis, and cytokine release. Increased
expression in epidermal keratinocytes of prurigo
nodularis patients.
TRPV2: role in antigen presentation in mice.
TRPV3 and TRPV4: role in sensory and keratinocyte
function. TRPA1: role in pain, hypernociception,
vasoregulation, barrier function. TRPV6: keratinocyte
differentiation
Gastrin-releasing
peptide
Activates GRPR
GRP: sensory nerves.

GRPR: superficial dorsal
horn of spinal cord
GRP mediates itch but not pain (histamine dependent

and independent).
(continued)
Neurobiology of the Skin
Autonomic
cholinergic nerves,
keratinocytes,
lymphocytes,
melanocytes,
dermal fibroblasts,
endothelial cells
::
Nicotinergic (nAChR)
and muscarinergic
(mAChR) ACh
receptors
Chapter 102
Acetylcholine (ACh)
1139
18
TABLE 102-1
Role of Nerves in Inflammation, Immunomodulation, Pruritus and Pain (Continued)

Pruritogenic
Stimuli (In
Alphabetic
Order)
Receptors
Sources,
Receptors by
which Expressed
Comments
Section 18
Histamine receptors
(H1R to H4R)
Sensory fibers
In humans, histamine induces itch by stimulating specific

sensory fibers, whereas H1 (and to a lesser extent H2)
antagonists reduce itch in numerous clinical trials. In
mice, H3 antagonists induce scratching behavior, whereas
H1 and H4 antagonists effectively suppress pruritus.
Proteases, kallikreins,
tryptase, trypsins,
cathepsins, (MMP1)
Partly proteinaseactivated receptors

(PARs), tryptic
enzymes
Keratinocytes,
endothelial cells, mast
cells, platelets
Massive itch behavior in mice overexpressing epidermal

kallikrein-7. Potential role of other kallikreins. Chymase
degrades pruritic and antipruritic peptides. Tryptase,
trypsin and cathepsin S induce inflammation and itch by
a neurogenic mechanism via PAR-2. Microbial proteases
may induce itch and inflammation via PAR-2.
PAR1 and PAR4 involved in pain.
Kinins
Bradykinin receptors
(B1R, B2R)
Endothelial cells,
immunocytes
Bradykinin induces pain rather than pruritus. B2R

antagonists reduce itch.
Leukotriene B4
Leukotriene receptors
Sensory nerves fibers,

keratinocytes
Leukotriene B4 induces itch and is also involved in the

substance P- and nociceptin-mediated induction of itch.
Neurokinin A (NKA)
and substance P (SP)
Tachykinin
(neurokinin) receptors
(NKRs)
Sensory nerve fibers
NKA: upregulates keratinocyte nerve growth factor

expression. SP: at low (physiologically relevant)
concentrations, primes mast cells. Mediates release of
TNF-, histamine, leukotriene B4, and prostaglandins
from mast cells (agents involved in pruritus and burning).
Nerve growth factor

(NGF), brain-derived
neurotrophic factor
(BDNF), neurotrophins
(NT-3, NT-4)
Specific receptors
Keratinocytes, mast
cells, fibroblasts,
eosinophils
NGF levels enhanced in atopic dermatitis. Induces

tryptase release from mast cells. Inducible by histamine.
::
Histamine
TrkA: NGF
TrkB: NT-4, BDNF
TrkA: enhanced in keratinocytes during inflammation.

NT-4: enhanced in atopic dermatitis and induces
sprouting of sensory nerves.
BDNF: increases eosinophil chemotaxis levels in atopic
dermatitis and inhibits apoptosis. Neurotrophins
sensitize receptive nerve endings and upregulate
neuronal neuropeptides and TRPV1.
TrkC: NT-3
Opioids
, , opioid
receptors (partly
receptor-independent
cell activation)
Nerves, keratinocytes
Antipruritic effect of -opioid antagonists (central

effect) and -opioid agonists (spinal cord level). Opioid
agonists do not provoke itch on injection or intradermal
application. -Opioid receptor upregulated in atopic
dermatitis.
Pituitary adenylate
cyclase-activating
polypeptide (PACAP)
and vasoactive
intestinal peptide (VIP)
VPAC receptors
Autonomic and
sensory nerve fibers,
lymphocytes, dermal
endothelial cells,
Merkel cells
PACAP: involved in flush, vasodilation, pain,

neurodegeneration. Induces release of histamine from
mast cells.
VIP: Histamine release from mast cells, allodynia (no
allodynia in atopic dermatitis) intensifies ACh-induced
itch in atopic dermatitis patients (together with ACh).
Prostaglandins
Prostanoid (P)
receptors
Sensory nerve fibers,

keratinocytes
Prostaglandin E2 induces itch sensitization in humans but

not in mice. Prostaglandin D2 reduces immunoglobulin
E-mediated scratching in mice. Thromboxane A2 induces
itch in mice.
ATP = adenosine triphosphate; IL = interleukin; TNF- = tumor necrosis factor-; VEGF = vascular endothelial growth factor.
1140
18
TABLE 102-2
Role of Nerves in Inflammation

Receptor
Source
Target Cells/Function
Acetylcholine
Nicotinergic and
muscarinergic
acetylcholine
receptors
Autonomic
cholinergic nerves,
keratinocytes,
lymphocytes,
melanocytes
Innervation of sweat glands and arteriovenous anastomoses;

keratinocyte and lymphocyte differentiation, proliferation,
adhesion, migration. 7-Nicotinergic receptor modulates
keratinocyte function, modulates skin microcirculation;
involved in atopic dermatitis.
Adenosine, ATP
Purinergic
receptors
Nerves,
keratinocytes,
endothelial cells,
immune cells
Involved in pain and hypernociception; neuronal cell death;

involved in vasoregulation and immune response (cytokine
release, cell adhesion molecules).
Catecholamine,
noradrenaline
Adrenergic
receptors
Autonomic
adrenergic nerves,
keratinocytes,
melanocytes
Innervation of blood vessels, erector pili muscles; pain

transmission; regulation of activity in natural killer cells and
monocytes; induction of apoptosis in lymphocytes. Regulate
dendritic cell function.
-Adrenergic-induced inhibition of keratinocyte migration.
Involved in sweating.
Galanin receptors
(GPCRs)
Sensory nerves
Inhibit inflammatory edema by reduction of microvascular

blood flow via Gal3R.
Substance P
Tachykinin
(neurokinin)
receptor
Sensory
nerve fibers,
keratinocytes
(inducible)
Mediation of skin edema, pruritus; upregulation of cell

adhesion molecule expression on keratinocytes and
endothelial cells; induction of release of IL-8, TNF-,
histamine, tryptase, leukotriene B4, prostaglandin D2;
regulation of sebaceous glands; involved in inflammatory
pain, contact dermatitis, immunomodulation, tumorigenesis
and metastasis.
Released by proteinase-activated receptor 2 (PAR-2) agonists.
Neurokinin A
Tachykinin
(neurokinin)
receptor
Sensory nerve
fibers
Upregulation of keratinocyte nerve growth factor expression.
Vasoactive intestinal
peptide
VPAC receptors
Sensory nerve
fibers, Merkel cells
Sweat secretion, vasodilation; proliferation, migration of

keratinocytes; histamine release from mast cells.
Downregulation of VPAC2 receptor in mast cells in atopic
dermatitis.
Pituitary adenylate
cyclase-activating
polypeptide
VPAC receptors
Autonomic
and sensory
nerve fibers,
lymphocytes,
dermal endothelial
cells
Vasodilatation, immunomodulation; effect on T cells and

macrophages; modulation of mast cell function; inhibition
of antigen-induced apoptosis of mature T lymphocytes;
downregulation of proinflammatory cytokines and
chemokines in T cells; upregulation of cytokines and cell
adhesion molecules in dermal microvascular endothelial
cells; nociception.
Calcitonin generelated peptide (CGRP)
CGRP receptors
Sensory nerve
fibers
Keratinocyte and endothelial cell proliferation; stimulation of

cytokine production.
Increased CGRP nerves in atopic dermatitis and nummular
eczema; released by PAR-2 stimulation.
Pro-opiomelanocortin
(POMC)
Melanocortin
receptors
Melanocytes,
keratinocytes,
endothelial cells,
Langerhans
cells, mast cells,
fibroblasts,
monocytes,
macrophages
Antagonism of effects of proinflammatory cytokines

(IL-17, IL-1, IL-6, TNF-, endotoxins); upregulation of IL-10;
induction of release of histamine from mast cells; inhibition
of nuclear factor B.
Thioredoxin regulates POMC genes.
MSH-induced exocytosis from melanosomes.
Melanocortin 1 receptor expressed on human keratinocytes.
Antioxidative and cytoprotective.
Galanin and galaninlike peptides
::
CGRP
Chapter 102
Neuromediator
IL = interleukin; MSH = melanocyte-stimulating hormone; TNF- = tumor necrosis factor-.
1141
18
Section 18
::
1142
pain and pruritus on the spinal cord level. Moreover,

gastrin-releasing peptide (bombesin) released to the
central nerve endings in the spinal cord activates the
gastrin-releasing peptide receptor (GRPR) on postsynaptic spinal neurons, thereby regulating selectively
itch transduction but not pain.15,16 Together, these data
implicate the spinal cord as an important regulator of
skinnervous system interactions as observed during
inflammation, pruritic diseases, and pain, and may be
a target for future therapies.
ANATOMY AND PHYSIOLOGY OF

THE SKIN NERVOUS SYSTEM
SENSORY NERVES
Most nerve fibers are found in the middermis and the
papillary dermis. Region-specific differences can be
observed with respect to the mucocutaneous border,
glabrous skin, and hairy skin.17 In the epidermis, sensory nerves are linked to keratinocytes, melanocytes,
Langerhans cells (LC), and Merkel cells. Cutaneous
nerve fibers are principally sensory, with an additional
complement of autonomic nerve fibers.18,19 In contrast
to sensory nerves, autonomic nerves never innervate
the epidermis in mammals. Sensory nerves innervate
the epidermis and dermis as well as the subcutaneous
fatty tissue2022 (see eFig. 102-0.1 in online edition).
Sensory nerves are categorized into two groups: (1)
the epidermal and (2) the dermal skin nerve organs.
The epidermal skin nerve organs consist of free nerve
endings or nerve organs (e.g., Merkel cells). In the
dermis, there are free sensory nerve endings, the hair
nervous network (Pinkus discs), and the encapsulated endings [Ruffini, Meissner, Krause, and Vater
Pacini (vibration) corpuscles, and mucocutaneous end
organ]. These can be subdivided into four groups: (1)
A- fibers (1222 nm) are highly myelinated, show a
fast conduction velocity (70120 m/second), and are
associated with muscular spindles and tendon organs.
(2) A- fibers are moderately myelinated (612 m)
and innervate touch receptors. (3) A- fibers have a
thin myelin sheath (15 m), show an intermediate
conduction velocity (430 m/second), and are generally polymodal. (4) The slow-conducting C fibers (0.5
2.0 m/second) are unmyelinated and thin (0.21.5 m)
(nociceptors). A- and A- fibers are mostly mechanically sensitive afferents (type I) localized on hairy
and glabrous skin and show a long latency to heat. A
subpopulation of A- fibers on hairy skin are mechanically insensitive (type II). A- fibers constitute approximately 80% of primary sensory nerves sprouting from
DRG, whereas C fibers make up approximately 20% of
the primary afferents.23,24
C-fibers are either polymodal nociceptors, which
can respond to chemical (c+), temperature changes
(h+) or mechanical (m+) stimuli, or more specialized,
which only respond to a combination (C-c+h+m) or a
single stimulus (C-chm+). Among human peripheral
nerves, 45% of the cutaneous afferent nerves belong
to a subtype of sensory nerves that are both mechano-
and heat-responsive C-fibers (C-cm+h+).25 However,

13% of these nerves are only mechanosensitive (C-m+),
6% only heat sensitive (C-h+), 24% are neither heat nor
mechanoresponsive (C-mh), and approximately 12%
are of sympathetic (cholinergic) origin. Fifty-eight percent of C-m+h+ respond to mustard oil, whereas 30%
of C-m+ or (C-mh) do so indicating the existence of
chemosensitive fibers among the other subtypes.25
Sensory nerves percept cutaneous stimuli such as
warmth, cold, or touch. The nerves for warmth are predominantly unmyelinated C-fibers, a subpopulation of
A- fibers respond to gentle cooling, whereas selective
C-fibers become activated during noxious cold. Many
subtypes of cells respond to touch and play an important role in mechanically induced pain. Thus, our body
system has designed less selective as well as highly
specialized nociceptors in order to guarantee body
integrity and survival.26
A specific receptor distribution on these different
sensory nerve subtypes appears to be important for the
various functions (temperature, chemical, mechanical)
and the sensations, which may derive thereof (prickling, stinging, burning, pain, itch). For example, mechanoreceptors exclusively express the T-type calcium
channel Ca(v)3.2 in the dorsal root ganglion of D-hair
receptors. The sodium channels Nav1.8 (SNS/PN3)
and Nav1.9 (SNS/SNS2) are expressed by both peptidergic as well as nonpeptidergic IB4+ (isolectin B4 from
Griffonia simplicifolia) neurons and have been shown
to be critically involved in certain subtypes of pain.27
Only certain small-diameter primary afferents express
the transient receptor potential vanilloid-1 (TRPV1)
receptor which is critically involved in heat sensation.28
Only nonpeptidergic (poor peptidergic) sensory fibers
express the purinergic P23 receptor. Exogenous factors like trauma, UV-radiation, temperature changes,
microbial agents, toxins, or allergens, as well as endogenous inflammatory triggers such as pH changes or
stress hormone responses are able to stimulate the activation and/or sensitization of certain sensory nerves.
The cellular events that transmit a stimulus (e.g., UV
radiation) to a certain response (burning pain) via activation of a certain pathway (activation of pain fibers
but not itch fibers and vice versa) are only poorly
understood.29,30
AUTONOMIC NERVES
Compared to sensory nerves, autonomic nerves represent only a minority of cutaneous nerve fibers. In
human skin, autonomic nerve fibers are derived almost
completely from sympathetic (cholinergic) and rarely
from parasympathetic (also cholinergic) neurons.31
The distribution of autonomic nerves is restricted to
the dermis, where they innervate blood vessels, arteriovenous anastomoses, lymphatic vessels, erector pili
muscles, eccrine glands, apocrine glands, and hair follicles.32
Postganglionic autonomic nerves in the skin
predominantly generate acetylcholine, although
observations have revealed an additional role for
neuropeptides. For example, neuropeptide Y (NPY)
SKIN NEUROPEPTIDES AND

NEUROPEPTIDE RECEPTORS
Classically, neuropeptides range from as few as 4 to
more than 40 amino acids. Because they are released
by nerve endings and modulate various biologic functions, they were originally defined as neuropeptides.
Later, these molecules were also found to be generated
by nonneuronal cells (e.g., epithelial cells and immune
cells). Therefore, the designation regulatory peptide may
be more appropriate.48 These peptides mainly activate
members of the G protein-coupled receptor superfamily with seven transmembrane domains. To date
more than 20 neuropeptides, including SP, neurokinin
A (NKA), neurotensin, CGRP, VIP, pituitary adenylate cyclase-activating polypeptide (PACAP), peptide
histidine-isoleucinamide, NPY, somatostatin (SST),
dynorphin, -endorphin, enkephalin, galanin, secretoneurin, melanocyte-stimulating hormone (MSH),
thyroid-stimulating hormone (TSH), or corticotropinreleasing hormone (CRH), have been detected in the
skin.1,2,49 Table 102-1 lists the neuropeptides, ion channels, and other molecules like NO involved in pruritus, pain, and inflammation. eFigure 102-0.1 in online
edition and Fig. 102-1 depict the basic concepts and
knowledge concerning these neuropeptides.
Various neuropeptides are produced and released by
a subpopulation of unmyelinated afferent neurons (C
fibers) known as C-polymodal nociceptors. In addition,
it has been shown that cutaneous cells themselves,
such as keratinocytes, microvascular endothelial cells,
Merkel cells, fibroblasts, and leukocytes, are capable
of releasing regulatory peptides under physiologic or
pathophysiologic circumstances.
In the skin, nerves are necessarily closely linked to
the vascular system. Dermal blood vessels are tightly
associated with sensory and autonomic nerve fibers,
they also synthesize neuropeptides and they express
receptors for neuropeptides. Arterial sections of arteriovenous anastomoses, precapillary sphincters of
metarterioles, arteries, and capillaries appear to be the
most intensely innervated regions. Large increases in
skin blood flow provide the necessary augmentation
of convective heat loss during environmental heat
exposure and/or exercise, and the reflex cutaneous
vasoconstriction is key to preventing excessive heat
dissipation during cold exposure. Sensory nerves are
important for vasodilation and neuropeptides from
sympathetic neurons such as NPY mediate vasoconstriction, which supports an important role for neuropeptides in thermoregulation, blood flow during
inflammation or tumorigenesis, as well as activation
of endothelial cells and smooth muscle cells. Both
endothelial cells and smooth muscle cells respond to
neuronal modulation in inflammatory diseases such as
atopic dermatitis and rosacea and during host defense,
neovascularization, and wound healing. Sensory as
well as autonomic nerves modulate the function of
sweat glands, sebaceous glands, apocrine glands, and
As outlined above, many subtypes of nerve fibers

exist to cover the multiple functions of the skin nervous system to maintain or reestablish body integrity.
18
::
BIOCHEMISTRY AND CELL

BIOLOGY OF THE CUTANEOUS
NERVOUS SYSTEM
This chapter focuses on the role of neuropeptides, TRP

channels, and cytokines in the skin (Table 102-1).
Chapter 102
and atrial natriuretic peptide33 are expressed solely by

autonomic nerve fibers.34
The cutaneous autonomic nervous system adjusts
sweat gland function, thereby regulating body temperature, and modulates water and electrolyte balance in
various organs. Under pathophysiologic conditions, autonomic nerves are involved in hyperhidrosis or hypohidrosis, congenital sensory neuropathy type IV, progressive
segmental hypohidrosis, diabetic neuropathy, syringomyelia, lepra, and dysfunction after sympathectomy.3538
Autonomic nerves exert their effects mainly by
releasing classical neurotransmitters (noradrenaline,
acetylcholine) orto a lesser extentcertain neuropeptides like vasoactive intestinal peptide (VIP). In
contrast, primary afferent (sensory) nerves release
different classes of molecules such as neuropeptides,
prostanoids, or nitric oxide (NO).1
Autonomic nerve fibers are crucially involved in
the regulation of vascular effects in the skin. Sympathetic nerve fibers release noradrenalin and/or NPY to
innervate arterioles, arteriovenous anastomoses, and
venous sinusoids, which results in vasoconstriction,
whereas parasympathetic nerves mediate vasodilation
through activation of venous sinusoids by the release
of acetylcholine and vasoactive intestinal peptide (VIP)/
peptide histidine methionine3942 (eTable 102-0.1 and Table
102-1 in online edition). Of note, C-fiber nociceptors can
develop responsiveness to adrenergic neurotransmitters by upregulating the corresponding receptors during trauma or inflammation. Thus, the sensory and the
autonomic nervous systems communicate and interact
in disease on the molecular level.
Small arteries, arterioles, and the arteriovenous
anastomoses are richly supplied with noradrenergic
nerves.43 Previous studies suggested that this system is
cholinergic and involves a cotransmitter, possibly VIP.44
Cholinergic sympathetic nerves are also known to stimulate eccrine sweat glands via muscarinic receptors,31
whereas higher concentrations of acetylcholine induce
an axon-reflex flare mediated via nicotinic receptors. In
the vasoconstrictor system, the transmitter appears to
be norepinephrine along with one or more cotransmitters. The best-characterized sympathetic cotransmitters
that participate in the regulation of blood flow include
adenosine triphosphate45 and NPY.46
Interestingly, even without intact sensory or autonomic function the skin reveals a nonneurogenic vasodilator and nonneurogenic vasoconstriction response.
The mechanisms for the nonneurogenic vasodilator
and vasoconstrictor components of the response to
direct cooling are poorly understood but may involve
several pathways including cholinergic stimulation,
NO and neuropeptides.5,47
1143
18
Cutaneous neurogenic inflammation
Exogenous
factors
Cytokines,
chemokines,
growth
Endogenous
factors
Vasodilation
Section 18
Edema
Immunomodulation
::
Sensory nerve
axon reflex
Pruritis and pain
Central
transmission
Figure 102-1 Cutaneous neurogenic inflammation. Exogenous trigger factors (heat, scratching, irritants, allergens,
ultraviolet light, microbiologic agents) or endogenous
trigger factors (pH changes, cytokines, kinins, histamine,
proteases, neurotransmitters, hormones, stress) may directly or indirectly stimulate nerve endings from primary afferent neurons. Signals are transmitted to the central nervous
system and thereby affect regions involved in pruritus,
pain, somatosensory reactions (scratching), and probably
emotional responses. In addition, peripheral nerve endings
stimulate neighboring afferent nerve fibers in the dermis
and epidermis in a process known as axon reflex. Stimulated
release of neuropeptides results in vascular responses (triple
response of Lewis, erythema by vasodilation, and edema by
plasma extravasation), modulation of immunocyte function (e.g., mediator release from mast cells), and regulation
of mediator release (cytokines, chemokines, growth factors)
from keratinocytes and Langerhans cells.
the pilosebaceous unit. In the following, we emphasize
the biological role of certain neuromediators and neurohormones in more detail.
CYTOKINES AND CHEMOKINES FROM

A NEURONAL PERSPECTIVE
1144
Cytokines are capable of inducing pruritus, and, conversely, cytokine inhibitors have been demonstrated to
reduce neurogenic inflammation, pain, and pruritus.
Thus, cytokines and chemokines may communicate
with sensory nerves via high-affinity receptors269274
(see eFig. 102-0.1 in online edition and Table 102-1).
Neurophilic cytokines include IL-1, IL-6, IL-8,
and IL-31.48,52 Of note, transgenic mice overexpressing
IL-31 released by T cells and macrophages developed
a chronic inflammatory skin disease characterized by

a T-cell infiltrate and pruritus, similar to atopic dermatitis in humans. IL-31 activates the IL-31 receptor
(IL-31R), a heterodimeric receptor composed of the IL31R A subunit and the oncostatin M receptor subunit.
Whether IL-31 exerts its pruritic effects via direct activation of IL-31R on sensory nerves or indirectly (e.g.,
via keratinocytes) is currently unknown. The finding
that keratinocytes express IL-31R suggests that IL-31
may induce pruritus through the induction of a yet
unknown keratinocyte-derived mediator that subsequently activates unmyelinated C fibers in the skin.
Therefore, one may speculate that IL-31 is upregulated in pruritic forms of cutaneous inflammation.275,276
These findings were confirmed in mice: the expression
of cutaneous IL-31 messenger RNA was significantly
higher in NC/Nga mice with scratching behavior than
in NC/Nga mice without scratching behavior.277 Therefore, IL-31 may participate in causing an itch sensation
and promoting scratching behavior.278,279 In addition,
IL-31 may be also a link in the communication between
eosinophils and keratinocytes in pruritic inflammatory skin diseases.280282 Primary cutaneous amyloidosis
(PCA) is an itchy skin disorder associated with amyloid
deposits in the superficial dermis. A gene mutation has
been recently described in PCA, a pruritic skin disorder
associated with amyloid deposits in the superficial dermis.283 Together, IL-31 may serve as a link between the
immune and neural systems by regulating inflammation as well as itch. For this reason, IL-31 and the IL-31R
are promising targets for the treatment of inflammatory
and itchy dermatoses such as atopic dermatitis, urticaria, and other genetically associated pruritic diseases.
Various antagonists such as the OSMR-L-GPL fusion
protein are currently under investigation.284
ROLE OF THE NERVOUS SYSTEM IN

SKIN PATHOPHYSIOLOGY
A number of human clinical diseases or symptoms,
appear to have a significant neurogenic component,
including atopic dermatitis, prurigo, pruritus-associated diseases, psoriasis, rosacea, urticaria, herpes zoster, or inflammatory arthritis (see Table 102-0.1).1 The
peripheral nervous system also modulates inflammatory responses or symptoms in other organs, such as
eye inflammation, asthma, inflammatory bowel syndrome, and transmits pain. Moreover, neuronal mediators play a role during wound healing by regulating
growth, proliferation, and angiogenesis.
The ability of neuropeptides to activate human mast
cells and induce urticaria has been appreciated for a
number of years.285 For example, chronic idiopathic urticaria and, to a lesser extent, pressure urticaria showed
enhanced SP- and CGRP-induced wheal-and-flare reactions (see Fig. 102-1). Certain transient receptor potential ion channels are expressed by sensory nerves as well
as by mast cells that can be activated by trigger factors
of urticaria like heat, cold, pressure, or food ingredients.
A neurogenic component in the pathophysiology
of psoriasis is suggested based on clinical obser-
18
::
In a mouse model, it could be observed that NGF accelerated the rate of wound healing.332 These findings
have encouraged successful treatment of leg ulcers in
humans with topical NGF.333,334 Parathyroid hormonerelated protein expression is temporarily upregulated
in migratory keratinocytes, myofibroblasts, and infiltrating macrophages in guinea pig skin, although
topical application of a parathyroid hormone-related
protein agonist did not change the healing rate or morphology in these wounds.335,336
NEP expression appears to be both increased and
redistributed in the wound environment during
wound healing, which indicates a role for neuropeptide-degrading enzymes in this process.337 In normal
skin, NEP immunoreactivity was restricted to the
basal layer, whereas during wound healing, NEP was
also detected in the suprabasal layer of human skin.
Future studies using transgenic and knockout animals,
in which certain components of the neurologic system
are overexpressed or deleted by homologous recombination, may make it possible to examine the role of
the cutaneous nervous system in normal and delayed
wound healing.338
Pruritus is one of the most frequent symptoms of
skin diseases and derives from stimulation of sensory nerve endings, spinal cord modulation, or
dysfunction of certain areas in the CNS (see Table 1020.1).48,65,222,339 Polymodal C fibers, stimulated by chemicals or heat, transmit signals to the spinal cord and
CNS, which results in itching. Accordingly, both the
peripheral cutaneous system and the CNS coordinate
the sensation of itch, which leads to the autonomic
reflex of scratching. Histamine is the best-studied,
albeit definitely not the only, mediator of pruritus.
New histamine receptors (e.g., histamine receptor-3,
histamine receptor-4) have now been cloned; their
role in human itch is poorly understood.212 Another
important mediator of pruritus in patients with atopic
dermatitis may be IL-31 (see Table 102-1, eFig. 102-0.1
in online edition).275,279,340,341 In notalgia paresthetica,
a neuropathy characterized by pruritus, pain, and
hyperalgesia, immunostaining for several neuropeptides revealed that affected areas had a significant
increase in intradermal nerve fibers as well as epidermal dendritic cells, which suggests that sensory nerve
fibers are involved in the pathogenesis of this disease.
Agents such as capsaicin that deplete neuropeptides
from sensory neurons have been shown to have a
therapeutic effect in diseases associated with pruritus
and pain. Other neuromediators such as opioids seem
to be involved in the pathophysiology of cholestatic
pruritus.342,343 Cholestatic pruritus can be significantly
reduced by application of an antagonist to 5-hydroxytryptamine.344 Like opioids, endogenous CB appear to
be implicated in itching.48,65,261,345 Under inflammatory
conditions,346 CB are capable of activating and sensitizing the TRPV1 receptor.347,348 Cannabinoid receptors also induce release of analgesic -endorphin from
murine keratinocytes.149 Aprepitant, a selective NK1R
antagonist, which has been recently demonstrated to
be beneficial for the treatment of pruritus and prurigo,75 may also be beneficial for the treatment of other
pruritic skin diseases.
Chapter 102
vation (e.g., stress induction) and is supported by

experimental studies.286289 Data suggest a role for
NGF as a mediator of inflammatory responses in
psoriasis, although its significance remains to be
established.290
In acute as well as lichenified lesions of atopic dermatitis, increased staining of cutaneous nerves or concentrations of neuropeptides has been observed.80,139,291297
Also, characteristics of the triple response (erythema,
wheal, flare) of neurogenic inflammation as well as
pruritus have been observed after injection of neuropeptides into human skin.298,299 The lesions of patients
with atopic dermatitis show enhanced concentrations
of mast cell tryptase, a ligand for the proteinase-activated receptor-2 (PAR-2), which is upregulated in
atopic dermatitis and mediates pruritus, inflammation, and upregulation of intercellular cell adhesion
molecule 1 or nuclear factor B.300303 A role for proopiomelanocortin peptides in the pathogenesis of atopic
dermatitis is supported by the in vitro observation that
-MSH modulates immunoglobulin E production and
the finding of increased levels of proopiomelanocortin
peptides in the skin of patients with atopic dermatitis.304,305 Some studies also suggest that NTs such as
NGF or NT-3 may participate in the pathophysiology
of atopic dermatitis (Table 102-2).306
Neuropeptides such as CGRP, PACAP, or -MSH, are
obviously involved in the regulation of epidermal antigen presentation.307310 Also, pretreatment of the skin
with capsaicin enhances contact hypersensitivity (CHS)
at the site of treatment. It has been suggested that capsaicin-sensitive neurons modulate this reaction via the
release of neuropeptides.114,311 Studies also indicate that
SP agonists can prevent impaired CHS and tolerance
after UVB irradiation.191 CGRP significantly inhibited
antigen presentation to antigen-specific T cells.114,312 The
effect of CGRP on murine LCs is probably mediated by
a specific CGRP receptor, which leads to intracellular
increase in cyclic adenosine monophosphate.113 Accordingly, IL-10 can be upregulated by CGRP.313 -MSH is
one of the most powerful neurohormones in terms of
its ability to modify CHS reactions.314316 PACAP is also
able to inhibit CHS reactions.310
The skin nervous system also plays a crucial role
during wound healing and impaired wound healing processes. Released neuropeptides participate in
inflammation, cell proliferation, cytokine, and growth
factor production, and neovascularization.317,318 Of
note, delayed wound healing occurred in animal models after surgical resection of cutaneous nerves.319323
For instance, decreased concentrations of SP, SST, and
CGRP were observed in wounds in rats324; elevated levels can be observed in other wound models.321,324 CGRP
promotes proliferation and migration of human keratinocytes325327 and stimulates proliferation of human
dermal endothelial cells.328 VIP has both inhibitory
and stimulatory effects on the proliferation of keratinocytes.325,326,329 Angiotensin II appears to influence
tissue repair via activation of the angiotensin I receptor in fibroblasts, which leads to collagen remodeling,
collagen gel contraction, and upregulation of collagenbinding integrins in vitro.330 NGF induces human skin
and lung fibroblast migration but not proliferation.331
1145
18
SUMMARY AND PERSPECTIVES
Section 18
::
In many ways, the nervous system modulates (and

eventually manipulates) the function of the skin,
which under physiological conditions leads to control
of skin homeostasis. However, under pathophysiological conditions, neuromediators can either aggravate
(proinflammatory) or ameliorate (anti-inflammatory)
disease development. The bidirectional interaction of
the skin with the peripheral nervous system as well as
the CNS plays a crucial role in skin homeostasis and
disease states, as seen for inflammation, pain, or pruritus. Recent discoveries have increased our knowledge about the molecular mechanisms regulating the
function of neuromediators, their receptors, and controlling enzymes. The development of modern techniques including proteomics, genomics, metabolics,
and molecular imaging of neuronal structures offer
exciting insights into the complex network between
skin, nerves, and immune system during inflammation, tumorigenesis, pruritus, or chronic pain. Various
applications like TRPV1 channel agonists/antagonists
or neuropeptide receptor antagonists are currently in
clinical or preclinical trials for the treatment of various skin diseases including atopic dermatitis, rosacea,
viral infection, pruritus, or pain. Using novel technical approaches and understanding new pathways of
neuro-immuno-endocrine communication, it will be
possible to learn how neuromedicine can contribute to
treat skin diseases and symptoms such as inflammation, cancer, pigmentation disorders, allergic reactions,
endocrine disregulation, painful skin diseases, or pruritic diseases.
KEY REFERENCES
1. Roosterman D et al: Neuronal control of skin function:
The skin as a neuroimmunoendocrine organ. Physiol Rev
86:1309-1379, 2006
26. Basbaum AI et al: Cellular and molecular mechanisms of
pain. Cell 139:267-284, 2009
28. Caterina MJ et al: The capsaicin receptor: A heat-activated ion channel in the pain pathway [see comments].
Nature 389:816-824, 1997
30. Slominski A et al: Corticotropin releasing hormone and
proopiomelanocortin involvement in the cutaneous
response to stress. Physiol Rev 80:979-1020, 2000
52. Steinhoff M et al: Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol 139:1479-1488, 2003
65. Paus R et al: Frontiers in pruritus research: Scratching
the brain for more effective itch therapy. J Clin Invest
116:1174-1186, 2006
168. Brzoska T et al: Alpha-melanocyte-stimulating hormone
and related tripeptides: Biochemistry, antiinflammatory
and protective effects in vitro and in vivo, and future
perspectives for the treatment of immune-mediated
inflammatory diseases. Endocr Rev 29:581-602, 2008
303. Buddenkotte J et al: Agonists of proteinase-activated
receptor-2 stimulate upregulation of intercellular cell
adhesion molecule-1 in primary human keratinocytes via
activation of NF-kappa B. J Invest Dermatol 124:38-45, 2005
341. Homey B et al: Cytokines and chemokines orchestrate atopic
skin inflammation. J Allergy Clin Immunol 118:178-189, 2006
Chapter 103 :: P
athophysiology and Clinical Aspects
of Pruritus

:: Gil Yosipovitch & Tejesh S. Patel
PRURITUS AT A GLANCE
Pruritus is the predominant symptom of skin
disease.
May originate in the skin or nervous system.
Clinical classification of itch includes:
pruritus on diseased (inflamed) skin
pruritus on nondiseased (noninflamed)
skin
pruritus presenting with severe chronic
secondary scratch lesions
1146
Chronic itch consists of multidimensional

phenomena including sensory, emotional, and
cognitive components.
Central and peripheral mediators in humans
include histamine, proteinases, opiates, substance
P, nerve growth factor, interleukins, and
prostaglandins.
Treatment should address the multifactorial
nature of pruritus including central pathways
and peripheral mediators.
INTRODUCTION

Pruritus may originate in the skin or in the CNS. There
is no single, definitive classification of pruritus. The
International Forum for the Study of Itch (IFSI) has
proposed a classification that distinguishes three clinical groups of patients as follows14:
Group I: Pruritus on diseased (inflamed) skin
Group II: Pruritus on nondiseased (noninflamed) skin
Group III: Pruritus presenting with severe chronic secondary scratch lesions, such as prurigo nodularis
Skin disease
Atopic dermatitis
Contact dermatitis
Poison ivy
Elderly idiopathic xerosis
Urticaria
Extensive psoriasis
Pityriasis rosea
Neurodermatitis: lichen
simplex chronicus, prurigo
nodularis, lichen amyloidosis
Burns
Acne
Linear immunoglobulin A
disease
Bullous pemphigoid
Collagen disease
Dermatomyositis
Sjgren syndrome
Scleroderma
Infection
Varicella
HIV disease
Onchocerciasis
Scabies
Superficial fungal infections
Estimated Prevalence
of Pruritus
100%
Unknown
Unknown
30%60%7
97%
80%
Unknown
Unknown
Unknown
67%87%8
Unknown
Unknown
50%70%9,10
Unknown
Unknown
38%
Unknown
45%11
Unknown
HIV-associated folliculitis in
25%50% of HIV patients;
nonspecific pruritic eruption
in 11%46% of HIV patients
5%67%12
100% (except Norwegian
scabies)13
Unknown
HIV = human immunodeficiency virus.

Adapted from Yosipovitch G: Epidemiology of itching in skin disease.
In: Itch: Basic Mechanisms and Therapy, edited by G Yosipovitch et al:
New York, Marcel Dekker, 2004, with permission.
Pathophysiology and Clinical Aspects of Pruritus
Itch is a symptom rather than a specific disease entity;

therefore, epidemiologic data for itch are limited. Nevertheless, itch has been found to be the dominant skin
complaint among all age groups.5 In a large cross-sectional study in Norway, the prevalence of pruritus was
approximately 8% among adults.6 Itch is a primary
symptom in a diverse range of skin diseases as well as
in systemic diseases. The prevalence of pruritus in different dermatologic and systemic diseases is outlined
in Tables 103-1 and 103-2.
Cause
::
EPIDEMIOLOGY
Prevalence of Itch in Skin Disorders and

Infectious Skin Diseases
Chapter 103
Pruritus (itching) is the predominant symptom of

skin disease and can best be defined as a sensation
that leads to a desire to scratch. All human beings
experience this sensation in the course of their lifetime; therefore, it is important to make a distinction
between acute itch, which is of a limited period of
time ranging from seconds to a week such as the itch
related to acute insect bite reaction, and chronic itch,
which lasts for months and is the focus of this chapter.1 Chronic itch is a multidimensional phenomenon
consisting of sensory, emotional, and cognitive components. In most cases, chronic itch results from interaction of the brain-skin axis. Although itch and pain
are separate and distinct sensations, itch has many
similarities to pain.2,3 Both itch and pain are unpleasant sensory experiences, follow similar neural pathways, and can severely impair patients quality of life.
However, the behavioral response patterns differ
pain elicits a reflex withdrawal, whereas itch leads to
a scratch reflex.
The limited understanding of itch results from the
subjective nature of itching, the absence of specific
and sensitive investigational methods to study the
neuropathophysiology and molecular basis of itch in
humans, the lack of convincing animal models and
incomplete knowledge of pharmacologic mediators of
pruritus. However, significant progress has been made
in the past decade with the discovery of new neural
pathways (both histaminergic and nonhistaminergic)
as well as novel receptors in humans and animals. The
concept that itch is transmitted to the central nervous
system (CNS) and processed in the brain should lead
to new approaches to antipruritic therapy.4
18
TABLE 103-1
The first group includes underlying dermatological

diseases, while the second and third group includes
patients with systemic diseases including diseases of
pregnancy and drug-induced pruritus as well as neuropathic and psychiatric diseases. In some patients,
more than one cause may account for pruritus (category mixed) while in others no underlying disease
can be identified (category others).14 It is also important to differentiate acute itch from chronic itch because
therapies that provide transient itch relief often do not
address the pathological processes underlying chronic
itch.1 Moreover, the biologic function of nerve fibers
most probably differs in chronic itch than acute itch.
ITCHSCRATCH CYCLE
Itch and scratching are interwoven together in both
acute and chronic itch conditions. Phylogenetically,
1147
18
TABLE 103-2
Basic etiologies of the itch-scratch cycle
Prevalence of Pruritus in Systemic Disease

Disease
Section 18
::
Chronic renal failure, end

stage
Hepatic
Cholestatic jaundice
Primary biliary cirrhosis
Hepatitis C
Cholestasis of
pregnancy
Hematopoietic
Polycythemia vera
Iron deficiency anemia
Multiple myeloma
Mastocytosis
Hodgkin lymphoma
Non-Hodgkin
lymphoma
Endocrine
Hyperthyroidism
Hypothyroidism
Carcinoid syndrome
Diabetes
Anorexia nervosa
Estimated Prevalence
of Pruritus
Scratch
25%85%
Itch
20%25%
100%
4%
Unknown
48%
Unknown
Unknown
Unknown
30%
Unknown
60%
Unknown
Unknown
11%
58%
itch is probably a mechanism for animals to remove

parasites residing in the hairy skin. Scratching is also
a behavioral response. A study in humans has shown
that repetitive scratching activates the prefrontal cortex in particular, an area of the brain implicated in
goal-directed and habit-learning systems.15 It is thus
possible that activity induced by scratching in the
prefrontal cortex may serve to drive the compulsion
to continue scratching and could also account for the
highly rewarding aspects of scratching. Furthermore,
the hedonic experience of scratching may be associated with release of endogenous opioids. Repetitive
scratching in chronic conditions such as atopic dermatitis and psoriasis further damages the skin and causes
secretion of neuropeptides and opiates that may further augment the vicious itch-scratch cycle (Fig. 103-1).
ALLOKNESIS: ITCHY SKIN
1148
Epidermal
barrier
Alloknesis is a phenomenon in which a normally

innocuous stimulus induces itch. For example, application of a fine brush to an itchy site induces itch.
Alloknesis is analogous to the better-known allodynia
(defined as pain due to stimuli, which does not normally provoke pain). This type of itch is mediated by
mechanical mechanoreceptor units as well as an ongoing activity of afferent C nerve fibers and is considered
a central neural sensitization response. Alloknesis
is common in chronic atopic dermatitis; sweating or
slight mechanical stimulation associated with wearing
wool exacerbates itch. The exact role of central sensitization in pruritus associated with specific diseases is
unknown.3
C nerve
fibers
Neuropeptides, tryptase
inflammatory mediators
Figure 103-1 Basic etiologies of the itch-scratch cycle.
ITCH TRANSMISSION IN THE SKIN

The only peripheral tissues from which itch can be
evoked are skin, mucous membranes, and cornea.
Interestingly, the nerves in the deeper layer of the
reticular dermis and subcutaneous fat do not transmit itch and inflammatory skin diseases affecting
these areas, such as panniculitis, cause pain but not
itch. Removal of the epidermis abolishes perception
of pruritus, suggesting that pruritus receptor units are
located predominantly within this layer.16 We suspect
that the epidermis acts as a receptor for itch, but a specific receptor has not yet been identified. Light microscope and ultrastructural studies of human skin have
shown the existence of intraepidermal nerve fibers
with free nonspecialized nerve endings extending
to the stratum granulosum.17 Many epidermal nerve
fibers stain positively for neuropeptides implicated
in itch transmission. It has recently been shown that
Mrgprs, a family of G protein-coupled receptors
expressed exclusively in peripheral sensory neurons,
function as itch receptors.18
Keratinocytes express a variety of neural mediators
and receptors, all of which appear to be involved in the
itch sensation.19 Mediators include opioids, proteases,
substance P (SP), nerve growth factor (NGF), and neurotrophin 4 whereas receptors include - and -opioid
receptors, proteinase activated receptor-2 (PAR-2),
vanilloid receptors, tropomyosin-related kinase A
(TRKA), transient receptor potential vanilloid (TRPV)
ion channels, gastrin releasing peptide receptor, and
cannabinoid receptors 1 and 2. Keratinocytes also have
voltage-gated adenosine triphosphate channels and
adenosine receptors similar to C nerve fibers. Because
these channels have a role in pain,20 these findings suggest that keratinocytes may act as itch receptors.
DEDICATED ITCH-TRANSMITTING C
NERVE FIBERS
Significant advances in our understanding of itch neurophysiology have been achieved in the past decade.
naires has enabled us to better understand the different

characteristics of itch.7,3335
18
THE CENTRAL PROCESSING OF ITCH
HISTORY
It is of prime importance to determine whether the
cause is related to a primary skin disease or systemic
disease. Diseases such as skin dryness or scabies may
exhibit few primary skin lesions; therefore, careful
history and laboratory evaluation can be particularly
important. It is important to differentiate between generalized pruritus and localized itch. Careful history,
including a full drug history, and physical examination including lymph nodes, are the starting points.
The history should take into account the multidimensional nature of itching and should include details of
quality, distribution, and timing. Any patient referred
with generalized pruritus in the setting of other family members with pruritus should be assumed to have
scabies until proved otherwiseskin signs may be
clinically inapparent, perhaps confined to a few small
nodules on the genitalia. In addition, patients with
localized pruritus, especially in a dermatomal distribution, that present with other sensory complaints such
as a burning sensation, loss of sensation or increased
pain should be evaluated carefully for neuropathic
itch. Figure 103-2 is an algorithm showing the
approach to a patient with pruritus.
CLINICAL FINDINGS
::
The central processing of itch has been demonstrated

using the neuroimaging techniques of positron emission tomography and functional magnetic resonance
imaging in healthy humans and patients with atopic
dematitis. In these studies, histamine-induced itch
activated various brain areas implicated in sensory
and motor function as well as emotionreflective of
the multidimensional aspects of this distressing symptom. A recent study showed that that the central processing of itch in atopic dermatitis is different from
that of healthy subjects. The anterior and posterior
cingulate cortex as well as the dorsal lateral prefrontal
cortex, which are involved in emotions, reward, and
memory of negative experiences were significantly
activated in patients with atopic eczema but not in
healthy subjects.36 The activation of the precuneus,
which is located in close proximity to the posterior cingulate cortex seems unique in itch and has rarely been
reported in pain imaging. The precuneus is involved
in episodic memory retrieval and could be associated
with the affective components involved in itch.36,37
Chapter 103
Microneurography has helped to disprove the historic

concept that pruritus and pain are simply responses
of the same neurons to mild versus intense stimuli,
respectively. Studies using electric field stimulation
coupled with microneurography have identified individual histamine-sensitive C nerve fibers that transmit
itch.21 The C nerve fibers have exceptionally slow conduction velocity, unusually wide innervation territories, and represent no more than 5% of total C fibers.
These neurons are sensitive to pruritogenic and thermal stimuli as well as capsaicin, but not mechanical
stimuli. The co-responsiveness of this subset of C neurons to temperature change as well as pruritic stimuli
is of interest because raising the temperature of skin
lowers the threshold of receptors to pruritic stimuli22
and most pruritic patients complain of aggravation
of pruritus in a warm environment. In chronic itch,
spontaneous activity in these C fibers occurs.23 In
contrast, the vast majority of C fibers are sensitive to
mechanical and heat stimuli and are entirely insensitive to histamine.24
The existence of a subset of dedicated itch-transmitting C neurons receives further support from studies
of spinal-cord pathways. Itch-transmitting primary
afferent C neurons synapse with secondary transmission neurons that cross over to the contralateral spinothalamic tract and ascend to the thalamus. In the cat,
microneurography identified lamina 1 neurons in the
lateral spinothalamic tract that selectively responded
to histamine, suggesting a central dedicated nerve
pathway for itch.25 Other C nerve fibers transmit
itch as well. Mechanically induced itch is commonly
observed clinically; for example, itch associated with
contact with wool cannot be explained by histaminesensitive nerve fibers. Moreover, in patients with
chronic pruritus, electrical or painful stimuli can also
induce itch.2628 Oral antihistamines are ineffective in
the treatment of most types of itch, suggesting that
nonhistamine-mediated fibers also play an important role. A separate nonhistaminergic itch processing
pathway activated by cowhage (Mucuna pruriens)
was discovered in peripheral nerve fibers of humans
as well as in the spinothalamic tract in primates.29,30
The active ingredient inducing itch by cowhage has
been found to be a cystine protease which acts through
PAR-2 and PAR-4.31 Therefore, two parallel subpopulations of primary afferent C-fibers and spinothalamic
tract neurons transmit itch in humans. Both of these
pathways are most probably not itch specific since
they also transmit burning sensations and respond to
the algogen, capsaicin. In addition, gastrin-releasing
peptide (GRP) receptor positive neurons were recently
found to constitute a dedicated neuronal pathway for
itch in the spinal cord of mice.32 The role of these neurons and their interaction with both histaminergic and
nonhistaminergic pathways in humans remains to be
elucidated.
The perceived sensation of pruritus can vary greatly
in quality. Patients may experience sensations of burning or pricking but the neurophysiologic and psychologic correlates of these differences have not yet been
elucidated. Information obtained from itch questionnaires based on previously developed pain question-
CUTANEOUS LESIONS
Secondary skin lesions characteristic of pruritus include
excoriations, lichenification, and hyper- or hypopigmentation. Lichenification results from continuous
1149
18
Approach to patient with pruritus
Pruritus assessment
Generalized
Localized
Section 18
With primary skin rash
Without primary rash
With rash
Without rash
Skin diseases
Systemic diseases
Psychogenic itch
Advanced aging
Drugs
Site specific:
Seb derm, LSC, vaginal
Site specific:
neuropathic
brachioradial, notalgia
paresthetica
psychogenic pruritus
Skin biopsy (if needed)
CBC + DIF
Liver enzymes
Renal function test
CHest x-ray
::
Figure 103-2 Approach to a patient with pruritus. CBC = complete blood cell count; DIF = differential; LSC = lichen simplex
chronicus; Seb derm = seborrheic dermatitis.
rubbing or scratching and consists of well-developed,
thickened plaques with marked accentuation of skin
creases (see Chapter 14). Post-inflammatory hyperpigmentation or hypopigmentation is common in patients
with skin phototypes 4 through 6 (see Chapter 75).
Lichenified plaques are most commonly distributed in
areas the patient can easily scratch or rub (i.e., nape
of neck, below the elbow, ankle, buttock, and genitalia). The butterfly sign consists of normal-appearing
skin in the middle of the back outlined by a butterfly pattern of contrasting hyperpigmentation in areas
subjected to persistent scratching, resulting from the
patients inability to reach the middle of the back.
Shiny fingernails may result from prolonged rubbing.
Prurigo nodules are excoriated papules that form nodules in patients with chronic pruritus (see Chapter 15).
In many cases, this type of itch is accompanied by a
painful, burning sensation suggestive of a neuropathic
component. Prurigo nodules are frequently associated
with emotional stress and obsessive-compulsive disorder; however, they can be also be a manifestation of
itch in patients with atopic dermatitis or chronic renal
failure. Such nodules are usually distributed over
extensor aspects of the limbs.
Some pruritic states have specific clinical patterns.
Despite severe pruritus, chronic urticaria usually
does not show secondary skin lesions associated with
scratching. Neuropathic itch in disease entities, such
as postherpetic neuralgia, brachioradial pruritus, and
notalgia paresthetica, is typically associated with pain
and burning sensation. Atopic dermatitis may also be
associated with burning sensation after scratching.89

SPECIAL TESTS
1150
Laboratory tests to be considered in the evaluation of

generalized pruritus are outlined in Box 103-1. Secondary laboratory considerations may include stool exami-
nation for ova and parasites, screening for hepatitis B

or C, plasma protein electrophoresis, and immunoelectrophoresis. A computed tomography scan of the chest
and abdomen may be justifiable to help rule out lymphoma. A skin biopsy is not warranted and only useful
to exclude clinically inapparent cutaneous mastocytosis, bullous pemphigoid or cutaneous T cell lymphoma.
(Box 103-2)
COMPLICATIONS
Pruritus can significantly impair patients quality of life
and have an effect on prognosis. Patients with chronic
pruritus often have difficulty sleeping, difficulty concentrating, decreased sexual desire and sexual function,
agitation, and depression.7,90 In addition, eczematous
Box 103-1 Recommended

Laboratory Tests for
Investigation of Patients with
Generalized Pruritus
Recommended
Complete blood cell count with differential
Chemistry profile: urea, creatinine, liver enzymes
Thyroid function tests
Chest radiograph
Optoinal
Stool Examination for parasites
Human immunodeficiency virus testing with
other associated symptoms and signs

of Generalized Pruritus without
Primary Skin Disease
Generalized pruritus can wax and wane. Changes in

the clinical presentation may be associated with seasonal changes, such as exacerbation of atopic dermatitis
in the winter, or changes between dry and humid environments. Pruritus associated with underlying internal
disease is often multifactorial, involving both systemic
and external factors, including ambient temperature
and humidity. Chronic itch associated with skin disease
may also include central neural sensitization.28,36
ITCH CAUSED BY SKIN DISORDERS

PRURITUS IN ATOPIC DERMATITIS. (See
Chapter 14.) Pruritus in atopic dermatitis remains a
CLINICAL COURSE
::
lesions resulting from scratching can become secondarily infected, particularly in patients with atopic dermatitis. Moreover, in a large multinational study in
hemodialysis patients, pruritus was associated with a
17% higher mortality risk.91
PSORIASIS. Itch in psoriasis is a significant but

underrecognized problem in dermatology. Several
studies have demonstrated that itch is a principal
symptom of psoriasis.100104 Among psoriasis patients,
77% experience pruritus on a daily basis.90 Dermatologists emphasize observable criteria of psoriasis, such
as visible lesions; however, itching frequently occurs in
areas of the body where no psoriasis plaques are visible. Scalp itching, in particular, is specific to psoriasis
and may require different therapies than pruritus in
other areas of the body.103,105
18
Chapter 103
Chronic renal disease

Cholestasis
Hyperthyroidism
Pruritus in hematologic disease and lymphoreticular malignancy
Hodgkin disease and non-Hodgkin lymphoma
Polycythemia vera
Myeloid and lymphatic leukemia
Myelodysplasia
Mastocytosis
Solid malignant tumors (paraneoplastic manifestation)
Human immunodeficiency virus-associated pruritus
Itching in advanced age
Aquagenic pruritus
Itching as a manifestation of psychiatric disease
Delusions of parasitosis
Itch associated with obsessive-compulsive
disorder
Itch associated with fibromyalgia and depression
Pruritus of anorexia nervosa
Neuropathic itch
Postcerebrovascular accident pruritus
Multiple sclerosis-associated pruritus
Pruritus of CreutzfeldtJakob disease
(prion pruritus)
Drug-induced pruritus
Opiate-associated pruritus
Hydroxyethyl starch-induced pruritus
controversial area and the molecular basis of pruritus

in atopic dermatitis remains largely unexplained.92
Whether itch precedes skin lesions or vice versa is also
an unresolved issue. What is certain is that a vicious
itch-scratch cycle (see Fig. 103-1) exists in atopic
patients, in which scratch damage enhances pruritus.
Itching is particularly acute in response to punctate
stimuli such as wool fibers. Alloknesis (see Section
Alloknesis: Itchy Skin) is a prominent feature of
the itch of atopic dermatitis and explains the bouts
of intense itching associated with sweating, sudden
changes in temperature, dressing, undressing, and
direct contact with wool.
A central (neurogenic) component to the itch of
atopic dermatitis is suggested by the poor response
to low sedation H1 antihistamines.93 The intensity of
itch in atopic dermatitis has been related to mental
factors, and itch may be induced by cognitive stress,
such as anxiety, as well as depression.9497 Of note, itch
intensity and disease severity were significantly correlated with brain activity in the anterior cingulate cortex as well as the insula in atopic dermatitis patients.36
Opioid peptides may serve as central and peripheral
mediators because opioid antagonists acting at these
levels are effective in some patients.98 Interestingly,
there is a significant downregulation of -opioid receptor expression in the epidermis of atopic dermatitis
patients.99 Nocturnal scratching is a major problem in
atopic dermatitis, occurs during superficial sleep, and
occupies 10%20% of the total sleeping time, leading to
tiredness and irritability.
NEUROPATHIC ITCH
POSTHERPETIC NEURALGIA. Postherpetic neuralgia commonly has neuropathic pain; and often,
associated neuropathic itch in 30%58% of such
patients. Pruritus commonly accompanies both acute
zoster and postherpetic neuralgia, particularly lesions
affecting the head, face, and neck.106,107
BRACHIORADIAL PRURITUS. Brachioradial
pruritus, a localized pruritus, is becoming increasingly common. Patients, usually fair skinned, affluent,
and middle aged, habitually indulge in golf, tennis,
sailing, or other leisure outdoor activities in sunny
climates.108,109 They develop persistent pruritus of the
outer surface of the upper arm, elbow, and forearm,
associated with clinical evidence of chronic sun damage and xerosis. The itch is often accompanied by a
1151
18
burning sensation. The itch may gradually become

more widespread. The pathophysiology is believed
to involve compression of spinal nerve roots in C4C6
and in rare cases it has been associated with spinal
nerve tumors.110 Of note, exposure to UV light has been
an eliciting factor.111 (See Chapter 90.)
Section 18
NOTALGIA PARESTHETICA. Notalgia paresthetica is a chronic localized itch, affecting mainly the
interscapular area especially the T2T6 dermatomes,
but occasionally with a more widespread distribution,
involving the shoulders, back, and upper chest. The
sensation perceived by the patient is part itch, part paraesthesia. There are no specific cutaneous signs, apart
from those attributed to scratching and rubbing. Amyloid deposition in skin biopsies is a secondary event.
The current view on etiology is that it is a neuropathic
itch due to nerve entrapment of the posterior rami of
spinal nerves arising at T2T6.112,113
::
1152
SYSTEMIC ITCH
PRURITUS OF CHRONIC KIDNEY DISEASE.
(See Chapter 150.) Pruritus is one of the most distressing symptoms of chronic kidney disease (CKD).
It affects 42% of patients on hemodialysis as reported
by the Dialysis Outcomes and Practice Pattern Study
(DOPPS).91 The DOPPS report and a large study in Japan
showed that CKD-associated itch induces depression,
sleep disturbance and increased mortality.91,114 Scratching is common and patients may be heavily excoriated
or the skin may appear lichenified or present with prurigo nodules. The back is invariably affected, and the
arm bearing the arteriovenous fistula is also a common
site in dialysis patients. Patients with CKD associatedpruritus often have dry skin, but correction of this by
emollients usually provides minimal relief.
The pathophysiology of CKD-associated pruritus
remains poorly understood. Current understanding
points towards central roles for the immune and opioidergic systems. It is postulated that the itch associated
with CKD is a manifestation of an immune system
derangement that results in a proinflammatory state.
In line with this theory, immunomodulators such as
ultraviolet B light,115 tacrolimus116 and thalidomide117
have been shown to alleviate CKD-associated pruritus.
An imbalance of the endogenous opioidergic system
has also received recent attention in terms of the pathophysiology of CKD-associated pruritus.118 An increased
ratio of serum -endorphin to dynorphin A has been
reported in HD patients compared with healthy controls, and the ratio increased with the increased intensity of itch.119 Moreover, a kappa-receptor agonist,
nalfurafine, was shown to significantly decrease itch
intensity and excoriations in HD patients.120,121 Other
proposed etiologic factors may include elevated calcium levels, release of pruritogenic cytokines during
hemodialysis, damage to C nerve fibers, proliferation
of sensory nerve endings in skin, increased numbers
of dermal mast cells, elevated plasma histamine levels,
secondary hyperparathyroidism and abnormal levels
of divalent cations.118,122,123 Secondary hyperparathy-
roidism, though common in patients with renal failure,

is a rare cause of renal pruritus. The proliferation of
nerve endings in skin is most likely a response to incessant scratching and rubbing, rather than the primary
cause of pruritus. Elevation of histamine levels, with or
without increased population density of dermal mast
cells, is also unlikely to be important because antihistamines are rarely effective.
PRURITUS OF CHOLESTASIS. (See Chapter

150.) Pruritus of cholestasis is highly distressing. The
unique feature of cholestatic pruritus is that the itch
initially starts and is most intense in the palms and
soles, which is usually not reported in other diseases
and later becomes more generalized. Of note, intractable itch in chronic liver disease may be an indication
for liver transplantation even in the absence fulminant
liver failure.124 Both peripheral and central mechanisms
are important. Cholestatic pruritus is associated with
high plasma levels of bile salts; however, there is little
or no evidence of a correlation between skin or serum
concentrations of bile salts and itching125 although
administration of cholestyramine, which lowers bile
salt levels, does provide some relief. Patients also have
elevated plasma opioid levels,126 and pruritus has been
shown to improve with treatment with opioid antagonists including naloxone, naltrexone, and butorphanol.127129 In addition, animal models of cholestasis are
associated with elevated levels of opioid peptides and
scratching, relieved by naloxone.130,131 Thus, combination of both bile salt-lowering and opioid-directed
strategies appear reasonable in the management of
pruritus of cholestasis.
Furthermore, recent studies have shown that
patients with cholestatic pruritus have elevated serum
levels of autotoxin and its substrate lysophosphatidic
acid (LPA) a signaling phospholipid. The activity of
autotaxin in cholestatic patients sera correlated with
the intensity of pruritus. LPA and autotaxin may therefore be potential targets in the treatment of cholestatic
pruritus.132
PRURITUS OF ENDOCRINE DISEASE. (See
Chapter 151.) Generalized intractable itching is a recognized feature of thyrotoxicosis and may be a presenting symptom.133 This may be due to increased blood
flow, which raises the skin temperature, which, in turn,
reduces the threshold to itching.22 Hypothyroidism is
less frequently associated with itch. Generalized itching is not a feature of diabetes mellitus.134 However,
anogenital itching is a common presenting feature, and
is due to mucocutaneous candidiasis. Localized itching of the scalp and lower extremities in the form of
lichen simplex chronicus can also be a manifestation of
diabetic neuropathy,135 which may respond to topical
capsaicin treatment.136 In addition, truncal pruritus of
unknown origin has been recently reported to be associated to diabetes and diabetic neuropathy.137
PRURITUS IN HEMATOLOGIC DISEASE AND
LYMPHORETICULAR MALIGNANCY. (See
Chapters 144 and 145.) Itch is common in hematologic
Itch is an early symptom of human immunodeficiency

virus (HIV) disease and may be associated with skin
disease or a result of systemic disease (e.g., hepatic,
renal, adverse drug reactions, lymphoma, and systemic and skin infections including Staphylococcus
aureus and Pityrosporum). However, it may occur as a
primary symptom of HIV.145 The most common example is eosinophilic folliculitis. Other common types of
itch in HIV are insect bite hypersensitivity reaction,
pruritic papules other than eosinophilic folliculitis,
and itch associated with skin xerosis and lichenoid
dermatitis, as well as exacerbation of seborrheic dermatitis and psoriasis.
PSYCHOGENIC ITCH
(See Chapter 104)
ADVANCED AGE AND ITCH. Itch is the most

common dermatologic symptom among people over
65 years of age.148,149 At least 50% of persons aged 70
years or older suffer from prolonged bouts of troublesome pruritus. Idiopathic itch in the elderly, sometimes
referred to inappropriately as senile pruritus, is common
and presents a diagnostic and therapeutic challenge.
Itch in senescent skin can result from a variety of causes
including dry skin, inflammatory skin diseases such as
low-grade eczema and scabies, as well as underlying
systemic disease, especially cholestasis and renal failure. Several drugs can induce pruritus without a rash
including opioids and angiotensin converting enzyme
inhibitors. However, in many instances, no cause is
found. Although dry skin is probably the most common associated factor, it may not be the cause of pruritus; many elderly patients have senescent skin without
xerosis. Other factors may play important roles, such
as age-related changes in nerve fibers and loss of input
from pain fibers leading to central disinhibition of itch.
Additional skin changes in elderly patients that may
contribute to itch include decreased skin surface lipids, decreased clearance of transepidermally absorbed
materials from the dermis, decreased sweat and sebum
production, and diminished barrier repair.150
PRURITUS OF HUMAN IMMUNODEFICIENCY VIRUS INFECTION. (See Chapter 198.)
MISCELLANEOUS TYPES OF ITCH
18
::
PARANEOPLASTIC PRURITUS. (See Chapter

153). Chronic itch could be a presenting sign of both
hematologic malignancies as well as solid tumors. It
may occasionally be present years before the tumor
becomes clinically detectable. It could also be present as part of a primary epidermal or dermal skin
disease associated with malignancy such as eruptive
seborrheic keratosis, malignant acanthosis nigricans,
erythroderma, transient acantholytic dermatosis
(Grover disease) and dermatomyositis.142 Traditionally, the onset of pruritus in a middle-aged or elderly
patient with an otherwise normal-looking skin
prompts a thorough investigation for underlying systemic causes, including internal neoplasia, although
the latter is an uncommon cause. Full investigation
for a causative solid tumor is probably not worthwhile in the absence of other skin or systemic findings suggestive of malignancy even if resources are
available.143,144
The prevalence of pruritus among psychiatric

inpatients is as high as 42% and appears related to
psychosocial stress.146,147 Patients with depression,
fibromyalgia, and other somatoform disorders can
suffer from severe itch that responds well to selective
serotonin reuptake inhibitors (SSRIs). Of importance,
delusions of parasitosis is one of the more challenging types of itch that dermatologists encounter. The
patient holds a false belief that they are infested with
parasites, although careful inspection reveals no supporting clinical findings. The patient often brings evidence in the form of collected fragments, although
on examination the material proves to be nonspecific
debris. The patients often refuse to see a psychiatrist.
Delusions of parasitosis is classically treated with typical antipsychotic agents; pimozide is most commonly
used by dermatologists. Olanzapine (5 mg/day) is
another option to treat this severe type of psychogenic
itch. Localized pruritus in the form of prurigo nodularis or anogenital pruritus could be a manifestation of
obsessive-compulsive disorders and anxiety.
Chapter 103
disorders. In widespread cutaneous T-cell lymphoma,

and erythrodermic forms of cutaneous T-cell lymphoma including Szary syndrome (T-cell leukemia),
intractable itch is difficult to manage. In polycythemia
vera, it occurs in approximately 50% of patients, is
often precipitated by contact with water (bath itch),
and is associated with raised blood histamine levels.138,139 In other lymphoproliferative diseases, itch can
also be precipitated by contact with water. In Hodgkin
disease, it may be a presenting symptom and occurs
in between 15%19% of patients.124,140 It can a be a presenting sign in non-Hodgkins lymphoma also. Of note,
recent data has shown functional abnormalities of
mast cells in patients with myeloproliferative disease
with an increased release of pruritogenic factors, such
as histamine, leukotrienes, and IL-31, when compared
to normal mast cells.141 In cutaneous mastocytosis (see
Chapter 149), itching occurs locally following rubbing
the skin, although it can be widespread in severely
affected patients, when it is usually associated with
systemic symptoms. Itching may occur in patients with
myeloid and lymphatic leukemia and myelodysplasia.
ITCH ASSOCIATED WITH BURNS AND

SCARS. (See Chapters 66 and 95.) Burn scars are com-
mon in both children and adults and are associated

with significant pruritus. The reported prevalence rates
of mild to severe itching were as high as 87%, 70% and
67% at 3, 12, and 24 months post burn respectively.8
Compared to healthy skin, burn-graft skin displays
significantly elevated SP nerve fibers as well as significantly elevated thresholds for pinprick, warming,
touch, and vibration.151 Keloids are frequently associated with itch at the periphery of the keloid lesion and
less frequently pain in the center of the keloid.152 These
1153
18
findings probably result from entrapment of small

nerve fibers.
AQUAGENIC PRURITUS. Originally described by

Shelley153 and subsequently characterized by Greaves
et al,154 aquagenic pruritus is a rare, intractable pruritus of unknown etiology found mainly in the middleaged and elderly.155 Characteristically, local itching
without visible skin signs is provoked by contact with
water. Notably, aquagenic pruritus can be associated
with lymphoproliferative disorders such as polycythemia vera.139,156
Section 18
TREATMENT OF PRURITUS
::
Unfortunately, there are no general-purpose antipruritic drugs. Treatment of pruritus depends on identifying and removing the cause, whether systemic or
cutaneous. False hopes of highly effective treatment
for those patients in whom no cause can be found
should not be raised. Recently, a kappa opioid receptor
agonist, nalfurafine, was officially approved in Japan
for clinical use as an antipruritic for CKD-associated
pruritus. The antipruritic effects of this drug on other
forms of itch still need to be elucidated. It is important to obtain a detailed history, including the precise
quality, timing, and distribution of the itch, so that
more focused therapy can be instituted. The sensation
of itching is heightened if the skin is warm,22,157 therefore measures should be taken to cool the skin down,
including tepid showering, light clothes, and air conditioning where appropriate. Cooling lotions, such as
calamine lotion or menthol 1%, may help. Of note a
subset of chronic itch patients report that hot showers
alleviate their itch for several hours.35,90
A general therapeutic ladder for generalized pruritus is presented in Fig. 103-3.
TOPICAL ANTIPRURITIC TREATMENTS

There is a lack of controlled studies for most topical antipruritic treatments. Many topical agents are
claimed to be effective for pruritus; however, few
claims are supported by more than anecdotal evidence.
Although capable of relieving pruritus due to inflammatory skin disease, corticosteroids are not intrinsically
antipruritic. Antihistamines are only antipruritic if the
pruritus is caused by histamine, as in urticaria. However, a number of pharmacologic mechanisms offer
promising avenues for treatment of itch. A summary of
topical antipruritic treatments is given in Table 103-3.
BARRIER CREAMS AND COMBINATION

THERAPIES. Emollients and barrier repair creams
1154
often reduce pruritus through improved barrier function. They help the stratum corneum to retain water
and provide an exogenous barrier to prevent transepidermal water loss. Such barrier creams are often effective treatments for itch associated with dry skin and
atopic dermatitis; however, the mechanism of their
antipruritic effects are not fully understood. Restora-
Therapeutic ladder for antipruritic therapies
Thalidomide and
apreptitant
Opoid agonists
or antagonist
Oral antidepressants
and neuroleptics
Sedating oral
antihistamines
Narrowband UVB
Topical
therapies
Figure 103-3 Therapeutic ladder for antipruritic therapies. UVB = ultraviolet B.

tion of the barrier minimizes fissuring and reduces
exposure of C nerve fibers. Atopic dermatitis patients
treated with ceramide-dominant emollients demonstrate improved transepidermal water loss and overall
severity of skin disease. Lipids, occlusives, and humectants also reduce damage to skin by decreasing contact
between skin proteins, lipids, and surfactants. Acidifying the stratum corneum may also reduce itch. High
pH solutions increase the swelling of the stratum corneum, change lipid rigidity, and increase secretion of
serine proteases, suggesting that neutral or acidic pH
solutions are less damaging.158
TOPICAL SALICYLATES. Clinical trials have

shown that applying a topical salicylic acid solution to
the skin relieves itch. Topical salicylic acid is a common keratolytic agent and may also increase hydration
and soften the stratum corneum by decreasing its pH
(see Chapter 222). Topical aspirin significantly reduced
pruritus in patients with lichen simplex chronicusa
form of localized itch85; however, oral salicylates do
not relieve pruritus except in polycythemia vera.
TOPICAL IMMUNOMODULATORS. (See Chapter 221.) Although topical immunomodulators, such
as tacrolimus and pimecrolimus, are used primarily
for atopic dermatitis, these medications are promising antipruritic treatments in other dermatologic
diseases as well. Other pruritic dermatoses treated
successfully with topical calcineurin inhibitors include
chronic irritative hand dermatitis, seborrheic dermatitis, graft-versus-host disease, lichen sclerosus, anogenital pruritus and prurigo nodularis. Tacrolimus and
pimecrolimus have both been shown to directly affect
C nerve fibers.159,160
18
TABLE 103-3
Topical Antipruritic Treatments

Notes
Barrier repair creams
N/A
Atopic dermatitis, dry skin
Salicylic acid
2%6%
Stinging
Tacrolimus
0.03%0.1% ointment
Atopic eczema, contact dermatitis
Stinging, burning sensation
Pimecrolimus
1% cream
Atopic eczema, contact dermatitis
Stinging, burning sensation
Menthol
1% cream
Patients who respond well to cold

showers
Skin irritation
Capsaicin
0.025%0.1% cream
Neuropathic itch (notalgia

paresthetica, postherpetic itch),
uremic itch, psoriasis, atopic
dermatitis
Poor compliance due to transient

burning sensation
Pramoxine
1.0%2.5%
Facial eczema, atopic eczema
Particularly effective for pruritus of

face
Polidocanol
5% urea + 3% polidocanol
(Lauromacrogol)
Atopic dermatitis, contact dermatitis,

psoriasis, uremic pruritus
Doxepin
5% cream
Atopic dermatitis
Drowsiness in 25% of patients;

allergic contact dermatitis
Atopic dermatitis, uremic pruritus
Combine with a barrier cream
Cannabinoids
COOLANTS AND COUNTER-IRRITANTS.
A distinct subset of sensory neurons may directly

sense changes in temperature via receptors of TRP ion
channels on cutaneous nerve endings. These include
vanilloid receptors, such as TRPV1, which respond to
warmth and capsaicin. These receptors act synergistically with other receptors involved in itch, such as
PAR-2 and SP receptor (Neurokinin 1). These receptors are targets for treatment of itch. Other receptors
from the same family include cold receptors, such as
TRPM8. Menthol has been used as a symptomatic topical treatment for pruritus for centuries and relieves
itch in some patients by activating nerve fibers that
transmit a cool sensation. Menthol may reduce itch
via TRPM8 receptors in keratinocytes and nerve
fibers.161,162 Menthol 1% cream is popular with patients
who have pruritic skin; however, higher concentrations can induce skin irritation.163 Those patients who
report that cold showers and ice relieve their itch tend
to respond extremely well to treatment with menthol.
CAPSAICIN. Topical capsaicin, the active compound

in the chili pepper, causes release of neuropeptides,
including SP, from C nerve fibers. The exact mechanism is not fully understood; however, prolonged
application of capsaicin to the skin depletes stores of
SP, desensitizes neurons, and abolishes pruritus at the
site of application. Capsaicin activates the vanilloid
receptor TRPV1, which is abundant in the epidermal
layer of the skin.17 Several reports have supported capsaicins value for localized, chronic pruritic disorders,
particularly those of neuropathic origin, including brachioradial pruritus, notalgia paresthetica, postherpetic
itch as well as pruritus associated with CKD, psoriasis
and atopic dermatitis.164,165 Unfortunately, compliance

is poor because initial application causes an intense,
transient burning sensation at application sites; however, this usually resolves after using the medication for
a few days or with application of a topical anesthetic.107
TOPICAL ANESTHETICS
Pramoxine. Pramoxine is a topical anesthetic that
reduces itch, especially when applied to facial areas, by

blocking the transmission of nerve impulses. Doubleblind studies have shown that pramoxine inhibits histamine-induced itch in humans and CKD-associated
pruritus.166,167
Indication
::
Dose
Chapter 103
Medication
Polidocanol.
Polidocanol is a nonionic surfactant

with both local anesthetic properties and moisturizing
effects. In an open-label study, a combination of 5%
urea and 3% polidocanol (Lauromacrogol) was found
to significantly reduce pruritus in patients with atopic
dermatitis, contact dermatitis, and psoriasis.168
TOPICAL ANTIHISTAMINES. Doxepin is a tricyclic antidepressant with potent H1- and H2-antihistamine properties and significant atropine-like
(anticholinergic) side effects. Doxepin 5% cream has
been shown to relieve pruritus in patients with atopic
dermatitis in a large placebo-controlled, double-blind
study.169 However, percutaneous absorption of doxepin, causing drowsiness, occurs in approximately 25%
of patients, limiting its usefulness. Allergic contact dermatitis is also a recognized adverse effect.
TOPICAL CANNABINOIDS. Uncontrolled trials
have shown that topical cannabinoids combined with
1155
18
a barrier cream have an antipruritic effect in patients

with atopic dermatitis and uremic pruritus.170
FUTURE TOPICAL THERAPIES. Although none

are currently available, topical drugs that inhibit serine
proteases may be an additional mechanism for future
antipruritic therapies. Drugs that act in a similar manner to prostaglandin (PG) D2 are currently being tested
in humans and may also have a potential therapeutic
role in itch.
SYSTEMIC ANTIPRURITIC
TREATMENTS
Section 18
::
1156
ANTIHISTAMINES. (See Chapter 229.) Pruritus due

to histamine is mediated exclusively via H1 receptors;
H2 antihistamines are ineffective in relieving pruritus. First-generation (classic) H1 antihistamines have
marked sedative and atropine-like (anticholinergic)
actions. Second generation (minimal- or low-sedation)
H1 antihistamines have lower lipophilicity and consequently are associated with less drowsiness and other
unwanted side effects. Sedative (first-generation) antihistamines are useful in severe chronic urticaria with
or without angioedema because they suppress pruritus and alleviate associated anxiety. Hydroxyzine
is especially valuable in this context along with doxepin. Second-generation H1 antihistamines are suitable
in the daytime for relief of pruritus due to urticaria;
however, the role of these nonsedating antihistamines
is limited in other pruritic disorders. A summary of
systemic antipruritic treatments is given in Table 103-4.
OPIATE ANTAGONISTS AND AGONIST
ANTAGONISTS. As previously mentioned,
-opioid receptor agonists can cause generalized pruritus.67,6971 -Opioid antagonists, such as naloxone
and naltrexone, have been used for the treatment of
pruritus associated with cholestasis, uremia, and dermatologic diseases. The efficacy of such opioid antagonists is supported by data from controlled clinical
trials.64,127,129,171173 Naltrexone was effective in the treatment of some cases of severe, intractable pruritus.174
However, such -antagonists are associated with significant side effects including hepatotoxicity, nausea
and vomiting, difficulty sleeping, and reversal of analgesia, among others. -Receptor agonists also inhibit
-receptor effects. In animal models, -opioid receptor
agonists inhibit pruritus and scratching induced by
SP or histamine.68,69 The novel agonist, nalfurafine
(TRK-820), has been shown to be effective in treatment
of severe uremic pruritus.121 Thus, agonists are a
promising treatment for severe itch.120
Butorphanol is a commercially available opioid agonist-antagonist analgesic with both -agonist activity
and -antagonist activity. Previous studies have found
that epidural butorphanol was effective in relieving pruritus associated with epidural morphine.175,176
Intranasal butorphanol is an effective treatment for
many patients with chronic, severe, and intractable
pruritus due to systemic diseases and inflammatory
skin diseases.177
ANTIDEPRESSANTS. The oral antidepressant

and selective noropinephrine re-uptake inhibitor,
mirtazapine, has been shown to relieve itch in some
patients.178,179 Unlike other SSRIs, mirtazapine is a
central presynaptic 2 noradrenergic inhibitor and
specific serotonergic antidepressant. Mirtazapine is a
safe medication without serious side effects and may
be an effective alternative for the treatment of nocturnal pruritus.179 It has been shown to be effective when
used to treat systemic pruritus as well as pruritus of
inflammatory skin diseases and in particular nocturnal
itch using a low dose of 15 mg at night. A recent openlabeled study showed paroxetine and fluvoxamine,
both selective serotonin reuptake inhibitors, to be efficient in the treatment of chronic itch.180
THALIDOMIDE. (See Chapter 235.) Thalidomide
has shown antipruritic efficacy in treatment of inflammatory skin diseases, such as prurigo nodularis, actinic
prurigo, eczema, and idiopathic elderly pruritus. It is
especially useful in pruritus associated with multiple
myeloma and lymphoproliferative disease. Thalidomide has been used for years as an immunomodulatory
agent whose spectrum of activity is not fully characterized. The antipruritic activity could be related to several
mechanisms, including inhibition of TNF- synthesis.
Although TNF- does not have any direct pruritogenic
effect, it is elevated in many pruritic dermatoses. Thalidomide may also act directly as a peripheral and central
nerve depressant. The major adverse effects of thalidomide are peripheral neuropathy and teratogenicity.
NEUROLEPTICS. Gabapentin is a structural analog
of the neurotransmitter -aminobutyric acid and has
been used as an anticonvulsant; however, its mechanism of action in the CNS is poorly understood. Studies
have shown that gabapentin is effective for treatment
of brachioradial pruritus, multiple sclerosis-induced
itch, other types of neuropathic itch as well as uremic
itch. Gabapentin appears to alter sensation and pruritus associated with itch related to nerve damage in
dermatologic and systemic disease. Gabapentin may
inhibit central itch pathways, as it does in pain. Pregabalin is a neuropathic pain medication that has a similar structure and function to gabapentin with fewer
side effects and can reduce neuropathic itch or alter
the sensation of itch in systemic diseases.113,181
SUBSTANCE P ANTAGONIST. Aprepitant, an
oral drug that antagonizes the effect of SP on neurokinin type 1 receptor has recently been shown to be
effective against pruritus associated with the Szary
syndrome in a case series of 3 patients.182
NONPHARMACOLOGIC
TREATMENTS FOR ITCH
PHOTOTHERAPY. (See Chapter 237.) Phototherapy
has been used for more than three decades to treat
different types of itch. Reports have suggested that
narrow band UVB may be as effective for treatment
18
TABLE 103-4
Nonclassical Systemic Antipruritic Treatments

Indication
Notes
Doxepin
25100 mg PO qd
Chronic urticaria
Drowsiness, dry mouth; abrupt withdrawal may cause

confusion; should not be coadministered with other
antidepressants
Hydroxyzine
25100 mg PO qd
Nocturnal pruritus,
atopic dermatitis, chronic
urticaria
Drowsiness, dry mouth; abrupt withdrawal may cause

confusion
Naloxone
0.002 g/kg/min
increased gradually up to
0.2 g/kg/min over 24 h
Cholestatic pruritus,
uremic pruritus
Hepatotoxicity, nausea and vomiting, difficulty sleeping,

reversal of analgesia
Naltrexone
12.550 mg PO qd
Cholestatic pruritus,
uremic pruritus
Hepatotoxicity, nausea and vomiting, difficulty sleeping,

reversal of analgesia; contraindicated in patients with
liver dysfunction
Nalfurafine
2.55 g PO qd
Useful in CKD-associated
pruritus
May cause insomnia, approved in Japan only
Butorphanol
(intranasal)
14 mg inhaled qhs
Intractable pruritus due

to systemic and some
inflammatory skin disease
Drowsiness, dizziness, nausea and vomiting
Mirtazapine
7.515 mg PO qhs
Systemic and
inflammatory skin disease
Drowsiness, increased weight and appetite, dry mouth
Paroxetine
1040 mg PO qd
Generalized pruritus
Insomnia, sexual dysfunction
Thalidomide
100 mg PO qd
Pruritus in multiple
myeloma and
lymphoproliferative
disease
Teratogenic, peripheral neuropathy, drowsiness,

expensive
Gabapentin
3003,600 mg PO qd
Neuropathic itch
Drowsiness, constipation
Pregabalin
75300 mg PO qd
Neuropathic itch
Drowsiness and weight gain
Aprepitant
80 mg PO qd
Purigo nodularis,
recalcitrant atopic
dermatitis, pruritus
associated with
malignancy and
epidermal growth factor
inhibitors
Alopecia, nausea
CUTANEOUS FIELD STIMULATION AND

ACUPUNCTURE. Cutaneous field stimulation
(CFS) is a new technique that electrically stimulates

afferent fibers, including nociceptive C fibers. CFS has
similarities to transcutaneous electrical nerve stimulation, which activates large myelinated nerve fibers;
however, CFS more specifically targets unmyelinated
C nerve fibers. CFS may act through endogenous
central inhibitory mechanisms that are normally activated by scratching.183 In patients with localized itching, CFS significantly reduces patient-reported itch
of pruritus as broadband UVB or psoralen and UVA

light. Phototherapy decreases the population density
of mast cells by inducing apoptosis, causes peripheral
nerve dysfunction, and reduces divalent cations in the
skin. Phototherapy is an effective treatment for itch
associated with atopic dermatitis, psoriasis, and CKD.
Remissions may last for as long as 18 months.
::
Dose
Chapter 103
Medication
and causes degeneration of epidermal nerve fibers.184

However, CFS is only practical for localized disease.
In addition, acupuncture at the correct points showed
a significant reduction in type I hypersensitivity itch
in both healthy volunteers and patients with atopic
eczema.185,186
BEHAVIORAL THERAPY TARGETING THE

CENTRAL NERVOUS SYSTEM. Stress and other
psychogenic factors are important in chronic itch.187,188

Atopic dermatitis patients have been shown to demonstrate an abnormal sympathetic and parasympathetic response to itch and mental stres.189 Studies have
shown that behavioral modification therapy reduces
both itching and scratching.190 Other possible behavioral interventions include stress reduction and biofeedback.188 Stress reduction using holistic approaches
such as meditation, yoga and mindfulness may have
adjunctive role in reducing itch intensity.
1157
18
KEY REFERENCES
2. Davidson S, Giesler GJ: The multiple pathways for
itch and their interaction with pain. Trends Neurosci
33(12):550-558, 2010
4. Patel T, Yosipovitch G: Therapy of pruritus. Expert Opin
Pharmacother 11(10):1673-1682, 2010
5. Weisshaar E, Dalgard F: Epidemiology of itch: Adding to the burden of skin morbidity. Acta Derm Venereol
89(4):339-350, 2009
14. Stander S et al: Clinical classification of itch: A position

paper of the International Forum for the Study of Itch.
Acta Derm Venereol 87(4):291-294, 2007
70. Yosipovitch G et al: Itch. Lancet 361(9358):690-694, 2003
113. Yosipovitch G, Samuel LS: Neuropathic and psychogenic
itch. Dermatol Ther 21(1):32-41, 2008
124. Wang H, Yosipovitch G: New insights into the pathophysiology and treatment of chronic itch in patients with
end-stage renal disease, chronic liver disease, and lymphoma. Int J Dermatol 49:1-11, 2010
Section 18
::
Chapter 104 :: Psychocutaneous Skin Disease

:: Evan Rieder & Francisco A. Tausk
PSYCHOCUTANEOUS DISEASES
AT A GLANCE
Primarily Psychiatric Disorders
Delusional: Delusions of Parasitosis,
Body Dysmorphic Disorder.
Factitial: Dermatitis Artefacta, Dermatitis
Para-Artefacta (Trichotillomania, Skin
Picking), Malingering.
Somatoform: Body Dysmorphic Disorder,
Atypical Pain/burning, Hypochondriasis,
Somatization.
Obsessive Compulsive Disorders.
Affecting approximately 5% of dermatology
patients.
Variable degree of insight, mostly poor.
Mostly self-induced lesions.
Poor prognosis if untreated.
Quality of life severely deteriorated.
1158
Scientific advances are shedding new light on the

understanding and treatment of long-recognized conditions located at the interface of dermatology and
psychiatry. Both arising from ectoderm, the skin and
the nervous system are connected by more than just
their common origins. The skin is one of the major
avenues by which humans perceive the world, and,
in turn, are perceived by it. When these perceptions

go awry, great distress may result. When the skin is
markedly affected by a primary dermatologic condition, psychological sequelae in the form of comorbidity often follow, greatly impacting patient quality of
life.
The central nervous system (CNS) can influence
the health of other organ systems, including the
skin. Psychophysiologic mechanisms for this interaction range from the stress responses mediated by
neuroadrenal connections and associated changes
in immunologic function, to the systemic and local
action of various neuropeptides and neurohormones.1,2
ROLE OF THE DERMATOLOGIST

Between 20% and 40% of patients seeking treatment
for skin complaints have some type of psychiatric
or psychological problem causing or complicating
the presenting symptoms.3,4 A large number of these
patients lack insight into the possible psychogenic
origin of their symptoms and are often reluctant to
accept any kind of psychiatric referral. Therefore, in
the absence of a psychiatry liaison clinic in the dermatologic setting,4 the dermatologist must be familiar
with the most common of these diagnoses, their clinical manifestations (both psychological and dermatologic), and the basic principles of treatment. When
approaching these issues, it is important to explore
psychiatric, and particularly psychotic, symptoms as
well as compliance with medications. Collateral informants such as family members can be quite helpful
if the patient grants permission. Lastly, the effects of
patient symptoms on familial and social life can be
of much assistance in understanding the issues to be
addressed.
CLASSIFICATION OF
PSYCHOCUTANEOUS DISEASES
Following the original description of C. Koblenzer,5
psychocutaneous diseases can be classified on the
basis of their primary etiology as:

Frequently, these diseases are manifested by selfinflicted dermatosis. The most significant difference
between them is the degree of insight or conscious
perception of autoinjury. The classification of these
disorders as delusional, factitial, somatoform, or compulsive is adapted for the clinical dermatological practice,
following the one described in Clinical Management
in Psychodermatology6 with the understanding that in
many instances, disorders may span through various
categories (Box 104-1), and may differ conceptually
from the DSM-IV (Diagnostic and Statistical Manual of
Mental Disorders, published by the American Psychiatric Association), which is directed towards the psychiatric practitioners7 and clinical studies.
DELUSIONAL DISORDERS
DELUSION OF PARASITOSIS
Subjects with delusional disorders present with somatic
complaints, no insight into the involved psychological
issues, and encapsulated monosymptomatic delusions.
Delusions are fixed, false beliefs that are not endorsed
Factitious
Dermatitis para-artefacta syndrome

Dermatitis artefacta syndrome
Malingering
Somatoform
BDD
Cutaneous dysesthesias
Somatization syndrome
Compulsive
Compulsive washing
BDD
BDD is classified by the DSM-IV as a somatoform disorder,

although some patients may be classified as having obsessivecompulsive disorders (OCD) and others as delusional.
by the larger cultural, ethnic, or religious community.

Patients unshakeable beliefs frequently coexist with a
fairly intact character and personality structure. The
most frequent form of this condition seen by dermatologists is delusion of parasitosis8 in which patients manifest the belief of being infested with parasites. Because
this is frequently the only overt manifestation of the
subjects psychosis, these patients most often present to dermatologists and entomologists rather than
to psychiatrists. Although we will describe below the
more common form of delusions of parasitosis, there are
other more rare forms of delusions such as hypochondriacal, where patients believes that they are afflicted
by a particular disease (such as AIDS, cancer, etc.), or
delusions of body odor. In many instances, patients
with body dysmorphic disorder (BDD) may have the
unshakeable delusional conviction that they have a
severe physical disfigurement.
PRIMARY PSYCHOGENIC
DISORDERS
Delusion of parasitosis
Body odor delusion
Hypochondriacal syndrome
Body dysmorphic disorders
(BDDa)somatic form
::
The classification can guide in implementing an

effective treatment approach including dermatologic,
psychiatric, and contextual aspects of the disease
aimed to interrupt the circular reinforcement of pathology. In this chapter, we focus on the description of the
most frequent primary psychogenic disorders that present
to the dermatologist, and require acknowledgement
and treatment.
Delusional
Chapter 104
Primary psychogenic disorders, which can present

with a variety of symptoms and behaviors, usually characterized by self-injury, that can lead to
perceived or actual dermatologic conditions, or
Primary dermatologic disorders that can be either
triggered or amplified by contextual causes (e.g.,
life stresses or interpersonal relationships) that may
lead to psychiatric comorbidities such as, anxiety, depression, and distress through their impact
on physical appearance and well being. In some
instances, the psychiatric comorbidities are not
merely the result of the detrimental aspects of skin,
but are associated to the pathophysiology of the
dermatological disease itself. An example of the latter is the association of psoriasis with depression, in
which both conditions share common inflammatory
pathways.
Box 104-1 Classification of the

Primary Psychocutaneous Diseases6
18
EPIDEMIOLOGY. This disease predominates in

middle aged to elderly females with premorbid social
isolation. In approximately 12% of patients, the delusion of infestation is shared or at least endorsed by a
family member (folie a deux).9,10
CLINICAL FINDINGS. Patients with delusional
parasitosis frequently present to the clinician in an
anxious, ruminative, overwhelmed state, with a history of visits to multiple physicians without satisfaction. In addition to proffering a long and detailed
history that includes visual or tactile hallucinations
of the organisms, the patient also frequently provides
evidence of the parasitic infection in the form of
clothing lint, skin crusts, or other debris, the so-called
matchbox sign11 (these items are collected in a
matchbox to be presented to the physicians), which is
1159
18
Section 18
Figure 104-1 Delusions of parasitosis. A. Excoriations secondary to the attempt to provide an exit route for the parasites.
B. After 2 months of treatment with aripiprazole.
::
delusionally misinterpreted as entire organisms, body

parts, larvae, or ova. Skin manifestations can be quite
variable, if present. Lesions ranging from mild excoriations (Fig. 104-1A) to large ulcers may reflect patients
unsuccessful attempts at treating the perceived infestation.12 Because this is a monosymptomatic delusional
disorder, some patients have a well-organized train of
thought and normal outward appearance and behavior, resulting in the conviction by those surrounding
them that the subject has a true infestation. The delusion becomes apparent to the physician when the subject is approached.
DIFFERENTIAL DIAGNOSIS. Actual infestation and underlying skin or systemic disorders must
be ruled out (see Box 104-2). Subsequently, the differential diagnosis of psychosis must be considered,
distinguishing between the primary psychiatric conditions that manifest with delusions of infestation. True
monosymptomatic hypochondriasis represents a form
of delusional disorder characterized by a discrete,
circumscribed delusional belief with possible associated hallucinations without clear syndromic changes
in affect or personality.7 On the contrary, patients with
uni- or bipolar depressive psychosis will describe
predominantly classic changes in mood, motivations,
sleep, and appetite. Schizophrenic patients may have
a history of previous psychotic episodes and often
show deterioration in global functioning, impaired
social relatedness, thought disorder, paranoid traits,
and more bizarre and extensive delusions and hallucinations. In arriving at the diagnosis, it is critical that
the clinician differentiate true delusions of parasitosis
from formication, which involves the cutaneous sen-
sation of crawling, biting and stinging, but lacks the

fixed unshakeable conception that the skin sensations
are induced by parasites.
PROGNOSIS
AND
CLINICAL
COURSE.
Although often regarded as chronic, unremitting,

and difficult to treat, these patients have an improved
recovery rate following appropriate pharmacologic
therapy.
TREATMENT. The critical tenet of treatment is to

keep the patient engaged. Empathetic listening, statements of concern, and examinations of the material that patients brings in help to establish rapport.
Because these patients will frequently reject psychiatric referrals,13 various authors have suggested means
of increasing trust, thus paving the road towards
psychiatric evaluation.13,14 It is critical that the dermatologist avoids confronting the patient directly, and
exhibits interest in the chief complaint patiently. After
a few visits, the physician may carefully introduce the
notion that the parasites may not be present, or that
the patient is so distressed by this condition, that the
prescription of psychotropic medication could be warranted. Targeted therapy is undertaken with antipsychotic medications (Fig. 104-1B).15 Pimozide has been
used historically as the drug of choice,16,17 although it is
now being replaced by atypical antipsychotics, which
are associated with a more favorable side effect profile
(eBox 104-2.1 in online edition).14,18 The clinician needs
to be aware of the need for monitoring for metabolic
syndrome characterized by abdominal obesity, insulin
resistance and impaired glucose tolerance, disturbance
in lipid metabolism, hypertension, and weight gain.
Box 104-2 Differential Diagnosis of Delusions of Parasitosis
1160
DERMATOLOGIC
SYSTEMIC
PSYCHIATRIC
Chronic folliculitis
Dementia
Cocaine use
Insect bite reactions
Malignancy (brain)
Amphetamine use
Cerebrovascular disease
Psychotic-spectrum illness
Dermatitis para-artefacta
Vitamin B12 deficiency
Affective disorders
18
In many instances, the psychotropic medication needs

to be introduced by the dermatologist, and only when
the patient begins to respond favorably is it possible to
obtain a referral to a psychiatrist.
FACTITIOUS DISORDERS
This group of syndromes is characterized by selfinflicted dermatological disease; they are mostly
differentiated based on the degree of insight or consciousness of their behavior.
CLINICAL FINDINGS. Although it has long been

observed that patients with dermatitis artefacta may
present with lesions in virtually all areas of the body
that can mimic most dermatoses, some common elements may hint at this diagnosis. Lesions are often in
areas readily accessible to the patient, and may have
geometric patterns or angulated borders surrounded
by completely healthy skin. Morphology is often
bizarre and does not conform to typical presentations
of known dermatoses (Figs. 104-2 and 104-3). Patients
are often unable to provide a clear history of the initial
appearance or evolution of the process, typically deny
any role in the production of the lesions, and may selfinduce the lesions in a dissociated state.22 Characteristically, the histopathology is unrevealing.
DIFFERENTIAL DIAGNOSIS. As in all cases of
factitious disease, the clinician must rule out possible
disease entities that are consistent with the history and
clinical findings. Unusual presentations of common illnesses and rare conditions must be entertained. However, exhaustive searches for primary skin pathology
without supporting clinical evidence may compound
the problem and actually perpetuate the patients fac-
titious behavior. Occlusive dressings (e.g., an Unna

boot) or other means of preventing manipulation by
the patient lead to healing of the lesions and are often
helpful strategies in clarifying the diagnosis.
TREATMENT. A supportive, nonconfrontational,

empathic approach to the patient is indicated initially. Immediate confrontation regarding the suspicion that the patients lesions are self-induced can be
counterproductive in that the patient often flees from
treatment. Frequent visits and symptomatic topical
treatments are initially useful.23 However, the clinician
must be careful not to collude in the patients abnormal illness behavior. Ultimately, the recognition of the
patients role in the production of the lesions must be
broached. The goal is to establish a trusting relationship such that the patient will accept a psychiatric
referral. Antidepressants (eBox 104-2.2 in online edition) and low-dose atypical antipsychotics (eBox 1042.1 in online edition) have been reported to be useful
adjunctive therapies.24,25 In the case of inflicted lesions
in a child protective services or equivalent agencies
must be alerted immediately to safeguard the welfare
of the child.
Figure 104-3 Dermatitis artefacta. Part of the nasal cartilage has been manually destroyed.
EPIDEMIOLOGY. Predominating in females, the

age of onset varies significantly from adolescence
through adulthood.21 Comorbid depressive and personality disorders may also be seen coexisting with
this rare syndrome.6
Figure 104-2 Dermatitis artefacta. Linear, sharply bordered ulcer.
::
Dermatitis artefacta is a form of factitious disorder

in which patients intentionally feign symptoms and
produce signs of disease in an attempt to assume the
patient role.6 Unlike patients with malingering who
engage in similar behavior for external or secondary
gain (such as monetary reward or relief from occupational or other social responsibilities), the factitious
patient seeks the primary gain of the emotional and
psychological benefits that accrue to those who are
ill. Patients with borderline personality disorder
also frequently exhibit self-mutilatory behavior19 as do
patients who consume cocaine or methamphetamine.
However, their reasons for self-mutilation are variable,
and are not usually consistent with efforts for primary
or secondary gain. Occasionally, a psychologically disturbed adult will induce skin lesions in their children.20
Chapter 104
DERMATITIS ARTEFACTA
1161
18
COURSE AND PROGNOSIS.
These are fundamentally determined by the underlying psychopathology. In those patients with severely disturbed
personalities, the recurrent self-defeating and destructive behaviors are likely to continue.
DERMATITIS PARA-ARTEFACTA
SYNDROME
Section 18
::
These are a group of factitious diseases, where problems of impulse control play a significant role; the
patients are conscious or semiconscious of manipulating their skin, but are unable to stop this behavior.
Trichotillomania is an impulse control disorder,7 characterized by repetitive pulling of hair, resulting in alopecia. Strict criteria also include a build up of tension
before hair pulling or when resisting an urge to do so,
pleasure or relief after pulling out the hair, and significant functional impairment and distress in the patient.
EPIDEMIOLOGY. Prevalence rates are estimated to

be between 0.5% and 3.5% with a mean age of onset
between 10 and 13 years. Despite its current classification, there are marked similarities with obsessive-compulsive disorder (OCD), which may have important
treatment implications.2628 Comorbid psychiatric disorders are depression, anxiety, and OCD.
CLINICAL FINDINGS. Trichotillomania presents
clinically with nonscarring alopecia, most commonly
with hairs broken at different lengths, normal overall hair density (Fig. 104-4), and a negative pull test29;
occasionally, repeated trauma may result in some scarring. Body areas involved typically include the scalp,
eyelashes, eyebrows, and pubic hair, with a majority of patients pulling hair from more than one site.
Rarely, this is followed by the ingestion of the hair,
leading to the potentially dangerous complication of
trichobezoar.30 Awareness of the behavior is partial to
complete in a vast majority of patients, and frequently
occurs while patients are engaged in isolated, sedentary activities. Attempts to resist the behavior and to
disguise its cosmetic sequelae are common. Typical
histopathologic findings that may be helpful in confirming the diagnosis in questionable cases include
catagen and telogen hairs, pigment casts, and traumatized hair bulbs without significant inflammation or
scarring.31 Perifollicular hemorrhage near the hair bulb
is diagnostic.
DIFFERENTIAL DIAGNOSIS. When patients do

not have awareness of pulling their own hair and present with alopecia, other etiologies of hair loss must be
ruled out.
TREATMENT. Because of trichotillomanias similarities to OCD, the use of selective serotonin reuptake
inhibitors (SSRIs) and clomipramine, as well as combinations with atypical antipsychotics have received
much attention (eBoxes 104-2.1 and 104-2.2 in online
edition).28,3237 However, psychopharmacologic data
have been conflicting, and the best-designed studies
have not demonstrated superiority of psychotropics
over nonpharmacologic interventions. Nonpharmacologic treatment of trichotillomania relies heavily upon
behavioral therapies, especially habit reversal, which
entails engaging the patient in a behavior incompatible
with hair pulling when the urge appears. The addition
of cognitive-behavioral or insight-oriented psychotherapy have good results; hypnotherapy may also be
very useful, particularly in children.38
PROGNOSIS AND CLINICAL COURSE. Trichotillomania is a chronic disorder and data on long-term
success of pharmacologic and psychotherapeutic interventions are inconclusive. Though children typically
have a benign course, adult-onset trichotillomania is
often associated with other psychiatric conditions and
sustained improvement has yet to be shown convincingly.
SKIN PICKING (NEUROTIC
EXCORIATIONS)
This is also a condition in which patients induce skin
lesions through repetitive, compulsive excoriation of
their skin. However, unlike patients with dermatitis
artefacta syndrome, these patients admit their role in
the production of the lesions.
1162
Figure 104-4 Trichotillomania. Hairs broken off at different lengths.
EPIDEMIOLOGY. This is the most common psycho-cutaneous disorder, reported in up to 2% of dermatology clinic patients39 with a predominance in
middle-aged females, and are frequently associated
with compulsivityimpulsivity spectrum and mood
disorders.40,41
18
Chapter 104
::
CLINICAL FINDINGS. Patients with skin picking

often describe significant itch leading to persistent
scratching, which is frequently antedated by considerable psychological stressors. The development of this
disorder has also been noted to be associated with the
marked limitation in activity seen in illness or senescence.42 The repeated excoriation can lead to the development of an itchscratch cycle, perpetuating the
behavior. Patients present with multiple excoriations
in various stages of evolution and healing, with postinflammatory hyperpigmentation and frequent scarring
(Fig. 104-5). The distribution of the lesions reflects their
self-inflicted nature with most being on the extensor
surfaces of the extremities, upper back, and face, sparing unreachable areas such as the central mid-upper
back. Frequently, patients develop excoriations overlying preexisting dermatosis, such as folliculitis and
acne; excessive manipulation of the latter leads to the
condition known as acne excorie. These patients
often spend many hours each day in front of the mirror
injuring the skin with instruments such as tweezers.
The trauma often results in temporary relief of anxiety. Prurigo nodularis can be considered an extreme
variant of this entity, characterized by severely pruritic
nodules varying from a few millimeters to 12 cm in
diameter, preferentially located on the extremities (Fig.
104-6) (see also Chapter 15).
DIFFERENTIAL DIAGNOSIS. The clinician must
evaluate the patient for causes of pruritus (see Chapter
103) and rule out possible internal diseases including
neoplasms, in particular, lymphomas. The differential
for the underlying psychiatric disorder,43 if present,
must include depressive and anxiety disorders and,
more rarely, excoriations secondary to delusions of
parasitosis.
Figure 104-6 Prurigo nodularis.
TREATMENT. Work-up for pruritus should be instituted in those patients that present significant itch.
In the absence of organic cause, these patients may
improve with phototherapy. Additional treatment
should be directed at underlying psychopathology
when identifiable. Antidepressants, helpful in both
depressive and anxiety disorders including OCD,44 are
very useful. Subsequent addition of low-dose atypical
antipsychotics has been found effective. Supportive
psychotherapeutic approaches and behavioral interventions as those used to treat self-injurious behaviors
in Tourettes syndrome may be helpful.45
Figure 104-5 Dermatitis para-artefacta: skin picking on

the breast of a 16-year-old girl.
COURSE AND PROGNOSIS. This can be a chronic

condition whose prognosis depends on the underlying
psychiatric illness.46 With appropriate therapy, patients
with affective and anxiety disorders may have excellent outcomes, with a symptom-free, normally functioning state.
MALINGERING
Malingerers intentionally induce skin lesions in order
to obtain secondary gains, often workmans compensation or disability. Since there is no patient motivation
for therapy, treatment is not possible.6,47
SOMATOFORM DISORDERS
This is a group of heterogeneous disorders where the
patients complain of a variety of symptoms that cannot
1163
18
be objectively verified by the physician, but they share

similar psychiatric underlying problematics.
BODY DYSMORPHIC DISORDER
Section 18
::
BDD is a chronic condition characterized by an excessive preoccupation or concern with a presumed defect
in physical appearance despite normal or minimally
objective anomalous findings.48 Also known as dysmorphophobia,49,50 this is a psychological experience that
also results in functional impairment, poor quality of
life, and low treatment response.
The nosological classification of BDD revolves
around the intensity with which patients hold on to
their abnormal beliefs. Those with unshakeable convictions are currently diagnosed as having a delusional
disorder.7 However, there appears to be a continuum
of intensity and insight from preoccupations, through
overvalued ideas to clear delusions.51 Those patients
that retain a certain degree of insight evidence characteristics more similar to the obsessivecompulsive
spectrum of disorders,51,52 a finding that has significant
potential treatment implications. BDD patients have
obsessive thoughts about their flaws and engage
in compulsive behaviors related to how they perceive
their appearance, similar to behavior seen in obsessive
compulsive disorder.53
EPIDEMIOLOGY.
The prevalence of BDD, is estimated to be from 0.7% to 2.4% in the general population to 12% in dermatology clinic patients, often
in association with mood disorders such as major
depressive disorder (MDD) (37%), social phobia (33%)
and OCD (26%).54,55 Improvement of MDD and BDD
seems to be closely related, with the improvement of
each disorder significantly predicting the remission of
the other. Improvement of OCD significantly predicts
remission of BDD, but not vice versa. Approximately
80% of patients report a history of suicidal ideation
and 24%28% have attempted suicide.5658
CLINICAL FINDINGS. Patients present with

intensely articulated distress about various body parts.
Most patients also develop ideas of reference in which
they think or are convinced that others notice and comment upon the presumed defect. Time-consuming,
compulsive behaviors often accompany the worrisome
thoughts, including repeated examination in mirrors,
covering up defects, and asking others for reassurance.
Consultations with other physicians and past operations on the perceived defect are common. Marked
restriction in social and occupational functioning is
seen in up to 98% of individuals, and 30% of patients
have been described as housebound.59 Thoughts and
attempts of suicide are frequent. Thus, current or past
suicidal ideation should be routinely assessed by the
practitioner. Particular monitoring may be needed with
younger patients as antidepressant action may increase
impulsivity and likelihood of suicidal attempts.58
1164
TREATMENT. Many patients with BDD will seek

dermatologic or surgical treatment over the course of
their illness. Evidence suggests that if patients receive

such treatment they do not improve, are usually disappointed with the results, and may even experience an
exacerbation of their symptoms. It is strongly recommended that cosmetic lines of treatment be avoided.
BDD is a severe and complex disorder that often
requires multimodal treatment using cognitive behavioral therapy (including exposure response prevention) and medication.60,61
Pharmacologic trials show a good response to SSRIs
(see eBox 104-2.2 in online edition), improving insight
while decreasing distress, compulsions, and frequency
and intensity of obsessions about perceived defects.
Interestingly, SSRIs appear equally effective for delusional as well as nondelusional patients. Efficacy usually requires 1216 weeks of relatively high dosages.
Issues of compliance require close monitoring, since
they are a frequent cause of treatment failure. A significant proportion of patients who fail one adequate
SSRI trial respond favorably to a second SSRI, suggesting that serial trials of similarly acting agents should
be administered in initially refractory cases. Lack of
clear success has been noted with other agents such as
antipsychotics, tricyclic antidepressants (TSA) (other
than clomipramine), benzodiazepines, and anticonvulsants.6267 Similar to patients with OCD, cognitivebehavioral therapy is strongly recommended.
PROGNOSIS AND CLINICAL COURSE. BDD is

a chronic illness without clear evidence for spontaneous remission without treatment. Pharmacotherapy
with appropriate medications may lead to improvement in a considerable number of patients. However,
effective doses of SSRIs are usually beyond those
approved by the FDA; the data also indicate high recurrence rates with discontinuation of treatment.64 Thus
patients may require long-term treatment, including
adjunctive insight oriented psychotherapy.57,60
SOMATIZATION DISORDER
These patients present to the physician with multiple
significant physical complaints and the belief that their
symptoms are due mostly to exposure to environmental causes. This disorder includes Gulf War syndrome,
multiple chemical sensitivity syndrome, amalgam
related syndrome, chemical or detergent allergies,
sick building syndrome, food intolerances, and candida hypersensitivity syndrome, among many others.
There is no medical proof of a direct causal relationship between exposure and the extent of complaints.
The widespread dissemination of information through
the Internet as well as the insistence of self-proclaimed
experts reinforces the patients misinterpreted beliefs.
HYPOCHONDRIACAL DISORDERS
Typically these patients express the conviction or
fear of suffering from a serious illness (such as AIDS,
venereal diseases or cancer) despite the lack of medical evidence.
CUTANEOUS DYSESTHESIAS
(ATYPICAL CHRONIC PAIN/BURN
SYNDROME)
OBSESSIVE-COMPULSIVE
DISORDERS (OCD)
These include dermatological findings that are the
result of disorders such as compulsive washing (xerosis, eczema) or rubbing (lichen simplex chronicus).
OCD is also related to BDD as well as some factitious
Dermatologists who elect to treat psychocutaneous

disorders routinely use a number of different classes
of psychotropic medications. Knowledge of the drugs
and their actions, indications, side effects, therapeutic doses, and potential drug interactions is critical.71
These drugs are classified according to their clinical
utility (e.g., antidepressants or antipsychotics) and
further identified by their chemical structure and/
or mechanism of action. All of the drugs discussed in
this section exert their clinical effects through modulation of neurotransmitter function in the CNS by altering presynaptic reuptake of the transmitters, blocking
their pre- and/or postsynaptic receptor binding, stimulating those receptors, or some combination thereof.
The most appropriately used in each of the following
three major classes are discussed: antipsychotics, antidepressants, and anxiolytics.
For a detailed discussion of these drugs, their side
effects, and precautions, see online edition of the book.
NONPHARMACOLOGIC
TREATMENTS FOR
PSYCHOCUTANEOUS DISORDERS
Psychogenic pruritus and itch in general are discussed

in Chapter 103.
PSYCHOTROPIC MEDICATIONS
USED IN DERMATOLOGY
::
PSYCHOGENIC PRURITUS
18
Chapter 104
Occasionally, patients will present to dermatologists

with complaints of burning, pain, or dysesthesias in
the skin or mucus membranes for which no identifiable pathology can be found. This can be a frustrating
situation for patient and clinician alike. A psychiatric approach to these patients may offer a means of
understanding the complex factors underlying this
syndrome, such as comorbid affective disorders, personality vulnerabilities, behavioral problems, and life
circumstances that may perpetuate the pain cycle and
maintain the patient in an illness role.
There is a significantly increased rate of depression in
patients with chronic pain syndromes and a clear relationship between lifetime depression and the development of medically unexplained symptoms, including
pain.68 Depression not only worsens the experience
of pain by psychologically magnifying negative perceptions, but may also interfere with the function of
descending monoaminergic neurons that dampen
nociceptive transmission.69,70 Other complicating factors include anxiety, which is also commonly seen in
patients with chronic pain.68 Personality disorders
influence all aspects of patients lives and may make
the burden of a chronic condition more challenging. At
times, family or social environments may unwittingly
play a role in undermining the chronic pain patients
rehabilitation by rewarding illness behaviors with
well-meaning, yet oversolicitous, attention. Pain states
can further be complicated if the patient develops an
inappropriate pattern of using prescribed analgesics.
For all of these reasons, the best course of action for
patients presenting with poorly explained chronic
pain is to refer them to a multidisciplinary pain center for thorough evaluation and treatment. The presence of burn syndrome may occasionally respond to
the administration of gabapentin (see eBox 104-2.2
in online edition). Milnacipran, an SNRI approved
for fibromyalgia (eBox 104-2.2 in online edition), also
may be effective for chronic pain/burn/dysesthesia
syndrome. Extreme forms of chronic dysesthesia can
resolve with the administration of antipsychotic medication, suggesting that it represents a form of delusion.
conditions such as trichotillomania or skin picking (see

above).
The dermatologist should request a consultation with

a psychiatrist or a liaison clinic during the treatment
of patients with psychocutaneous disorders as soon as
it is amenable to the patient. Although dermatologists
are becoming more comfortable with the use of certain
psychotropic medications, they generally do not have
the time or the training to use effectively nonpharmacologic modalities. Therefore, it is sufficient that the
practicing dermatologist be aware that a variety of
adjunctive, stress-reducing approaches are available,
including hypnosis, biofeedback, progressive muscle
relaxation, and psychotherapy (Box 104-3). Although
no modality has been demonstrated to be superior to
another, certain types of therapies may be more effective for a given condition. Diagnosis should drive
choice of therapy.
Box 104-3 Nonpharmacological

Treatments

Cognitive-behavioral therapy
Insight-oriented psychotherapy
Hypnosis
Mindfulness-based cognitive therapy
Biofeedback
Family therapy
1165
18
KEY REFERENCES
3. Gupta MA: Psychocutaneous disease. Dermatol Clin 4:591745, 2005
5. Koblenzer C: Psychosomatic Concepts in Dermatology. Orlando, FL, Grune & Stratton, 1987
Section 18
::
Chapter 105 :: C
utaneous Manifestations
of Drug Abuse

:: Haley Naik & Richard Allen Johnson
MUCOCUTANEOUS MANIFESTATIONS
OF DRUG ABUSE AT A GLANCE
The morphology and arrangement of skin
lesions can identify persons with former and
current drug dependency.
Skin lesions associated with drug use can
be related directly to the drug itself, mode
of drug delivery, and/or adulterants or
infectious agents mixed with the drug.
Drug addiction-related bacterial infections
predominantly involve the skin and soft
tissue. Culture-guided antibiotic therapy
is essential because infection with unusual
organisms, antibiotic-resistant strains, and
polymicrobes is more common.
Behavioral effects of drug use can lead to the
transmission of sexually transmitted diseases
and blood-borne pathogens including
Treponema pallidum, hepatitis B virus,
hepatitis C virus, human immunodeficiency
virus, and human T-lymphotropic viruses 1
and 2.
INTRODUCTION
1166
6. Harth W et al: Clinical Management in Psychodermatology,

1st edition. New York, Springer, 2008
14. Sandoz A et al: A clinical paradigm of delusions of parasitosis. J Am Acad Dermatol 59(4):698-704, 2008
59. Phillips KA: Understanding Body Dysmorphic Disorder.
New York, Oxford University Press, 2009
72. Koo JYM, Lee CS: Psychocutaneous Medicine. New York,
Marcel Dekker, 2003
Drug abuse and addiction can be suspected or diagnosed on the basis of mucosal and cutaneous findings.
The administration of drugs may cause cutaneous stigmata and eruptions predominantly through local or
systemic, toxic or hypersensitivity-induced effects as a
result of the drug itself, adulterants, infectious agents,
or the mode of drug delivery.
DEFINITIONS
Illicit drug use is a maladaptive pattern involving selfadministration of prescribed or recreational drugs.
Chipping is a lay term used to describe a pattern of drug
use in which the user is not physically dependent, but
rather sustains controlled use of a drug. A certain
percentage of users will progress to drug dependence, a
physical and/or psychological need for the effects of a
chemical in order to avoid withdrawal symptoms associated with abstinence (Box 105-1). Drug dependence
often leads to drug abuse, an intense desire to recurrently
obtain increasing amounts of one or more chemical substances to the exclusion of all other activities, resulting in
Box 105-1 Criteria for Drug

Dependence
The presence of three or more of the following, occurring any time in the same 12-month period:
Tolerance
Withdrawal symptoms
Sustained intent or unsuccessful efforts to abate
drug use
Administration of drug in higher doses and longer
duration than initially intended
Significant time devoted to obtaining the drug or
recovering from its effects
Relinquishment or reduction of social, occupational
or recreational activities because of drug abuse
Continued drug use despite awareness of the presence of a persistent or recurrent physical or psychological problem caused or exacerbated by the drug
Adapted from American Psychiatric Association: Diagnostic and
Statistical Manual of Mental Disorders IV-TR, 4th edition. Washington DC, American Psychiatric Press, 2000.
Box 105-2 Criteria for Drug Abuse
The presence of one or more of the following, occurring within a 12-month period:
Adapted from American Psychiatric Association: Diagnostic and

Statistical Manual of Mental Disorders IV-TR, 4th edition. Washington DC, American Psychiatric Press, 2000.
Alcohol
Club drugs
Cocaine
Heroin
Inhalants
Lysergic acid diethylamide (LSD)
Marijuana
3,4-Methylenedioxymethamphetamine (MDMA,
Ecstasy)
Methamphetamine
Phencyclidine (PCP)
Prescription medications
Steroids (anabolic)
Tobacco
Betel is widely used in South Asia, Southeast Asia

and the South Pacific.
EPIDEMIOLOGY
In 2004, the United Nations World Drug Report estimated that between 3% and 5% of the global population used illicit drugs.3 In 2008, the National Survey on
Drug Use and Health in the United States estimated
that:

20.1 million Americans aged 12 or older (8% of

that population) were currently using illicit drugs
including marijuana/hashish, cocaine, crack,
heroin, hallucinogens, inhalants or prescriptiontype psychotherapeutics.
The drugs most commonly associated with emergency department visits in 2001 included cocaine,
marijuana, benzodiazepines and heroin, in that order
(Fig. 105-1).
PATHOGENESIS
Studies in concordant twins have shown a strong
influence of genetic inheritance on the susceptibility to
drug use.5 The potential of a drug to cause addiction
varies. The processes by which genes regulate physical
reactions to addictive drugs have not been clearly elucidated. Repeated exposure to cocaine causes a change
at the level of gene expression that leads to altered levels of the specific brain protein called cyclin-dependent
kinase-5. This protein regulates the action of dopamine,
which potentiates the euphoric effects of cocaine and
other drugs.6 Narcotics disable the neurons that normally inhibit the release of dopamine while amphetamines and cocaine increase dopamine signaling,
either by directly stimulating its release, or by blocking
its absorption. Environmental factors such as history
of sexual abuse during childhood, severe family dysfunction with drug abusing, detached or mentally ill
parents, poor social skills, and drug-using peers are
also clearly important.
The mechanisms of addiction, tolerance and dependence are complex. Addictive drugs flood the synapses of the mesolimbic system, especially the nucleus
accumbens, with excessive amounts of dopamine, augmenting the hedonic tone and producing a euphoric
state. The subsequent pleasurable reactions of the frontal cortex, amygdala, and hippocampus are exaggerated. The association of drug use and euphoria in these
brain areas is reinforced with each exposure until the
user no longer controls behavior, at which point addiction has resulted.7 Chronic users have sustained activation of the cAMP response element-binding (CREB)
protein, a trigger for the production of dynorphin and
other proteins that shut off dopamine release, preventing the individual from finding pleasure in usually
enjoyable activities and requiring subsequent fixes
with higher doses of drug to overcome the effects of
Cutaneous Manifestations of Drug Abuse
::
clinically significant physical, emotional or social distress (Box 105-2). Tolerance defines a physiologic state
in which progressive increases in the dose of a drug are
needed to achieve the effects previously experienced
at smaller doses. Some drugs chiefly induce physical
dependence, while cause predominantly psychological dependence.1
The National Institute of Drug Abuse (NIDA)
(http://www.drugabuse.gov/)2 considers the following agents to be drugs of abuse in the United States:
18
Chapter 105
Recurrent substance use resulting in a failure to

fulfill major role obligations at work school, or
home
Recurrent substance use in physically hazardous
situations
Recurrent substance-related legal problems
Continued substance use despite having persistent
or recurrent substance-related social or interpersonal problems
Marijuana was the most commonly used illicit drug

(15.2 million past month users).
The most commonly injected drugs were heroin and
cocaine.
Almost 2 million current cocaine users, comprising
0.7% of the population, were estimated.4
The actual number of individuals who use heroin
is difficult to determine because there has been a
growing tendency to sniff, snort or smoke rather
than to inject heroin intravenously or subcutaneously.
An estimated 70.9 million Americans (28.4%) aged
12 or older were current users of tobacco in any
form.
Of Americans aged 12 and older, 51.6% had consumed alcohol at least once in the 30 days prior to
being surveyed; 23.3% reported drinking heavily
(>5 drinks on >5 occasions).
1167
18
Number of emergency department visits associated with various drugs
Section 18
::
LSD
GHB
Ketamine
Antihistamines
Antibiotics/antivirals
Ecstasy (MDMA)
PCP (Angel dust)
Prozac (Fluoxetine)
Aspirin
Paxil (Paroxetine)
Barbituates
Oxycodone
Amphetamines
NSAIDs
All antidepressants
Heroin
Benzos (Xanax, etc.)
Marijuana
Cocaine
2,821
3,340
3,474
4,112
5,282
5,542
6,102
6,362
8,499
8,932
9,506
18,409
18,555
22,663
61,012
93,064
103,972
110,512
50,000
150,000
200,000
Figure 105-1 Number of emergency department visits associated with various drugs. Cocaine, marijuana and benzodiazepines were the most common drugs associated with emergency department visits in 2001. Data from the United States
Substance Abuse and Mental Health Services Administration, 2001, http://thedea.org/statistics.html.158
tolerance. Addictive drugs also inhibit or excite neuronal activity in various areas of the nervous system.
To compensate for these alterations, neuroadaptation
develops with either formation of new neuroreceptor
sites or diminished synthesis and sensitivity of neurotransmitters and neuroreceptor sites. Discontinuation of the drug reverses the neuroadaptation process
and results in an exaggerated neural response that produces withdrawal symptoms.
CLINICAL FINDINGS ASSOCIATED

WITH COMMONLY USED DRUGS
ALCOHOL
1168
100,000
193,043
Ethyl alcohol, or ethanol, is the intoxicating ingredient

found in alcoholic beverages. It is a central nervous
system depressant that impairs brain function and
motor skills and is rapidly absorbed from the stomach
and small intestine into the bloodstream. Heavy use
can increase the risk of liver disease, stroke and certain
cancers.
Direct liver toxicity of alcohol can cause hepatomegaly, jaundice, shrunken liver in the setting of cirrhosis, and hypoalbuminemia leading to Muehrcke lines
and Terry nails (see Chapter 89). Hyperestrogenemia
can lead to gynecomastia, palmar erythema, spider
angiomata, and testicular atrophy. Portal hypertension secondary to alcohol-induced liver cirrhosis can
lead to an enlarged spleen, ascites, variceal bleeding,
hemorrhoidal bleeding and caput medusae. Dupuytren contractures due to fibroblastic proliferation and
disorderly collagen deposition may be seen in 66% of
alcohol abusers. Asterixis and confusion are seen in
patients with hepatic encephalopathy. Alcohol withdrawal delirium, also known as delirium tremens,
is characterized by tachycardia, hypertension, body
temperature elevation and delirium. Ataxia, confusion and lateral gaze palsy are indications of Wernicke
encephalopathy. Wernicke encephalopathy followed
by anterograde and retrograde amnesia along with
confabulation characterize Korsakoff syndrome.
CLUB DRUGS
Club drugs include -hydroxybutyric acid (GHB, date
rape drug), flunitrazepam (Rohypnol, roofies), ketamine, MDMA, and LSD (Table 105-1). These drugs
tend to be used by teenagers and young adults in
social settings. In 2008, NIDA showed that among
12th graders, 1.3% had abused flunitrazepam, 1.2%
had abused GHB and 1.5% had abused ketamine at
least once in the year prior to their being surveyed.8
GHB is sedating and can cause coma and seizures. It is
being used increasingly by bodybuilders, who believe
that it helps to metabolize fat and build muscle. Flunitrazepam is also sedating and can incapacitate users
and cause amnesia; when combined with alcohol, this
drug can be lethal. Ketamine distorts perception and
produces feelings of detachment from the environment and self.
18
TABLE 105-1
Drugs: Street Names and Routes of Administration
Booze
Brew
Juice
Ingestion
Anabolic
steroids
Gym candy
Juice
Pumpers
Stackers
Ingestion
Injection
Betel
Bunga (Tagalog)
Cau (Vietnamese)
Jambe (Javanese)
Kunya (Burmese)
Paan (Sanskrit)
Supadi (Nepali)
Shupari (Bengali)
Alcohol
Flunitrazepam
LSD
Acid
Blotter
Dots
Ingestion
Marijuana
Ganga
Grass
Mary Jane
Pot
Reefer
Weed
420
Smoke inhalation
Ingestion
MDMA
Adam
E
Ecstasy
Love
X
XTC
Ingestion
Methamphetamine
Chalk
Crystal
Glass
Ice
Meth
Speed
Ingestion
Injection
Nasal inhalation
Smoke inhalation
Phencyclidine
Angel dust
Fuel
Ozone
PCP
Rocket
Wack
Ingestion
Nasal inhalation
Smoke inhalation
Prescription
medications:
Opioids, CNS
depressants,
stimulants
Dust, dillies
(dilaudid)
Emsel, Gods drug
(morphine)
Oxy, cotton
(oxycontin)
Rids, vitamin R
(Ritalin)
Ingestion
Club Drugs
Chewed
Bogie, cancer
stick, cigs
(cigarettes)
Chaw, snuff,
chew (smokeless
tobacco)
Chewed
Smoke inhalation
Fantasy
G
Georgia Home
Boy
Liquid ecstasy
Soap
Ingestion
Roofies
Ingestion
Club Drugs
GHB
Route of
Administration
Ketamine
Jet
Special K
Vitamin K
Cocaine
Blow
Coke
Crack
Flake
Snow
Heroin
H
Junk
Ska
Smack
Injection
Smoke inhalation
Inhalants
Poppers
Snappers
Whippets
Inhalation
Ingestion
Nasal inhalation
Injection
Transdermal
application
Tobacco
Street
Namesa
Drug
::
Route of
Administration
Chapter 105
Street
Namesa
Drug
More terms at NIDA (National Institute of Drug Abuse) http://www.drugabuse.gov and Office of National Drug Control Policy website
http://www.whitehousedrugpolicy.gov.2,159
COCAINE
Cocaine (benzoylmethylecgonine) is an alkaloid
extracted from the leaves of the coca plant Erythroxylon coca.915 It is a powerful sympathomimetic, vasoconstrictor, local anesthetic, and stimulant. Cocaine
hydrochloride is a powder that can be can be nasally

inhaled or injected intravenously or subcutaneously,
also known as skin popping (Fig. 105-2). Crack
cocaine or crack, the freebase rock crystal form
of cocaine hydrochloride, is smoked (Table 105-1).
Freebase refers to the pure basic form of an amine, as
1169
18
Section 18
::
1170
Figure 105-2 Skin popping scars. Multiple white angular

atrophic scars on the dorsal forearms and hands.
opposed to its salt form. The amine is usually a natural
alkaloid product.
Cocaine can produce intense vasoconstrictive effects
by directly stimulating the central nervous system and
increasing peripheral catecholamines. The vasospastic
action of cocaine is greatest at one hour after use and can
be associated with ischemia, infarction and hemorrhagic
injuries of most organ systems including the skin.1618 The
ischemic effects of cocaine in the skin can lead to acute
multifocal skin necrosis,19 chronic skin ulcers,20 cutaneous fibrosis,21 blackened hyperkeratotic crack hands22
and claw-like parrot beak curvature of the nails. These
changes are commonly found in association with pernio
and some atrophy of the distal portions of the digital
pulp secondary to ischemia. At skin-popping sites, there
may be central pallor surrounded by ecchymosis due to
the vasoconstrictive properties of cocaine acting locally at
the injection site with hemorrhage occurring in the surrounding tissue. Skin popping is a method of drug administration whereby a substance is injected subcutaneously
or intradermally, but not intravenously and not typically
intramuscularly. Individuals with vasomotor instability
are more susceptible to these types of reactions.23
Inadvertent or deliberate direct intraarterial injection of cocaine can cause severe tissue ischemia and
necrosis via direct vasoconstriction. Individuals experience an initial intense burning pain, followed by
cyanosis and marked edema. Compartment syndrome
may also result. In the most severe cases necrosis leads
to amputation.24,25 Skin popping also puts one at risk
for developing secondary amyloidosis.
Cocaine-induced vasospasm may cause major internal organ injury including acute myocardial ischemia, cerebrovascular accidents, renal infarction26 and
splenic infarction.18,27 Vasoconstriction of mesenteric
vessels and the direct toxic effect of cocaine on gastro-
intestinal mucosa can result in acute abdominal crises

(known as crack belly) secondary to perforations, intestinal ischemia and infarction.28,29
Various vasculitic and vasculopathic processes have
been associated with cocaine use including pseudovasculitis,30 urticarial vasculitis,31 ChurgStrauss vasculitis,32 Raynaud phenomenon,33,34 HenochSchonlein
purpura, necrotizing vasculitis35,36 and Buerger disease
(see Chapters 163, 164, and 173).37,38
The local anesthetic properties of cocaine make it
difficult for individuals to feel traumatic injury. This
leaves users prone to repetitive trauma from the irritant properties of the drug itself and implements of
drug delivery, thus exposing them to an increased risk
of infection.39 Missing a vein and injecting into the surrounding tissue creates a niche environment in which
bacteria can thrive.40 Repeated needlesticks increase
the likelihood of cutaneous infection and transmission
of blood-borne viruses.41
Mucosal manifestations of ischemia secondary to
cocaine inhalation or smoking include dental caries,42
gingival recession,43 oral blisters44 and nasal and palatal
perforation.45 Insufflating (snorting) cocaine may lead
to recurrent epistaxis, intranasal crusting, rhinitis and
chronic sinusitis.42,46 Inhalation utensils themselves can
act as vectors for viruses and may induce snorters
warts. Nasal septum perforation reduces nasal support and results in a broad, flat nose or saddle nose
deformity.4649 Nasal septum perforation typically
occurs prior to development of palatal perforation.
Cocaine burns of the upper airway are associated with
hoarseness, dysphonia, odynophagia, dysphagia and
stridor.23,26,5053 Crack cocaine smoke has a direct toxic
effect on the corneal epithelium of the eye. Repeated
exposure to the alkaloid smoke may cause an irritant
effect leading to excessive eye rubbing and subsequent
infectious complications, and chemical burns.51
Drug reactions including acute generalized exanthematous pustulosis54 and StevensJohnson syndrome 55 have also been reported.
The stimulant properties of cocaine are associated
with increased metabolism and dramatic weight loss.56
Psychiatric conditions, most commonly delusions of
parasitosis and subsequent formication are experienced approximately 20% of the time in cocaine users
(also known as coke bugs)57 (see Chapter 104). Recent
reports have emerged of febrile agranulocytosis and
often vasculitis with prominent involvement of the ear
lobes secondary to cocaine adulterated with levamisole, an anthelmintic medication used in veterinary
medicine to control parasites in livestock.58,59
HEROIN
Natural and semisynthetic derivatives of the opium
poppy are known as opiates. Biologically natural
opiates include morphine and codeine, while semisynthetic opiates such as heroin and hydromorphone
are derived from biologically active opiates. Diacetylmorphine, or heroin, crosses the bloodbrain barrier
and binds opioid receptors in the brain, resulting in
its euphoric, analgesic and anxiolytic effects. Heroin
foreign materials in the dermis after cooking of the

drug and/or flaming of needles (Fig. 105-4).63
Diluting or cutting heroin to retail street strength
is a common practice. Common diluents for white
powder heroin include quinine, lactose, lidocaine, caffeine, lemon juice, inositol, dextrose, sucrose, procaine,
starch, magnesium silicate and mannitol.64 Diluents
may cause lymphatic destruction, foreign body granulomas, cutaneous nodules, ulcerations, panniculitis
and dermal sclerosis secondary to irritation and dermal inflammatory processes (Fig. 105-5).6567 The subsequent vascularized granulation tissue in and around
chronic ulcers may be used as a site for drug injection.20
(see eFig. 105-5.1 in online edition) Black tar heroin is a
dark, gummy form of heroin that is less refined and
cheaper than the white powder variant. It is mixed
with a variety of diluents including dextrose, burnt
cornstarch, instant coffee and dirt.68 The mixture may
18
Chapter 105
is the most common parenterally injected illicit drug,

either by intravenous or subcutaneous (skin popping)
administration. Heroin may also be inhaled. With a
peak rush at 78 seconds, it is the fastest-acting and
via smoking most potent opiate, accounting for up to
90% of opiate use in the United States.
Scarring is the primary cutaneous stigma of injection
drug use. The antecubital fossa is the usual starting
point of intravenous drug use, followed sequentially
by the upper arms, hands, neck, feet, legs, groin and
digits.60 Linear cord-like scars along a vascular distribution (track-marks), are formed after repeated injections along a superficial vein, resulting in venous
thrombosis and subsequent fibrosis.61 (Fig. 105-3) Skin
popping scars are irregular round hypopigmented or
hyperpigmented, atrophic or hypertrophic scars or
keloids.62 (see Fig. 105-2) Soot tattoos or shooting tattoos result from soot deposition or the introduction of
::
Figure 105-3 Track marks formed after repeated

intravenous drug injections. (A) Inflammatory
tracks of the dorsal hand, (B) inflammatory tracks
with associated ulcers, nodules and abscesses on
the hands and forearms, and (C) fibrotic tracks on
the dorsal forearms.
1171
18
Section 18
chondritis has been described in individuals injecting

brown heroin diluted with lemon juice.78
Inhaling smoke and then exhaling it into another individuals mouth (known as shotgunning) is associated
with efficient transmission of respiratory pathogens. 79
Opiates induce histamine release that results in subsequent pruritus that starts almost immediately after
heroin injection and can last 10 minutes to 24 hours.80
Urticaria, severe angioedema and bronchospasm have
also been reported with heroin use.80
Rare morbilliform eruptions, fixed drug eruptions
and a case of toxic epidermal necrolysis have also been
reported.62,64,81 Adulterants are thought to be responsible for most of these reactions.
Secondary systemic amyloidosis is an important
cause of renal disease in heroin users. Its pathogenesis
is thought to be associated with chronic antigenic stimulation and prolonged inflammation secondary to cutaneous infections. Patients were observed to progress to
end stage renal disease over several months to 3 years.82
::
3,4-METHYLENEDIOXYMETHAMPHETAMINE
Figure 105-4 Soot tattoo. Soot tattoos result from the
deposition of soot and other foreign materials in the
dermis. Foreign materials may be introduced via adulterated drugs and/or introduction of needles with adherent
soot after flaming for sterilization.
also contain dust and pathogens introduced during the
process of manufacturing or storage.64,66 Irritant substances can also cause sterile chemical cellulites and
abscesses.
Cutaneous infections are common in injection drug
users (Table 105-1). Skin popping and black tar heroin
use are associated with cutaneous necrosis and necrotizing ulcers.6972 An increase in Clostridial infections
including wound botulism due to Clostridium botulinum, tetanus due to Clostridium tetani, and rapidly
progressive myonecrosis with a fulminant shock syndrome due to Clostridium sordellii have been observed
with the use of black tar heroin in California.7376
Fungi have been cultured from confiscated heroin
specimens.77 Systemic candidosis characterized by
painful nodules and pustules on the scalp and hairbearing areas, chorioretinitis or uveitis, and costo-
3,4-methylenedioxymethamphetamine (MDMA, ecstasy),

along with lysergic acid diethylamide (LSD) and hallucinogenic mushrooms, is one of the most commonly
used illicit hallucinogens (Table 105-1). More than
7 million persons have tried MDMA at least once in
their lifetime. MDMA is a synthetic stimulant with
psychoactive properties that acts both by causing a
massive synaptic release of serotonin, and to a lesser
extent dopamine and norepinephrine, as well as inhibiting the reuptake transporters within the synapse. Its
short-term effects include inducing euphoria, a sense
of enhanced intimacy with others, and diminished
anxiety and depression. Adverse health effects can
include nausea, chills, sweating, teeth clenching, muscle cramping, and blurred vision. MDMA is usually
ingested, but may be injected or inhaled with effects
lasting for 36 hours. It is frequently used in combination with alcohol, cannabis, amphetamine or cocaine,
resulting in unpredictable effects.83
MDMA is associated with xerostomia and is therefore often coupled with soft drinks, which may lead
to dental caries. The neurotransmitter release associated with MDMA induces bruxism, trismus and teeth
grinding that can wear down tooth enamel. Direct
application of MDMA to the gums may cause necrotizing gingivitis and widespread perioral and intraoral
swelling. MDMA can also interfere with systemic temperature regulation that can, rarely, be lethal.
METHAMPHETAMINE
1172
Figure 105-5 Foreign body response and cellulitis.

Angular ulcerations, firm erythematous nodules, and
warm tender induration at the site of subcutaneous and
intravenous injection of adulterated heroin.
Methamphetamine is a very addictive synthetic stimulant that affects the brain and central nervous system
through the release of dopamine, norepinephrine, and
serotonin. By concurrently blocking reuptake of these
neurotransmitters, sensations of euphoria, lowered
inhibitions, feelings of invincibility, and hyperactivity
are produced.84 Metamphetamine a white, odorless,
ANABOLIC STEROIDS
Most anabolic steroids are synthetic substances similar to the male sex hormone testosterone. They may be
ingested or injected, and are used especially by athletes
to build muscle and enhance athletic performance. In
2000, approximately 3.6% of male and 0.9% of female
twelfth graders in the United States had used anabolic
steroids. Their abuse is most commonly associated with
acne vulgaris, striae formation and alterations in hair
growth.
Anabolic steroids induce sebaceous gland enlargement and the development of comedones through
abnormal follicular keratinization.92,93 Steroid-associated acne is characteristically distributed on the face,
shoulders, chest and back.93 It can progress to acne conglobata and fulminans secondary to the brisk immune
response to Propionibacterium acnes in individuals who
have never even had acne.94 Steroid-associated acne
does not always respond to routine therapy and may
Through the use of tobacco, nicotine is one of the most

heavily used addictive drugs in the United States. Cigarette smoking accounts for 90% of lung cancer cases
in the US. Tobacco is an agricultural product processed
from the leaves of plants in the genus Nicotiana, which
can be smoked or chewed (more precisely, placed
between gingival and buccal mucosa) to allow nicotine
absorption via oral mucosa. Nicotine in the tobacco
leaves is responsible for the vasoconstrictive effects of
smoking via increased vasopressin secretion and stimulation of the sympathetic nervous system, thereby
causing peripheral vasoconstriction.104108 Smoking a
single cigarette can produce cutaneous vasoconstriction for up to 90 minutes.109 Smoking decreases tissue
oxygenation via vasoconstriction and by increasing
carboxyhemoglobin, thereby limiting the bloods oxygen carrying capacity.110 Smoking also increases platelet aggregation111 and blood viscosity,112 and decreases
prostacyclin formation.113 This combination of mechanisms also leads to impaired postoperative wound
healing in smokers.114,115 The tar in cigarettes increases
a smokers risk of lung cancer, emphysema, and
bronchial disorders. The carbon monoxide in smoke
increases the chance of cardiovascular diseases.
Although the mechanism is unknown, smoking
tobacco has also been linked with premature aging and
rhytid formation. Elastin from photoprotecting skin in
smokers is thick and fragmented, resembling that of sundamaged skin but involving the reticular rather than the
papillary dermis. Chronic dermal ischemia of as well as
Sedatives as a class of drugs includes benzodiazepines,

hydroxybutyrate, flunitrazepam and cannabis. Cutaneous manifestations and reactions to this group of drugs
is quite rare, however drug reactions have been rarely
associated with benzodiazepines, including type IV
morbilliform drug hypersensitivity eruptions,89 acute
generalized exanthematous pustulosis to tetrazepam90
and erythema multiforme to clonazepam.91
TOBACCO
18
::
SEDATIVES
persist for weeks to months following discontinuation

of the drugs (see Chapter 80).93,95
Anabolic steroid use is also associated with alterations in hair growth, including hirsutism and androgenic alopecia, both of which are often more noticeable
in women and may not be reversible with discontinuation of the drug.93,96,97 Males can develop testicular
atrophy, gynecomastia and infertility. Women may
experience menstrual changes, male-pattern alopecia, and deepening of the voice. Teenagers risk permanently stunted height and accelerated pubertal
changes.
Steroid use is associated with striae formation secondary to dramatic hypertrophy of muscle tissue.98
Gingival enlargement has also been observed in those
using anabolic steroids for greater than one year. Systemic effects of steroid abuse include hepatic damage,
jaundice, hypertension and dyslipidemia.
Bacterial abscesses may occur at steroid injection
sites secondary to nonsterile injection techniques.93,96
Repeated injection into the same site can result in
inflammation and oil-induced granuloma formation.99
Soft tissue pseudotumors100 and rhabdomyolysis101
have also been reported in injectors.
In addition to causing de novo conditions, anabolic steroid use is also associated with exacerbation
of existing acne and psoriasis.93 Case reports have
described exacerbation of angiolipomas102 and latent
acute hereditary coproporphyria as well.103
Chapter 105
bitter-tasting powder that can be ingested orally,

snorted or injected. It may also be smoked in its rock
crystal form.85 Short-term effects include feelings of
euphoria, decreased fatigue associated with difficult life
situations, headache, difficulty concentrating, diminished appetite, abdominal pain, vomiting, diarrhea,
disordered sleep, paranoid or aggressive behavior, and
psychosis. Long-term use of methamphetamine use is
associated with anorexia, neurotoxicity, neurodegeneration, and clinical depression that may lead to homicidal and suicidal ideation and action.85
An increased rate of skin and soft tissue infections have been reported in methamphetamine users,
including increased rates of methicillin-resistant Staphylococcus aureus (MRSA) infections in noninjection
drug users. Methamphetamine use is associated with
formication that can lead to subsequent skin picking,
skin breakdown, and portals of infection (see eFig.
105-5.2 in online edition). Use of methamphetamine
and other sexually stimulating drugs can also increase
direct skin-to-skin sexual contact and transmission of
MRSA86 (Table 105-1).
Methamphetamine users are at risk for developing
meth mouth, or oral decay characterized by poor oral
hygiene, xerostomia and rampant caries typically
on the smooth surfaces of teeth, and excessive tooth
wear.87 Methamphetamine use has also been associated with psychosis and subsequent self-injurious
behavior including genital mutilation.88
1173
18
ciated with heavy cigarette smoking in young men.

Cutaneous manifestations include blanching, cyanosis, burning, tingling, ulceration, necrosis, and gangrene (see Chapter 170).
Cigarette smoking has been shown to exacerbate
and possibly induce palmoplantar pustulosis.135,136
Both allergic and irritant contact dermatitis characterized by itching and burning, have been documented
to nicotine patches.137 Allergic contact dermatitis to the
tobacco leaf has also been reported in tobacco harvesters and factory workers.138,139
Section 18
Figure 105-6 The nicotine sign. The orange hue of

tobacco can lead to yelloworange discoloration of the
fingertips and fingernails in chronic cigarette smokers.
Clubbing of the distal digits indicates the presence of
chronic lung disease.
::
1174
the decreased collagen synthesis likely play roles in the

damaging elastic fibers.116 Increased plasma neutrophil
elastase activity secondary to smoking may contribute
to abnormal elastin.117 Smoking also causes a yellow
brown discoloration of the fingers and fingernails of digits habitually holding the cigarette (Fig. 105-6).118
Cigarette smoking and chewing tobacco use are
associated with a number of mucosal conditions. Leukokeratosis nicotinica palati (nicotine stomatitis, smokers
palate) is characterized by uniform keratosis of the hard
palate with multiple tiny umbilicated erythematous
papules representing the inflamed orifices of minor
salivary glands.119 This benign oral lesion is seen exclusively in smokers and is caused by the tars and heat in
tobacco smoke. Resolution is usually complete within
2 weeks of smoking cessation. All forms of tobacco
use play a significant causative role in the development of leukoplakia.120 Leukokeratosis nicotinica glossae
(also known as tongue) is a homogeneous leukoplakia
affecting the anterior two-thirds of the dorsal tongue.121
Acute necrotizing ulcerative gingivitis trench mouth,
Vincent disease is caused by bacteria but is not communicable. Smokers tend to have fewer oral aphthous
ulcers than nonsmokers due to decreased mucosal
blood flow resulting from the vasoconstrictive effect of
nicotine. Yellow discoloration of teeth secondary to tar
deposition is also commonly observed.
Oral verrucous carcinoma, black hairy tongue, oral
melanosis and oral warty dyskeratoma have been
linked to tobacco use, but the connection is not as
strong as in the aforementioned conditions.122,123
All forms of tobacco are associated with an increased
risk of oral cancer.124127 Cigarette smoke may act as a
direct carcinogen or via systemic absorption.128,129
Smokers are also at an increased risk of developing
squamous cell carcinomas at sites other than the oral
mucosa, likely because of the immunosuppressive
effects of smoking.130132 Immune dysregulation associated with smoking is thought to be the reason that
smokers with melanomas present with more advanced
lesions and have a poorer disease prognosis.133,134
Thromboangiitis obliterans (Buerger disease) is an
obstructive vascular disease that is indisputably asso-
BETEL
Betel (Piper betle) belongs to the Piperaceae family; its
leaf has an important social and cultural role in South
Asia, Southeast Asia and the South Pacific. Betel leaves
are chewed with the areca nut (also known as betel
nut), calcium hydroxide, Acacia catechu bark, and
occasionally tobacco in a wrapped package known as
betel quid. Betel leaves are used as a stimulant, antiseptic and breath freshener. The areca nut contains the
alkaloid and stimulant arecoline which promotes salivation and stains saliva and teeth dark red to rust-colored. Calcium hydroxide keeps the active ingredients
alkaline, thereby enabling its sublingual absorption
and entry into the bloodstream.
Continuous chewing of betel quid maintains constant moisture at the oral commissures which, when
coupled with continuous friction of opposing surfaces,
causes maceration, erosion and fissures. These lesions
can be mistaken for angular cheilitis, candidiasis or
vitamin-deficiency associated perleche.140 The mixture
is usually kept between the teeth and lip and may thus
cause burning and erosions of the buccal mucosa.140
Chewers mucosa results from the direct chemical action
of the quid and/or traumatic effect of chewing, and is
characterized by a brownishred discoloration of the
buccal mucosa with an irregular desquamative epithelial surface. These mucous membrane findings are
not thought to be malignant or premalignant.141 Oral
lichenoid lesions regress with decrease in frequency,
duration or change in site of placement of the quid.142
Oral submucous fibrosis is directly related to betel
quid chewing and affects the buccal mucosa, lips, retromolar areas, soft palate and occasionally the pharynx and esophagus.143 It is characterized by prodromal
oral dysesthesia aggravated by spicy foods, followed
by early blanching mottled mucosal lesions and subsequent late development of palpable vertical fibrous
bands in the buccal mucosa and around the mouth
opening requiring surgical release for sufficient opening of the mouth.144 Trismus, dysphagia, xerostomia,
rhinolalia and tongue stiffening present late in the disease course. Mucosal petechiae, leukoplakia and epithelial dysplasia are also seen.145,146 The most serious
complication of oral submucous fibrosis is the development of oral carcinoma, which can be seen in up to
10% of users and is typically localized to the buccal
tongue and labial mucosa.147 Of all oral cancers in Taiwan, as many as 86.2% of cases have been reported to
be in betel quid chewers.148
18
POLYSUBSTANCE ABUSE
TABLE 105-2
Common Infectious Agents Associated with

Drug Abuse and Addiction
Class
Infectious Agent
Bacterial
Streptococcal species
Clostridium botulinum
Eikenella corrodens
Anaerobes
Unusual organisms
Fungal
Dermatophytes
Candida
Aspergillus
Mucor
Viral
herpatic viruses
Human T-cell lymphotropic virus
Hepatitis B virus
Hepatitis C virus
Sexually transmitted
Chlamydia trachomatis
Neisseria gonorrhoeae
Human papilloma viruses
Treponema pallidum
In addition to the local reactions and systemic effects

of specific drugs themselves complications of drug use
must also be considered.
Injection drug use is associated with inoculation and
transmission of infectious agents leading to local skin
and soft tissue infections and abscesses, as well as the
subsequent hematogenous spread of microbes. Grampositive cocci including Staphylococcus aureus, group A
-hemolytic streptococcus and other streptococci are the
most commonly observed microbial agents.149151 Anaerobes are the second most common group of bacteria to
be isolated, while Gram-negative bacteria are less commonly isolated. The source of the pathogens is variable,
but most originate from the flora of the skin and oropharynx secondary to needle-licking practices and use
of saliva to clean or moisten skin and injection implements.149 Abscesses and cellulitis occur in 22%65% of
drug users152 (Fig. 105-7). Irritant substances including the
drug or its diluents may cause sterile chemical cellulitis
and abscesses. Systemic infections including bacteremia,
endocarditis, osteoarthritis, and systemic candidosis may
result. Systemic candidosis is the most common systemic
fungal infection in injection drug users (Table 105-2).
Direct intra-arterial injection of drugs may cause
severe ischemia and necrosis. Early intense burning is noted in the injected area, followed by marked
edema, compartment syndrome, cyanosis, and livedoid patches of the affected limb within a few hours.
Distal necrosis may occur in the most severe cases, and
has been seen with the use of drugs such as cocaine,
heroin, pentazocine, diazepam, amphetamine and others25,153,154 The local cytotoxicity of a drug may cause
a chemical endarteritis resulting in vasospasm and
thrombosis.
The behavioral effects of injection drug use has been
associated with an increased risk of sexually transmitted diseases as well as blood-borne diseases transmitted through unsterilized needles including hepatitis B
virus (HBV), hepatitis C virus (HCV), human immu-
nodeficiency virus (HIV) and human T-lymphotropic

virus (HTLV) (Table 105-2).
The repeated trauma of venipuncture, local infections
and the irritant drugs and adulterants can lead to superficial and deep venous thrombosis. Chronic venous
insufficiency can result from vein trauma, necrotic ulcers
at sites of past subcutaneous injection, vein thrombosis
and blockage of the lymphatic system.155,156
Other noninfectious diseases associated with drug
use include psychiatric disease, accidental injury due
to altered mental status and trauma due to criminal
violence or domestic abuse.
::
COMPLICATIONS
Figure 105-7 Cellulitis at the site of repeated drug injection. Tender warm erythema and induration surrounding
a chronic ulceration at the site of routine drug injection.
Secondary infections at injection sites can be caused by
introduction of pathogens via unsterilized needles, adulterated drugs, and at sites of compromised skin integrity.
S. aureus infectious endocarditis occurred following bacteremia from this site.
Chapter 105
Polysubstance abuse, the concurrent use of several

drugs with different pharmacologic effects, is becoming increasingly common. The diversity of reported
drug use combinations suggests that achieving some
perceptible change in state may be the primary motivator driving this practice. One drug may be used to
enhance the effects of another, as with the combined
use of benzodiazepines and methadone or cocaine
and heroin (speedballs). Polysubstance abuse can cause
adverse health consequences, such as pulmonary disease, reproductive dysfunction and immunosuppression in chronic cocaine and psychostimulant abuse.
It may also exacerbate preexisting conditions such as
hypertension and cardiac disease. The concurrent use
of some drugs, including cocaine and opiates, is frequently associated with deleterious behavior such as
needle sharing by injection drug users.
1175
18
TABLE 105-3
Drug Detection in Body Fluids and Hair

Substance
Blood/Saliva
Urine
Hair
Alcohol
1224 hours
624 hours
Up to 90 days
Amphetamines (except meth)
12 hours
13 days
Up to 90 days
Methamphetamine
13 days
35 days
Up to 90 days
MDMA (Ecstasy)
25 hours
24 hours
Up to 90 days
Benzodiazepines
648 hours
Therapeutic use: 07 days Chronic use

(>1 year)
46 weeks
Up to 90 days
Section 18
Cannabis
23 days, up to 2
weeks in heavy users
37 days, up to >30 days after heavy use and/

or in users with high body fat
Up to 90 days
Cocaine
25 days
25 days with exceptions for certain kidney

disorders
Up to 90 days
::
Codeine
23 days
Cotinine (break-down product of

nicotine)
24 days
24 days
Up to 90 days
Morphine
13 days
24 days
Up to 90 days
Heroin
12 days
34 days
Up to 90 days
LSD
03 hours
2472 hours (tests for LSD are very

uncommon)
Up to 3 days
Methadone
24 hours
3 days
Up to 90 days
PCP
13 days
37 days for single use; up to 30 days in

chronic users
Up to 90 days
Urine data from Labcorp I. Drugs of Abuse Reference Guide, 2004, https://www.labcorp.com/pdf/doa_reference_guide.pdf. accessed May 1, 2011.
DIAGNOSIS
While mucocutaneous findings can be suggestive of
drug use drug testing is needed to identify the agents
used. Bodily fluids including saliva, blood, urine and
hair can be used in drug detection. Urinalysis for qualitative detection of psychoactive substances and their
metabolites is often the fastest way to determine ingestion of a substance (Table 105-3).
Systemic conditions secondary to the effects of substance abuse should also be part of the evaluation of
these patients. Cutaneous infections at sites of trauma,
ulcers, or necrosis should be swabbed or biopsied
for culture to identify and treat causative organisms.
Thorough evaluation and imaging may be required to
rule out injury to or involvement of vital organs and
bony structures. In injection drug users, thorough
cardiac evaluation and examination of mucocutaneous and acral surfaces should be undertaken to access
for embolic phenomenon. Evaluation for transmitted
infections such as HIV, hepatitis and sexually transmitted diseases may be required.
1176
It is imperative to rule out primary infectious causes

of ulcers, nodules, skin and subcutaneous infections in
suspected drug users. Inflammatory and vasculopathic

processes such as pyoderma gangrenosum, livedoid
vasculopathy and medium vessel vasculitides must
be considered in the setting of ulcers and nodules.
Evidence of distal vascular compromise can be seen
in pernio, thromboembolic phenomenon and Raynaud phenomenon. The edematous phase of scleroderma, eosinophilic fasciitis and secondary lymphatic
obstruction are rare entities to consider the setting of
distal extremity swelling. Infectious and noninfectious
granulomatous diseases [including tuberculosis, leishmaniasis, granulomatosis with polyangiitis (Wegeners) and sarcoidosis] can present with nasopalatal
infiltration and perforation. Patients with pruritus and
formication may require evaluation for infestation,
metabolic or psychiatric etiologies of their symptoms.
TREATMENT
A detailed discussion of the treatment of drug abuse
and dependence is beyond the scope of this chapter,
but it is essential to recognize that these are chronic
illnesses that require long-term strategies. Combined
medical and behavioral therapy are important elements of a therapeutic process comprising detoxification, treatment and relapse prevention. Amelioration
of withdrawal symptoms is key to initiation of therapy. A multidisciplinary approach including addiction
can provide advice on safe injection techniques and

instituting strictly supervised heroin, diamorphine or
buprenorphine prescription programs for long-term
injectors.157 This may help reduce the risk of life-threatening infection from nonsterilized drugs, prevent
overdose from drugs of unknown purity, break the
link between drug use and criminal activity to acquire
drugs and decrease the number of injections in public
places.
18
KEY REFERENCES
::
Skin Signs of Physical Abuse
2. Abuse NIoD: 2010, http://www.drugabuse.gov, accessed

Jun 2010
23. Payne-James JJ, Munro MH, Rowland Payne CM: Pseudosclerodermatous triad of perniosis, pulp atrophy and
parrot-beaked clawing of the nailsA newly recognized syndrome of chronic crack cocaine use. J Forensic
Leg Med 14(2):65-71, 2007
58. Zhu NY, Legatt DF, Turner AR: Agranulocytosis after
consumption of cocaine adulterated with levamisole.
Ann Intern Med 150(4):287-289, 2009
66. Heng MC, Feinberg M, Haberfelde G: Erythematous
cutaneous nodules caused by adulterated cocaine. J Am
Acad Dermatol 21(3 Pt 1):570-572, 1989
86. Cook HA, et al: Heterosexual transmission of community-associated methicillin-resistant Staphylococcus
aureus. Clin Infect Dis 44(3):410-413, 2007
145. Pindborg JJ et al: Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 92(3):224-229, 1984
Chapter 106
counseling, social work support and management of

associated infectious, vascular, cardiac and hepatic
complications is critical to comprehensive care.
Potential therapies for opiate dependence include
drug detoxification (office-based, inpatient or ultra
rapid under anesthesia), agonist maintenance (injectable diacetylmorphine, methadone, levomethadyl or
buprenorphine), antagonist maintenance (naltrexone)
and pharmacologic treatment of withdrawal symptoms (clonidine, lofexidine or guanfacine).
Treatment options for tobacco addiction include
nicotine replacement therapies (patch, spray, gum
and lozenges). Bupropion and varenicline have been
approved by the Food and Drug Administration for
management of nicotine addiction. Behavioral interventions include group and individual therapies, and
telephone quitlines.
Outpatient and residential treatment centers can
provide environments in which individuals can participate in therapeutic communities and benefit from
behavioral therapy and peer support. Alternative
therapies including acupuncture may also prove useful in combination with medical and behavioral therapeutic interventions. Although relapses are common,
successful outcomes are accomplishable, indicating
the importance of candid, supportive, nonjudgmental,
care-facilitating discussions in patients whose drug
use has been revealed through skin examination.
The transmission of infectious disease via injection
drug use can be addressed by encouraging physicians
to prescribe sterile injection equipment, setting up
injection rooms staffed by healthcare personnel who
Chapter 106 :: Skin Signs of Physical Abuse

:: Howard B. Pride
ABUSE AT A GLANCE
Child abuse, elder abuse, and domestic
violence are common.
Abuse is a problem of all socioeconomic
classes and races.
Bruising on soft padded areas of the body and
patterned bruising that are multiple and in
different stages of healing are suspicious of abuse.
Burns that are bilateral and uniform are
suspicious of abuse.
Law mandates the reporting of all suspected
cases of child abuse and, in some states, elder
abuse.
CHILD ABUSE
Child abuse is an uncomfortable topic for most practitioners and is a source of anxiety, anger, and confusion
among those who care for children. True incidence
statistics are difficult to determine, but each year in
the United States, of the approximately three million
children referred to child protective services, approximately one million are determined to be the victims of
abuse and neglect (or about 12 cases per 1,000 children)
and approximately 1,500 die from abuse or neglect.1
Clearly, those whose practices involve the dermatologic care of children encounter real or suspected child
abuse. Practitioners must have some basic knowledge
of abuse and its evaluation to appropriately manage
these cases.
Because many forms of physical abuse have external manifestations, the skin examination may serve as
the first clue that abuse is taking place. Conversely, a
broad knowledge of skin diseases provides a unique
1177
18
TABLE 106-1
Conditions Mistaken for Abusive Bruising
Section 18
::
True petechiae and purpura

Disorders of coagulation
EhlersDanlos syndrome
Infections
Rocky Mountain spotted fever
Meningococcal infections
Group A streptococcal infections
Palpable purpura of vasculitis
Valsalva petechiae
Lichen sclerosus
Folk remedies
Cao gio: rubbing vigorously with a hard object such as a
coin
Cupping: suction mark left by the cooling of a warm
metal cup
Nodular lesions mimicking deep bruises
Neuroblastoma
Vascular malformations
Dermatomyositis-associated nodules
Erythema nodosum
Discolorations that look like bruises
Phytophotodermatitis
Maculae coeruleae from lice infestation
Mongolian spots
Dye from blue jeans
Inflammatory conditions that mimic bruising
Urticaria/angioedema/urticarial vasculitis
Pernio
Conditions that mimic whip marks
Striae
insight into those diagnoses that may mimic various

forms of child abuse (Tables 106-1 and 106-2). The literature is rich in examples in which an astute clinician
averted the disastrous results of a false claim of abuse
by correctly diagnosing a dermatologic condition.
True abuse must be reported and a thorough evaluation conducted. It is essential that practitioners develop
TABLE 106-2
Conditions Mistaken for Nonaccidental Burns
1178
Folk remedies (Maquas, or moxibustion): burns delivered
near diseased organs or therapeutic sites as in acupuncture
Impetigo/ecthyma
Sunburn/xeroderma pigmentosum
Burns from objects heated by sun
Electric burn from an enuresis blanket
Chemical burn from use of undiluted acetic acid
Chemical burn from Icy Hot balm
Chemical burn from calcium chloride
Diaper dermatitis
Pernio
Fixed drug eruption
TABLE 106-3
Helpful Agencies for Information on Abuse and

Domestic Violence
Child Welfare Information Gateway, 1250 Maryland
Avenue, SW, Eighth Floor, Washington, DC 20024, Ph:
(800) 394-3366, email: info@childwelfare.gov, http://www.
childwelfare.gov/
Childhelp National Headquarters, 15757 N. 78th Street,
Suite B, Scottsdale, AZ 85260, Ph: (480) 922-8212, http://
www.childhelpusa.org
Domestic Violence International Resources, http://www.
vachss.com/help_text/domestic_violence_intl.html
International Network for the Prevention of Elder Abuse,
http://www.inpea.net, e-mail contactus@inpea.net
International Society for Prevention of Child Abuse and
Neglect, 13123 E. 16th Ave, B390, Aurora CO 80045, Ph:
(303) 864-5220, Fax: (303) 864-5222, email: ispcan@ispcan.
org, http://www.ispcan.org
National Adult Protective Services Association, 920 S.
Spring Street, Suite 1200, Springfield, IL 62704, Ph: (217)
523-4431, Fax: (217) 522-6650, http://www.apsnetwork.org
National Center on Elder Abuse, c/o Center for Community
Research and Services, University of Delaware, 297 Graham
Hall, Newark, DE 19716, Ph: (302) 831-3525, Fax: (302)
831-42525, e-mail ncea-info@aoa.hhs.gov, http://www.
elderabusecenter.org
National Committee for the Prevention of Elder Abuse,
1612 K Street, NW, Suite 400, Washington, DC 20006, Ph:
(202) 682-4140, Fax: (202) 223-2099, email: ncpea@verizon.
net, http://www.preventelderabuse.org
National Coalition Against Domestic Violence, 1120 Lincoln
Street, Suite 1603, Denver, CO 80203, Ph: (303) 839-1852,
Fax: (303) 831-9251, email mainoffice@ncadv.org, http://
www.ncadv.org
National Resource Center on Domestic Violence, 6400 Flank
Drive, Suite 1300, Harrisburg, PA 17112, Ph: (800) 537-2238
ext. 5, Fax (717) 545-9456, http://www.nrcdv.org
a relationship with the institution or individual in their

area who is best able to manage these difficult cases.
Ideally there should be an abuse team consisting of
a dermatologist, pediatrician, social worker, medical
photographer, and, when needed, pediatric subspecialists such as orthopedists, hematologists, psychologists, and gynecologists. The need for specialization
in this field is highlighted by the institution in the
United States of pediatric subspecialty board certification in child abuse, beginning in 2010. It is most helpful if ones relationship is forged with the abuse team
before an abuse incident and a set protocol for dealing
with alleged or suspected abuse is established in the
practitioners office. Local emergency phone numbers
for reporting abuse can be obtained from the Child
Welfare Information Gateway or Childhelp National
Headquarters (Table 106-3).
Child abuse spans all ages with 32% of abused children being younger that 4 years of age, 24% being 47
years of age, and 19% being 811 years of age. Typical
children who suffer abuse have emotional or behavioral problems, have special medical needs, have several siblings, live in single-parent households, or live
at or below the poverty level. Abuse is approximately
18
two times more common in Pacific Islanders, American Indians, Native Alaskans, and African American
children compared to the average American population. Perpetrators tend to have emotional or psychological problems, have frequently been victims of
abuse themselves, abuse drugs or alcohol, are perpetrators of spousal abuse or have a history of marital
discord, have marginal parental skills or knowledge,
and have poor self-esteem. Parents are the perpetrator
80% of the time.2 Although these profiles are helpful,
it is important to remember that any child may be the
victim of abuse.
Figure 106-1 Purpura and erosions on the soft, padded

areas of the buttock and thighs, representing very obvious
abuse. (Used with permission from Paul Bellino, MD.)
::
small triangle at the base (Fig. 106-2) representing the

interdigital and finger web spaces, occurs after a slap
injury. Grab or pinch marks can be recognized by their
location on soft padded areas and their unusual patterning. Circumferential purpura or hemosiderin pigmentation (Fig. 106-3) suggests a ligature injury, which
would be difficult to explain as accidental. Bite marks
(Fig. 106-4) are always inflicted, although they are
sometimes from siblings or other children. The shape
and size of the marks can identify an adult mouth versus a bite from a child. It is helpful to include a ruled
measuring scale in any photographs to help forensic
identification at a later date.
The head is the most common target of physical
abuse (see eFig. 106-4.1 in online edition). Black eyes
are common accidental injuries but are more suspicious if they are bilateral or are unaccompanied by
evidence of trauma to the nose or superior orbital
ridge. Subconjunctival hemorrhages can be seen in
0.5%13.0% of typical newborns, but a large subconjunctival hemorrhage beyond 1 and 2 weeks of life is
suspicious of abuse. Petechiae in the periorbital region
Figure 106-2 Linear purpura representing the interdigital

spaces from a hand slap. Note the inferior triangular shape
that corresponds to the finger web space. (Used with permission from Paul Bellino, MD.)
Bruising is the result of blunt trauma, delivered either

accidentally or intentionally. Active children, particularly toddlers, are prone to multiple bruises, and the
identification of abusive injury is fraught with difficulty. The size, shape, color, and feel of a bruise varies
on the basis of anatomic site, the degree of force used,
the firmness of the object delivering the force, and the
underlying health of the injured individual. Great care
and attention to detail must be exercised when evaluating these children who likely have been brought to
the office for some other complaint. The history should
include as much detail as possible and inconsistencies
in the parents story clearly documented in the medical
record (eTable 106-3.1 in online edition).3 It is essential
to perform a total body, skin, and mucous membrane
examination. It is also important to note the childs
behavior and parentchild interactions.
The color of all bruises should be noted and clearly
documented. This may aid in determining the age
of a bruise and may point out inconsistencies in the
caretakers history. Multiple bruises of differing colors
may indicate ongoing trauma rather than one isolated
incident. Caution must be exercised in dogmatically,
stating the time of injury based on bruise characteristics because color depends on the intensity, depth,
and location of the injury. There is good evidence that
a bruise with any yellow color must be older than 18
hours, but a bruise may be red, blue, or purple/black
throughout its life span, from beginning to resolution.
Bruises of identical age and cause on the same person
may not appear as the same color and may not change
at the same rate.4 It is most prudent to document color
without alluding to a specific age of a bruise in the
medical record. Faint bruised might be more easily
visualized with the use of a Woods lamp.
Although there are no absolute differentiating features, certain aspects of an intentionally inflicted bruise
may suggest abuse. Because young children tend to
explore in a forward direction, accidents are more frequent on the distal arms and legs, knees, elbows, and
forehead. Soft, padded, posterior, and protected areas
of the body are far less likely to be accidentally injured.
Bruises on the abdomen, buttocks (Fig. 106-1), thighs,
genitalia, ear lobes, and cheeks are uncommon, so
marks in these areas should raise concern.
Inflicted bruises often leave patterned imprints of
a hand, whip, or hard object. Linear purpura, with a
Chapter 106
THE BATTERED CHILD
1179
18
Section 18
::
1180
Figure 106-3 Linear, circumferential hyperpigmentation

at the site of previous ligature. (Used with permission from
Paul Bellino, MD.)
have been seen in children with abuse related retinal
hemorrhages. Accidental bruising or other injuries to
the oral mucous membranes are unusual and should
be considered as suspect (see eFig. 106-4.2 in online
edition).
Any bruises in a young infant who is not yet pulling to a stand should raise concerns of abuse or of an
unsafe environment (see eFig. 106-4.3 in online edition). A shaken infant may have bruising on the hands
because he or she is liable to be flailing during the
shaking incident (see eFig. 106-4.4 in online edition).
Concern should be raised whenever the history of an
accident is inconsistent with the developmental level
of the child.
INFLICTED BURNS
The most common agent involved in childhood burns,
both accidental and inflicted, is hot liquid. Accidents
such as inadvertently stepping into a hot tub or pulling
Figure 106-4 Human bite marks. (Used with permission

from Paul Bellino, MD.)
a hot liquid off a table counter or stove leave irregular

or geographic burn patterns that lack symmetry. By
contrast, inflicted scalds tend to be symmetric, with
sharply demarcated edges and an absence or paucity
of splash marks. In one study, all the children whose
bathtub burns were inflicted had associated features
of abuse, including bruises, fractures, or evidence of
neglect.5 Stocking and glove burns result when the feet
or hands are forcibly held under hot water. The uniformity of the burn indicates that the child was not able to
reflexively withdraw from the scalding water as would
happen with accidental immersion. A common pattern
of inflicted immersion burn involves the buttocks, low
back, and thighs. The child is flexed at the waist and
dipped into the hot water, frequently as a punishment
for a toilet training accident. The resultant pattern may
give zebra stripes on the abdomen due to sparing of
the flexural skin that is protected from the scald when
bent forward. A donut hole pattern of sparing might
be seen on the buttock if the child is pushed forcibly
to the bottom of the tub that is cooler than the scalding water.6 Inflicted splash burns are much more difficult to differentiate from accidents. A careful history is
needed to detect inconsistencies between the proposed
injury and the physical examination. When doubt
exists, it is mandatory that child protective services be
contacted.
An inflicted contact burn can be recognized by the
pattern that duplicates the object creating the injury
(see eFig. 106-4.5 in online edition). Accidental contact
burns tend to be smaller, less severe, less patterned, and
of irregular depth. When a child is held against a hot
object, the depth is more uniform, the pattern is more
clearly defined, and the burn is more severe. Irons,
curling irons, hot plates, and cigarettes are objects commonly used to inflict burns.7 Some burns may, in fact,
be accidental but represent inadequate supervision and
neglect. This situation is also harmful to children and
needs to be reported to the appropriate agencies.
SEXUAL ABUSE
It is estimated that more than 300,000 children suffer from sexual abuse each year in the United States.
The lifetime risk of sexual abuse is approximately
25%40% for girls and approximately 10% for males.
Sexual abuse is defined by the American Academy of
Pediatrics as the engaging of a child in sexual activities that the child cannot comprehend, for which the
child is developmentally unprepared, and cannot
give informed consent and violate the social taboos of
society.8 This broad definition includes inappropriate
touching, genital penetration, fondling, and sexual
kissing, but also includes noncontact activities such
as exhibitionism, voyeurism, and the involvement of
a child in verbal sexual propositions or the making
of pornographic pictures or movies. Clearly, many
forms of sexual abuse leave no physical examination
findings.
Girls are more likely than boys to suffer sexual abuse
and the risk rises in preadolescence (Fig. 106-5). Most
abuse is at the hands of someone known to the child
TABLE 106-4
18
Conditions Mistaken for Sexual Abuse

Genital warts pose a particularly difficult problem

for practitioners. They certainly can be sexually transmitted to children, and the possibility of sexual abuse
needs to be discussed with parents. However, there is
much evidence that genital warts can be acquired perinatally from an infected mother, through autoinoculation from warts on other parts of the body or through
nonsexual contact with caretakers.11 Children younger
than 3 years of age at the onset of warts are least likely
to have acquired their warts from sexual contact,
whereas children with onset after 5 years of age have a
much greater risk of having suffered sexual abuse. The
ages in between represent a gray zone. Other signs of
abuse will seldom be present to aid in the diagnosis,
and human papillomavirus typing is not helpful. History provides the most valuable insight into the correct
diagnosis; again, it is imperative that an abuse team
be involved. At the authors institution, all children
with perianal or genital warts are referred, in a nonaccusatory and nonjudgmental fashion, to the hospitals
abuse social worker and pediatrician as routine protocol.12
::
and only 10% is carried out by strangers. Victims

and perpetrators span all racial, religious, and socioeconomic spectrums but risk factors for sexual abuse
include the presence of a stepfather, single-parent families, children whose mothers are extensively out of the
home, a history of parental violence, parents who have
suffered abuse themselves, parental substance abuse,
and low household income level.
Most victims of sexual abuse have no physical
findings.9,10 Pregnancy, positive cultures for sexually transmitted diseases, presence of sperm or acid
phosphatase, acute genital or anal injuries without
plausible explanation, and marked hymeneal opening enlargement with associated hymeneal disruption are very definitive signs of abuse. However, it is
very seldom that such signs are present. The American
Academy of Pediatrics Committee on Child Abuse and
Neglect recommends that certain findings are consistent with, but not diagnostic of, abuse. These include
chafing, abrasions or bruising of the inner thighs and
genitalia, scarring, tears or distortion of the hymen, a
decreased amount or absent hymeneal tissue, scarring
of the fossa navicularis, injury to or scarring of the posterior fourchette, scarring or tears of the labia minora,
and enlargement of the hymeneal opening, even without disruption of the hymen.8
The childs spoken word is the most valuable piece
of evidence in establishing sexual abuse. All historical information must be very well documented and
preserved with the same care as any piece of forensic
evidence. It is immensely important to enlist the help
of an experienced abuse team in obtaining the history
and completing an appropriately thorough physical
examination with the aid of colposcopic observations.
The skin examinations greatest contribution may
be in correctly diagnosing those dermatoses that may
look similar to sexual abuse but are not. Irritant dermatitis, atopic dermatitis, psoriasis, seborrheic dermatitis,
pinworms, candidiasis, scabies, and other common
dermatoses tend to cluster in the diaper region and
should be easily diagnosed with a critical eye. Other
conditions that have been reported as mimickers of
sexual abuse are listed in Table 106-4.
Chapter 106
Figure 106-5 Sexual abuse. Perianal wound in a 3-yearold girl after anal penetration. (Used with permission from
Dr. Francesca Navratil, Zurich, Switzerland.)
Lichen sclerosus
Crohn disease
Localized vulvar pemphigoid
Perianal streptococcal dermatitis
Hemangiomas
Urethral prolapse
Entities that look like condylomata acuminata
Focal epithelial hyperplasia
Darier disease
Pigmented vulvar hamartomas
Pseudoverrucous papules
Epidermal nevus and inflammatory linear verrucous
epidermal nevus
Entities that look like herpes simplex
Localized varicella/zoster
ELDER ABUSE
Elder abuse is one of the fastest growing forms of
abuse. Although statistics vary, the National Center
on Elder Abuse in Washington, DC, estimates that 1
to 2 million Americans 65 years of age or older are victims of various forms of abuse each year. Abuse may
affect a range of 2%10% of the elderly population.
Those older than age 80 years are two to three times
more likely to suffer abuse, and the American population in this age range continues to increase each year.
For every case of reported elder abuse, at least another
five cases go undetected.13 All segments of society are
affected. Although there is inherent inaccuracy in these
statistics, it is readily apparent that elder abuse is common enough for a busy dermatologist to encounter a
few abused patients every week.
1181
18
TABLE 106-5
Types of Elder Abuse

Neglect: 55%
Physical abuse: 15%
Financial and material abuse: 12%
Emotional or psychological abuse: 8%
Sexual abuse: 1%
Unspecified forms of abuse: 9%
The US National Academy of Sciences has defined

elder abuse as:
Section 18
::
(a) intentional actions that cause harm or create a serious risk of harm (whether or not harm is intended) to a
vulnerable elder by a caregiver or other person who stands
in a trust relationship to the elder, or (b) failure by a caregiver to satisfy the elders basic needs or to protect the
elder from harm.
Acts of commission and omission are thus included

in the definition. Types of abuse and their respective
incidence rates are listed in Table 106-5. More than one
type of abuse can occur simultaneously.14,15
Abuse most often occurs at the hands of caregivers
or family members who have frequent close contact
with patients and often may live with them. Historically, adult children of the abused patient have been
the most common perpetrators, but most recent data
show that spouses now account for the majority of
abuse cases. Men are more likely to abuse than women.
The abuser is often financially dependent on the victim, and they are usually in a shared living situation.
However, financial abuse is more common among
those who live alone. Risk factors for abuse are listed
in Table 106-6. Note that the risk factors have far more
to do with the caretaker than the abused patient. In
particular, the level of debility or health status of the
patient does not predict abuse.
Physical abuse is defined as the intentional application of any force that causes bodily injury, pain, or
impairment to an elderly individual. It may include
acts such as hitting, beating, shaking, kicking, slapping, pushing, pinching, burning, overly aggressive
force-feeding, and the improper use of physical or
chemical restraints. The signs discussed in Section
TABLE 106-6
Risk Factors for Elder Abuse
1182
Older age
Lack of access to resources
Low income
Social isolation
Minority status
Low level of education
Functional impairment
Substance abuse by elder or caregiver
Previous history of family violence
History of psychological problems
Caregiver stress
Cognitive impairment
Child Abuse above apply to elder abuse as well and

include multiple bruises or fractures in different stages
of healing, bruises in normally well-protected areas
such as the inner thighs, odd-shaped injuries such as
from pinching or slapping, belt marks or patterned
bruising (see eFig. 106-5.1 in online edition), unusual
welts or puncture wounds, cigarette burns, rope marks
that might indicate restraints, bed sores, strangely patterned alopecia, attempts to hide part of the body, and
signs of malnutrition or dehydration. Because many
of these signs, particularly multiple bruises, can occur
normally in elderly individuals, detection of abuse can
be very challenging. Unexplained repetitive injuries or
explanations by caretakers that do not match the pattern of injury are concerning. Caretakers who act withdrawn, infantilize the patient, or insist on providing
the medical history should alert the clinician.
It is important to interview by directing questions to
the patient rather than the caregiver, and it is prudent
to try to arrange a time to confer with and examine the
patient alone. Repetitive follow-up visits help develop
a rapport with the patient and allow serial observation
of past and ongoing injuries. The assurance of confidentiality facilitates garnering sensitive information.
Once abuse is suspected, most states mandate that
physicians contact the appropriate authorities. Information on a particular states laws can be obtained
from the National Center on Elder Abuse (see Table
106-3). The nearest medical centers social service
department is well equipped to offer guidance, but the
agencies listed in Table 106-3 are also helpful resources.
Treatment, support, and counseling may be needed for
the perpetrator as well.
DOMESTIC VIOLENCE
Domestic violence is a pattern of coercive behaviors
that may include repeated battering, psychological abuse, sexual abuse, social isolation, deprivation,
and intimidation perpetrated by someone who is
or was involved in an intimate relationship with the
victim. Conservative estimates say that in the United
States approximately 1 million people suffer domestic violence each year, but the actual number likely
approaches 4 million. Women comprise approximately
90%95% of all victims, and men 95% of all perpetrators. Forty percent to 60% of men who abuse their
partner or spouse are also abusing their children. In
the United States, approximately one in three women
suffers a least one physical assault during her life, and
1,500 women are murdered by their husbands or boyfriends each year.16,17 Domestic violence is a devastatingly common problem.
The profiles of domestic abuse are similar to child
and elder abuse. Women ages 1929 years are the most
common victims, with other risk factors being low
income, mental health issues, alcohol or substance
abuse by the victim or the perpetrator, pregnancy, large
age difference between partners, separated or divorced
status, and a family history or personal past history of
abuse and violence. Women with educational or occupational levels above that of their partners may be at
suggesting a defensive posture and might include purpura, sprains, dislocations, and fractures to the wrist or
forearms, palms, and soles.
The social service department at the local medical
center is a good resource for information and help on
domestic violence. The National Domestic Violence
hotline (800799-7233) is a 24-hour resource for women
who need to find a local shelter. Other helpful organizations can be contacted (see Table 106-3).
18
KEY REFERENCES
::
1. Legano L, McHugh MT, Palusci VJ: Child abuse and neglect. Curr Probl Pediatr Adolesc Health Care 39:31e1, 2009
6. Kos L, Shwayder T: Cutaneous manifestations of child
abuse. Pediatr Dermatol 23:311, 2006
7. Swerdlin A, Berkowitz C, Craft N: Cutaneous signs of
child abuse. J Am Acad Dermatol 57:371, 2007
14. Abbey L: Elder abuse and neglect: When home is not safe.
Clin Geriatr Med 25:47, 2009
16. Zolotor AJ, Denham AC, Weil A: Intimate partner violence. Prim Care Clin Off Pract 36:167, 2009
17. Toohey JS: Domestic violence and rape. Med Clin N Am
92:1239, 2008
Chapter 106
higher risk. Abusers are typically underachievers with

occupational status below their educational level.16,17
Whenever possible, the patient should be interviewed
alone, without the partners presence. A thorough
examination should be done with a nurse chaperone,
but not the partner, in the room. Repeat visits may be
used to document new or progressing skin findings
and to build trust with the patient. Statements such as
Because domestic violence is such a prevalent problem,
we have begun to ask about it routinely may open the
door to more discussion regarding difficulties at home.
Literature and posters in the clinic setting with information and hotline numbers for abuse victims indicate the
common reality of abuse and may facilitate disclosures.
For various reasons, a victim may not want to reveal
abuse. Implausible explanations for an injury or a
delay in seeking medical attention may be clues of
abuse. Signs of depression, excessive use of sedatives,
chronic pain disorders, or vague stress-related symptoms may be subtle signs of abuse.17
Physical examination findings are the same as outlined for child and elder abuse. The distribution of
injuries tends to be central, and the perpetrator may
choose to injure hidden areas, such as the breast or
genitals, to deter detection. Unlike infants or debilitated adults, blows to a young adult may be to areas
1183
Skin Changes across

the Span of Life
PA RT
From Birth to Old Age
Chapter 107 :: N
eonatal, Pediatric,
and Adolescent Dermatology

:: Mary Wu Chang
NEONATAL, PEDIATRIC, AND ADOLESCENT DERMATOLOGY AT A GLANCE
Many dermatologic diseases exhibit different
manifestations in newborns, infants, and
children.
Some dermatoses are encountered only in
neonates and infants and therefore require
special attention.
Obtaining a history and methods of clinical
examination in infants and children differ
from the approaches chosen for adults. In
adolescents, different skills are required to
enhance compliance.
Many outpatient procedures in pediatric
dermatology can be done easily with
appropriate planning and age appropriate
Just as dermatology cannot be separated from internal medicine, pediatric dermatology is inseparable
from general pediatrics. Since most dermatologists
have experience and training in internal medicine but
less exposure to pediatrics and neonatology, an introduction to the special issues that can arise in pediatric
dermatology is presented herein. As it is impossible to
techniques. Necessary biopsies should not be

avoided simply because of a patients young
age.
The infant has increased risk for systemic
toxicity from topically applied substances;
the risk is even greater in premature infants.
Children with disorders of barrier function are
at high risk of excess percutaneous absorption
and toxicity as well.
Drug labeling for pediatric patients is different
from that in adults and most therapeutic agents
are prescribed off-label.
discuss all of pediatric dermatology in one chapter, the

focus is instead on certain methods, diseases, and issues
divided by three age divisions: neonates and infants,
children, and adolescents. Topics of special importance
such as pediatric medication use and biopsy pitfalls are
discussed. Methods to enhance success in outpatient
procedures in pediatric dermatology are also reviewed.
19
TABLE 107-1
Ten Helpful Tips in Pediatric Dermatology
Section 19
::
1. The child is the patient, not the parents.

2. Biopsy when indicated, regardless of age. (Refer if necessary)
3. Be aware of the family situation: Does the child live in two
homes? Are the parents going through a divorce?
4. Be aware of the parents perception of the child: Was
there difficulty in conceiving? Prematurity? Significant
early illness?
5. A team approach with the pediatrician, neonatologist,
or family physician is most efficient. Psychiatrist
comanagement may be indicated (e.g., isotretinoin issues
or trichotillomania).
6. Chronic illness in one person affects the entire family
(e.g., severe atopic dermatitis).
7. Guide parents and patients to appropriate Internet
resources, but always review materials for accuracy
beforehand.
8. Obtain consent from parents, and assent from children,
for procedures and photos.
9. An adolescents confidentiality must be maintained
unless there is a danger of harm to the patient, or others.
Consider interviewing patient alone without parents for a
portion of the visit. Consider a chaperone in the office for
full skin exams.
10. Remember the aphorism, To cure sometimes, to relieve
often, to comfort always.
Successful care of the pediatric patient is best

achieved via comanagement with the neonatalogist,
pediatrician, or primary care physician. In addition,
an understanding of the parental or family situation is
important. For example, children living in two households (due to divorced parents) may do best with two
sets of medications, one in each home, to enhance
compliance. Table 107-1 reviews ten helpful tips in
practicing pediatric dermatology. As an example, if
Internet access exists, patients or parents will likely
search online for medical information before or after
the office encounter. Parents and patients should be
warned that medical information on the Internet is
often inaccurate.1 It is wise to direct them to specific
Internet Web sites, support groups, or pamphlets, but
these resources should be reviewed before recommending them.
Lastly, the aphorism, To cure sometimes, to relieve
often, to comfort always, should always be kept in
mind when delivering pediatric care. Parents often
have higher expectations, and a heightened level of
worry and concern for their children and the office
visit cannot be rushed.
NEONATES AND INFANTS
1186
The neonatal period is defined as the first 30 days of life.

Neonatal skin diseases evolve much more rapidly than
adult skin diseases, and some conditions that initially
appear to be serious turn out to be trivial, whereas in
others, the opposite is true. Infancy is defined as beginning after the first 30 days of life.
NEONATAL SKIN
After birth, the neonates skin undergoes a series of
changes in adaptation to the extrauterine environment.
In utero, the skin of the fetus is protected by the vernix
caseosa and is immersed in amniotic fluid. After birth,
the vernix is wiped off, and the skin is exposed and
adapts to the dry ambient air. For example, desquamation of the upper layers of the stratum corneum occurs
normally in all infants and is believed to be a normal
adaptive process.
Research regarding the maturation of the neonatal
stratum corneum in neonates has produced varying
results, and the question of when full barrier function
is achieved is not fully answered. Barrier stabilization
appears to be a dynamic process, one dependent upon
a balance between different biologic and environmental parameters. Postnatal life is believed to accelerate
stratum corneum maturation in premature and term
infants. Parameters such as skin thickness, skin pH,
and stratum corneum hydration indicate that neonatal
skin is continuously adjusting to the extrauterine environment, in contrast to the adult skin, which remains
in a steady state.2
In vivo studies of human skin show that infant
stratum corneum and epidermis is thinner than
adult skin and has higher transepidermal water loss
(TEWL) rates, but infant stratum corneum has higher
water content. Infant corneocytes and granular cells
are smaller than adult corneocytes suggesting a more
rapid cell turnover than in adults.3
Infants have an increased risk for systemic toxicity
from topically applied substances. This is due in large
part to the great surface areabody mass ratio in the
infant. In addition, the infants metabolism, excretion,
distribution, and protein binding of substances can be
significantly different from those of an adult and add
to increased risk of toxicity.4
The postmature infant (>40 weeks gestation) typically has dry and cracked or peeling skin noted soon
after birth (Fig. 107-1). Shedding of the dry peeling
skin of postdates infants occurs spontaneously in the
first month of life, leaving normal, healthy skin. Topical care should include moisturizers and avoidance of
overbathing.
Premature infants, particularly those born before 34
weeks of gestation, have markedly decreased epidermal barrier function and an even greater surface area
body mass ratio than term infants. In addition, the
immature organs of the premature infant may affect
the metabolism, excretion, distribution, and protein
binding of chemical agents. Local or systemic toxicity
can occur in the premature infant not only from topical
medications, but also soaps, lotions, or other cleansing
solutions.4,5
Increased skin fragility is a hallmark of prematurity
(gestational age less than 37 weeks). Epidermal and dermal injury may lead to significant cutaneous pain even
with routine handling and nursing care. The premature
infant is at risk for infection and sepsis from skin-associated organisms entering through breaks in the thin and
fragile skin and via iatrogenic portals of entry. Sweating
EXAMINATION TECHNIQUES
Neonatal, Pediatric, and Adolescent Dermatology
in the premature infant is functionally reduced and contributes to poor thermal regulation. Heat regulation is
dysfunctional due to a thin subcutaneous fat layer for
insulation, poor autonomic control of cutaneous vessels, and a large surfacebody ratio. In the nursery, the
premature infant is usually placed in a temperature and
humidity-controlled isolette until the infant matures
and temperature and fluid regulation stabilizes.
In the 1990s researchers reported application of
petrolatum-based emollient therapy to be beneficial
in hospitalized preterm infants, decreasing transepidermal water loss.6 Subsequently, various emollients
and regimens have been tested in infants of variable
prematurity and birthweight. Improved skin integrity consistently improved in these studies, however,
a threefold increase in the incidence of systemic candidiasis was reported after emollient therapy was
implemented in extremely low birthweight (1,000 g)
premature infants in one neonatal intensive care unit.7
Another outbreak of systemic candidiasis occurred in
very low birthweight neonates (1,500 g) in a different
neonatal intensive care unit.8 A 2004 Cochrane review
concluded that prophylactic application of topical ointments increased the risk for nosocomial infection and
advised against their routine use in preterm infants.
In contrast, randomized, controlled studies in impoverished Bangledeshi preterm neonates have demonstrated decreased mortality rates when sunflower seed
oil or Aquaphor ointment was applied by massage,
compared to premature infants not receiving massage or emollients.9 Until prospective, controlled trials
are performed, neonates receiving petrolatum-based
emollient therapy should be carefully monitored for
infections, particularly those infants with birthweights
less than 1,500 g.
::
Figure 107-1 The feet of a postmature newborn. The dry,

hyperlinear, and scaly skin is typical of a postdates baby.
There are also pustules of transient neonatal pustular melanosis.
A complete history includes gestational and birth history as well as family history. Exposures during pregnancy, including medications, illicit drugs, and infectious diseases such as varicella and sexually transmitted diseases, should be reviewed. Obstetric data,
including placental appearance and cultures, can be
invaluable. In examining an infant, the most important
element is thoroughness. Whether the infant is examined in the lap of the parent or on the examination table,
all surfaces, including the creases and valleys of body
folds and the diaper region (including the genitalia),
deserve close examination. A vascular stain, vasoconstricted macule, or erosion can be the presenting sign
of a hemangioma.12 A stray hair may later strangulate
an appendage and should be removed. Infants with
digital tourniquet (pseudoainhum) and clitoral tourniquet have been described.13,14 Congenital lesions of
all classifications (e.g., pigmented, vascular, aplasias)
warrant closer inspection to rule out associated findings. Midline lesions on the face, scalp, or spine may
have central nervous system (CNS) connections and
should not be biopsied without proper evaluation (see
Table 107.7). The diaper area has its own unique set of
problems and deserves examination at every visit.
The infant is vulnerable and completely dependent
on the caretakers. The social support system and family structure must be considered when implementing a
medical plan. There are times when the parents desire
for treatment may not be in the best interest of the patient.
Medical and surgical decision making for the infant
is based primarily on function rather than cosmesis.
For example, extraction of a natal tooth is indicated if
breast-feeding is impaired; whether or not the tooth is
a component of a genetic syndrome is a separate issue.
19
Chapter 107
Once at home, bathing once or twice a week in plain

water is sufficient for most infants; if bathing is more
frequent, moisturization with unscented, simple emollients is recommended. The face, hands, and diaper
area may be cleansed daily using a small amount of
a mild, unscented, pH-neutral cleanser. Well-meaning
parents often bathe their infants too frequently and
use a multitude of products on their infants skin. In
addition to irritation and asteatosis, these practices
may increase the risk of allergic contact dermatitis in
infants. It has been estimated that the average newborn is exposed to approximately 10 skin care products
in the first month of life, leading to exposure to more
than 50 different chemicals ranging from mildly toxic
to toxic.10 Parents should be taught that less is best.11
DISEASES OF NEONATES
AND INFANTS
TRANSIENT DERMATOSES OF THE NEONATE. Skin conditions encountered in newborns
that tend to resolve by 30 days of age are considered

to be transient. They are very common and many are
expected in newborns.
1187
19
Caput Succedaneum and Cephalohematoma. Caput succedaneum is subcutaneous edema
Section 19
over the presenting part of the head and is a common

occurrence in newborns. Cephalohematoma is a subperiosteal collection of blood and is less common. Both
lesions are due to shearing forces on the scalp skin and
skull during labor.
Caput succedaneum is soft to palpation, and borders
are ill-defined. Cephalohematoma is bounded by the
suture lines of the skull and often feels fluctuant. If
purpura is extensive, it can lead to hyperbilirubinemia.
Congenital lymphedema or lymphatic malformations
(such as in Turner syndrome) can mimic caput succedaneum. Both caput succedaneum and cephalohematoma resolve spontaneously; however, caput usually
fades in 710 days, whereas cephalohematoma slowly
resolves over several weeks.
::
Milia. Milia are multiple pinpoint- to 1-mm papules

representing benign, superficial keratin cysts. They are
seen most commonly on the nose of infants and may
be present in the oral cavity as well, where they are
called Epsteins pearls. They are expected findings in
the newborn and resolve spontaneously within a few
weeks of life.
Sebaceous Gland Hyperplasia. At
least 50%
of normal newborns have sebaceous gland hyperplasia (Fig. 107-2). Tiny (<1-mm) yellow macules or
papules are seen at the opening of each pilosebaceous
follicle over the nose and cheeks of term newborns. It
is a benign condition that clears spontaneously by 46
months of age.
Erythema Toxicum Neonatorum. Erythema

toxicum neonatorum (ETN) is an idiopathic, common
condition seen in up to 75% of term newborns. It is
rarely seen in premature infants. Blotchy erythematous macules 13 cm in diameter with a 14-mm
Figure 107-3 Erythema toxicum neonatorum. Erythematous macules, some with a tiny central papule or pustule,
on the arm of a 1-day-old newborn.
c entral vesicle or pustule are seen in ETN (Fig.107-3).

They usually begin at 2448 hours of age, but delayed
eruption as late as 10 days of age has been documented.15 These follicular-based lesions can be located
anywhere but tend to spare the palms and soles. A
smear of the central vesicle or pustule contents will
reveal numerous eosinophils on Wright-stained preparations. A peripheral blood eosinophilia of up to
20% may be associated, particularly in infants, with
numerous lesions. Transient neonatal pustular melanosis (TNPM) lesions conrail neutrophils rather than
eosinophils, and individual lesions heal with residual
pigmentation, which is not seen in ETN. Bacterial
infections, Pityrosporum folliculitis, and congenital
candidiasis also may mimic ETN. Bacterial and fungal
culture of lesions and Gram staining will help differentiate among these entities. ETN is benign and clears
spontaneously by 23 weeks of age without residua.
Transient Neonatal Pustular Melanosis.
1188
Figure 107-2 Sebaceous hyperplasia on the nose of a

1-day-old infant.
TNPM is an idiopathic pustular eruption of the newborn that heals with tiny brown-pigmented macules
(Fig.107-4). It is less common than ETN and is more
prevalent among newborns with darkly pigmented
skin. Lesions are usually present at birth or shortly
thereafter, but may appear as late as 3 weeks of age,
as superficial vesicles and pustules, with ruptured
lesions evident as collarettes of scale. Pigmented macules are also often present at birth or develop at the
sites of resolving pustules or vesicles within hours or
during the first day of life; occasionally babies are born
with the tiny melanocytic macules, suggesting in utero
vesiculation. Lesions can occur anywhere but are common on the forehead and mandibular area. The palms
and soles may be involved. Smear of the vesicle or
19
Chapter 107
::
Figure 107-4 Transient neonatal pustular melanosis. A. A newborn with congenital, thin-walled pustules that rupture
easily. B. Hyperpigmented macules appeared by 10 hours of age.
pustule contents will reveal a predominance of neutrophils with occasional eosinophils on Wright-stained
preparations.16
Miliaria rubra is frequently confused with ETN and
TNPM. The erythema around miliaria rubra is small in
area (12 mm versus 2030 mm in ETN). The central
pustule of TNPM may mimic congenital candidiasis,
Pityrosporum folliculitis, or bacterial folliculitis lesions.
Herpes simplex should be considered if lesions are
vesicular. A Gram-stained slide of the pustules of ETN
or TNPM will not show organisms. A Wright-stained
slide usually will show a predominance of neutrophils. TNPM is a harmless condition that requires no
treatment. The pustules usually disappear within 57
days of age, leaving residual pigmented macules that
resolve over 3 weeks to 3 months.
Mottling. Mottling is a blotchy or lace-like pattern of

dusky erythema over the extremities and trunk of neonates that occurs with exposure to cold air. Virtually all
babies demonstrate mottling at some time during the
newborn period due to immaturity of the autonomic
control of the cutaneous vascular plexus. This physiologic mottling disappears on rewarming, differentiating it from cutis marmorata telangiectatica congenita
and livedo reticularis. Normal mottling resolves spontaneously by 6 months of age.
Harlequin Color Change.
Harlequin color
change is a rare vascular phenomenon occurring in
low-birthweight infants. When the infant is placed on
one side, an erythematous flush with a sharp demarcation at the midline develops on the dependent side,
and the upper half of the body becomes pale. The color
change usually subsides within a few seconds of placing the baby in the supine position but may persist for
as long as 20 minutes. The exact mechanism of this

unusual phenomenon is not known, but it may be due
to immaturity of autonomic vasomotor control. Harlequin color change is seldom seen after 10 days of age.
Sucking Blisters. Sucking blisters may be present at
birth as the result of intrauterine sucking, but are more

commonly seen during the first weeks of life. Sucking
blisters are usually solitary, intact oval or linear blisters, erosions, or drying crusts, arising on noninflamed
skin of the dorsal-radial aspect of forearms, wrists,
or fingers or on the upper lip. They resolve within a
few days. If the affected extremity is brought up to the
infants mouth, the infant will often commence sucking at the site, confirming the diagnosis. Herpesvirus
infection is often considered when sucking blisters are
encountered, but lesions of Herpes simplex infection are
grouped vesicles occurring on an erythematous base
or punched out, hemorrhagic erosions.
Benign Cephalic Pustulosis.
Neonatal acneiform facial lesions usually develop within the first

30 days of life and are estimated to occur in 50% of
newborns (Fig.107-5). This benign eruption appears
to be hormonally mediated (see Chapter 80) and has
been attributed to overgrowth of Malassezia sp., and
termed benign neonatal cephalic pustulosis.17 Most
cases resolve spontaneously, but the eruption can be
treated topically with ketoconazole, benzoyl peroxide, or erythromycin. True neonatal acne is probably
much less common than benign cephalic pustulosis
and can be distinguished by the presence of comedonal lesions. Similarly, infantile acne usually shows
true comedones, sometimes with papules, pustules,
and even cysts. An example of infantile acne is seen
in Figure107-6.
1189
19
Alopecia Areata.
Section 19
Alopecia areata occurs in all

ages (see Chapter 88). All forms of alopecia areata
occur in infants and children (patchy, universalis,
etc.), with the same disease presentation and treatment challenges as in adults. Onset at younger than 2
years of age is estimated to occur in 1%2% of alopecia
areata patients; however, it may be under-recognized
and more common. Several cases of congenital alopecia areata have been documented. Early onset is considered to be a poor prognostic marker. Total alopecia
during the first year of life after having hair at birth
should be distinguished from genetic disorders, such
as congenital atrichia with papular lesions and vitamin D resistance.
Figure 107-5 Benign cephalic pustulosis. Tiny papulopustules on the cheeks of a 3-week-old infant.
::
HAIR LOSS IN THE INFANT18

Telogen Effluvium. Telogen
effluvium occurs
frequently in newborns and is often overlooked. The
hair loss may be gradual or sudden, and may occur as
soon as the first few days of life, with the telogen hairs
shed by 34 months of age. No treatment is indicated
as spontaneous resolution is the rule.
A transient circumscribed patch of nonscarring alopecia develops at the occiput in many infants. Thought
to be due to a combination of physiologic telogen effluvium and localized pressure from lying in the supine
position, occipital alopecia spontaneously resolves.
Triangular Temporal Alopecia.
Triangular
temporal alopecia is a form of nonscarring hair loss
noted at 25 years of age as a triangular-, oval-, or
lancet-shaped area of alopecia at the frontotemporal
scalp. Often, a thin row of hair separates the affected
area from the forehead. The terminal hairs are replaced
by vellus hair. The condition is often mistaken for alopecia areata; however, distinguishing features include
the typical location and shape, the presence of vellus
hairs, and the absence of exclamation point hairs or histologic findings of alopecia areata. There is no known
treatment, and the condition persists unchanged.
However, triangular temporal alopecia is benign and
will not expand.
1190
Figure 107-6 Infantile acne. True comedones and inflammatory papules are noted on the cheeks of a healthy
10-month-old girl.
Tinea Capitis. Tinea capitis can occur at any age,

including infancy (see Chapter 188). Hair loss associated with scaling, broken hairs, pustules, or black dots
should prompt a potassium hydroxide scraping and
fungal culture to confirm the diagnosis. Just as in older
children, Trichophyton tonsurans is the most common
dermatophyte, and oral griseofulvin is the treatment
of choice. Tinea capitis and fungal infections are discussed in Chapter 188.
BIRTHMARKS. Birthmarks represent an excess of
one or more of the normal components of skin per unit
area: blood vessels, lymph vessels, pigment cells, hair
follicles, sebaceous glands, epidermis, smooth muscle,
collagen, or elastin. Although most birthmarks are of
little medical or psychosocial consequence, the social
and cultural impact of a disfiguring birthmark should
not be underestimated, from both the patients and the
parents perspectives.19 The age-old theory of maternal
imprinting is still widely accepted in many countries,
including the United States, and the mother may be
subtly or actively blamed for congenital conditions in
the newborn. With selective photothermolysis offered
by lasers and advances in surgical and topical therapies, therapeutic options are increasing.
The two most common birthmarks are the nevus
simplex (see Chapter 172) and Mongolian spots (see
Chapter 122). Nevus simplex (also known as salmon
patch, nevus flammeus, angels kiss, or stork bite) represents a capillary malformation of the skin. It occurs
most commonly on the glabella, upper eyelids, and
nuchal area. Nevus simplex appears with high frequency in all races, occurring in 70% of white infants
and 59% of black infants. Mongolian spots, which represent collections of dermal melanocytes, are seen in
80%90% of infants of color but in only 5% of white
infants.20,21 Solitary caf-au-lait macules are extremely
common and benign, however, the appearance of multiple caf-au-lait macules raises the possibility of neurofibromatosis type 1 (see Chapter 141). Other common birthmarks are listed in Table 107-2.
HEMANGIOMAS. Infantile hemangiomas are the
most common tumors of infancy. They must be differentiated from vascular malformations and other vascular anomalies. Hemangiomas are discussed in detail
in Chapter 126.
TABLE 107-2
Common Birthmarks in the Newborn

Mongolian spots
Nevus simplex (nevus flammeus, salmon patch, stork bite,
angels kiss)
Port-wine stain
Hemangioma of infancy (infantile hemangioma)
Epidermal nevus, including nevus sebaceus
Congenital nevocellular nevi
Congenital melanocytic nevi
Nevus depigmentosus
Caf-au-lait spots
Cutis Marmorata Telangiectatica Congenita. Cutis marmorata telangiectatica congenita
is characterized by persistent coarse cutis marmorata,

telangiectasia, and sometimes associated underlying
cutaneous atrophy and ulceration (Fig.107-7). Its incidence is sporadic, and its etiology is obscure. Theories of vascular malformation are currently favored.
Diagnosis is usually evident on clinical examination.
Usually a lower extremity is involved, but location
on the trunk or upper extremity is not uncommon. A
multitude of associated anomalies can occur, including
limb asymmetry, hemangiomas, other vascular birthmarks, pigmented nevi, and aplasia cutis congenita
(ACC). However, the majority of patients have a good
cussed in the following sections. Table 107-3 lists

differential diagnoses for selected cutaneous conditions encountered in neonates and infants.
Pustules
Transient neonatal pustular melanosis
Congenital candidiasis
Pustular psoriasis
Neonatal cephalic pustulosis
Bacterial sepsis
Blisters
Sucking blisters
Aplasia cutis congenital
Cutaneous mastocytosis
Neonatal pemphigus
Varicella
Impetigo
Epidermolytic ichthyosis
The red scaly baby
Physiologic scaling and redness (postdates) infant
Psoriasis
Atopic dermatitis
Scabies
Immunodeficiency
Hypohidrotic ectodermal dysplasia
Netherton syndrome
The collodion baby
Lamellar ichthyosis
Congenital ichthyosiform erythroderma
Gaucher syndrome
X-linked ichthyosis
Epidermolytic ichthyosis
::
UNCOMMON DERMATOSES OF THE NEONATE. Selected dermatoses of the neonate are dis-
Selected Differential Diagnosis of Neonates

and Infants
Chapter 107
LYMPHANGIOMAS. Both types of lymphatic malformations, microcystic (lymphangiomas) and macrocystic (cystic hygromas), are discussed in Chapter 172.
TABLE 107-3
19
The blueberry muffin baby

TORCH infections
Congenital leukemia
Congenital self-healing reticulohistiocytosis
Blue rubber bleb nevus syndrome
Twin-twin transfusion
TORCH = toxoplasmosis, other agents, especially syphilis, but

also hepatitis B, coxsackie virus, Epstein-Barr virus, varicellazoster virus, and human parvovirus, rubella, cytomegalovirus,
herpes simplex virus.
rognosis, with half demonstrating improvement of

p
the mottled appearance over the first 2 years.22
Subcutaneous Fat Necrosis of the Newborn.
Figure 107-7 Cutis marmorata telangiectatica congenita.

Note the atrophic, dusky, stellate patches with overlying
telangiectasias.
Subcutaneous fat necrosis of the newborn is characterized by firm, circumscribed, reddish or purple subcutaneous nodules or plaques that appear over the back,
cheeks, buttocks, arms, and thighs (Fig.107-8; see Chapter 70). The lesions usually begin within the first 2 weeks
of life and resolve spontaneously over several weeks.23
1191
19
Aplasia Cutis Congenita (ACC). ACC represents
Section 19
::
Figure 107-8 Subcutaneous fat necrosis of the newborn.

This infant developed an erythematous firm mass on the
back by 2 weeks of age. She later developed hypercalcemia.
Sclerema Neonatorum. Sclerema is diffuse hard-
ening of the skin in a sick premature newborn that is

now rare because of improved neonatal care. The onset
is characteristically after 24 hours of age. The skin feels
hard and immobile and looks yellow and shiny. The
trunk is always involved. Severely ill premature newborns that have suffered sepsis, hypoglycemia, metabolic acidosis, or other severe metabolic abnormalities
are at risk. Biopsy sections show edema of fibrous
septa surrounding fat lobules, but no fat necrosis, differentiating it from subcutaneous fat necrosis of the
newborn. The etiology of this rare condition is unclear,
and infant mortality is high.
1192
a failure of skin to fully develop, most often on the scalp,

and less commonly elsewhere (Fig.107-9). It is often an
isolated finding, but a multitude of associated conditions have been described. ACC has no single underlying cause. Some cases may represent a forme fruste of a
neural tube defect.24 In the most common form of ACC,
oval, sharply marginated atrophic macules are seen on
the midline of the posterior scalp. They are usually solitary, but may be multiple. Aplasia cutis is always hairless, and may appear vesicular, ulcerated, or covered by
a thin epithelial membrane. When healed, lesions are
usually atrophic scars, but sometimes develop a keloidal scar. Epidermis, dermis, and fat all may be missing, or a single layer may be absent. Lesions may range
from a few millimeters to many centimeters in diameter.
Lesions at birth of epidermolysis bullosa (see Chapter
62) may resemble ACC, especially on one or both legs.
Scalp ulcers at birth of aplasia cutis may be mistaken
for obstetric trauma. Other forms of congenital circumscribed hair loss should be considered. Midline blisters
or erosions should not be biopsied, scraped for herpes cultures, or otherwise traumatized. After a careful
examination to rule out associated malformations, ACC
is treated conservatively to allow healing. Surgical revision of the scar later in childhood or adolescence can be
done electively to improve cosmesis.
Hair Collar Sign. The hair collar sign is a ring of

darker and/or coarser terminal hairs on the scalp, typically surrounding ACC, dermoid cyst, encephalocele,
meningocele, or heterotopic brain tissue.25 The hair collar sign itself is a marker of cranial dysraphism and its
presence, like aplasia cutis, mandates careful examination of the infant, particularly of midline structures
and fusion planes.
Anetoderma of Prematurity. A specific form
of iatrogenic anetoderma (see Chapter 67) has been
described in extremely premature infants (born at
2430 weeks gestation) with very low birthweight and
prolonged neonatal intensive care hospitalization.26
Figure 107-9 Two infants with aplasia cutis congenita. A. Scalp erosions grouped at the vertex scalp. Scraping or biopsy
is contraindicated. B. An atrophic, well-circumscribed round patch with visible capillaries on the scalp of an infant. (A used
with permission from 1991 Yale Resident Photograph Collection.)
INFECTIONS OF THE NEONATE
Staphylococcal infections
Impetigo
Staphylococcal scalded-skin syndrome
Omphalitis
Breast abscess (usually due to Staphylococcus aureus and
Gram-negative organisms)
Viral infections
Varicella
Fungal/candidal infections
Scabies
NEONATAL HERPES SIMPLEX VIRUS INFECTION. (See Chapter 193.) It is estimated that untreated
neonatal herpes simplex virus (HSV) has a 50% mortality rate, with three-fourths of survivors suffering neurologic sequelae. The greatest risk of neonatal herpes
occurs when the delivery is vaginal and the mother has
primary genital herpes (as opposed to recurrent herpes, in which the mother has antibodies protective to
the neonate), the herpes infection involves the cervix,
and the infant is premature and delivered with instrumentation (e.g., scalp electrodes).
The vast majority of cases are due to HSV type 2. The
typical lesions of herpes are present in the skin, eye,
or mouth in a large majority of infected neonates, but
some patients with CNS or disseminated disease never
have skin lesions (Fig.107-10).28 Vesicles present during the first 24 hours of life suggest in utero acquisition of HSV, but onset during the first week to 10 days
of life is more common, representing exposure to the
virus during the delivery.28
A high index of suspicion should be maintained
even in the absence of maternal infection or history
of genital herpes. Specimens for Tzanck smear, direct
CONGENITAL VIRAL INFECTION. Petechiae,

purpura, jaundice, hepatomegaly, splenomegaly,
microcephaly, encephalopathy, ocular abnormalities,
anemia, thrombocytopenia, conjugated hyperbilirubinemia, or elevated serum hepatic transaminases should
prompt the consideration of congenital viral infection,
particularly if these signs arise in combination. Cutaneous infections of the neonate are listed in Table 107-4.
Bacterial infections, such as staphylococcal scalded
skin syndrome; and viral infections, such as varicella,
are discussed in Chapters 193 and 194.
Selected Cutaneous Infections in the Neonate
::
Infants younger than the age of 2 months are less

able to localize infection due to immature immunologic function, and life-threatening sepsis can develop
insidiously. Subtle clues such as a decrease in body
temperature, poor feeding, or other nonspecific signs
are taken seriously by the pediatrician, and a rule out
sepsis admission is implemented when suspicions are
high. At a minimum, blood, cerebrospinal fluid, and
urine cultures are obtained, and intravenous antibiotic
therapy begun pending cultures.
TABLE 107-4
19
Chapter 107
A retrospective review of 11 cases noted the appearance of round, flat atrophic patches on the chest and
abdomen (including the periumbilical region), developing at age 6 weeks to 5 months. Eight patients had
lesions at sites where adhesive monitoring leads had
been removed, and five patients had circular ecchymotic patches from removal of adhesive monitoring
leads prior to the occurrence of the anetoderma. The
anetoderma did not improve with time. One child
underwent surgical excision of the disfiguring lesions
at age 7 years. Given the presumed relationship of the
development of anetoderma and skin trauma mainly
from adhesive leads, avoidance of pressure (e.g., placing leads on the ventral chest when the infant slept on
the back) markedly reduced the risk of occurrence.27
Figure 107-10 A and B. Herpes simplex infection in two infants. Grouped vesicles on an erythematous base. Pustules and
erosions are also present. (A used with permission from Alvin H. Jacobs, MD.)
1193
19
fluorescent antibody assays, and/or viral cultures

for HSV should be obtained. Cultures require 12120
hours to grow, and in all infected or suspected neonates, cultures of skin lesions, urine, nasopharynx,
eyes, and cerebrospinal fluid are indicated. If available,
a polymerase chain reaction test can be very helpful in
rapid diagnosis. Intravenous acyclovir should be instituted as soon as possible after specimens are collected
to minimize the chance of replication of virus in the
CNS and systemic dissemination of HSV. Prompt recognition and early therapeutic intervention lead to an
improved outcome in the HSV-infected infant.28
Section 19
CONGENITAL MALFORMATIONS
OF THE SKIN
::
Figure 107-11 Supernumerary digit, a common minor

malformation.
MINOR ANOMALIES. Congenital malformations

are developmental defects and are frequently observed

A
1194
Figure 107-12 A and B. Nasal glioma initially thought to be a hemangioma of infancy. A firm, reddish slightly pedunculated was noted
off of the midline of the nasal root. The MRI showed no intracranial
connection. C. Nasal glioma. Firm subcutaneous mass noted at birth.
in newborns. Single minor anomalies occur in approximately 15% of all newborns and are, by definition, of
no functional significance. The supernumerary digit
(Fig.107-11), supernumerary nipple and the accessory
tragus are common examples of minor malformations.
The occurrence of two is less common, however, and
the presence of three or more is unusual; a complete
thorough physical examination is indicated to rule out
other congenital abnormalities.29,30
CUTANEOUS MARKERS OF DYSRAPHISM.
TABLE 107-5
Congenital Lumbosacral Midline Skin Lesions

and Risk of Occult Spinal Dysraphism
Risk of
Occult Spinal
Dysraphism
Congenital Lumbosacral
Midline Lesion
Intermediate
Group 2: Ultrasound if younger than

age 4 month (then MRI if ultrasound
is abnormal), MRI indicated for age
>4 month, or if sonographic expertise
unavailable
Atypical sacral dimple (deep, farther
than 2.5 cm from the anus, size
5 mm)
Unclassified hamartoma
Aplasia cutis congenita
Deviation of gluteal crease
Low
Group 3: No imaging needed

Port-wine stain
Hypertrichosis (unless large and/or
unusual)
Pigmented nevus
Simple sacral dimple (<5-mm
diameter, 2.5 cm or closer to the
anus)
Mongolian spot
MRI = magnetic resonance imaging.

Adapted from Guggisberg D et al: Skin markers of occult spinal dysraphism in children: A review of 54 cases. Arch Dermatol 140:1109,
2004, with permission.
Group 1: MRI indicated

Two or more lesions of any kind
One lesion + spinal cord dysfunction
Lipoma
Tail
Dermal sinus
::
High
Chapter 107
The skin and the nervous system are both derived

from the ectoderm. The neural ectoderm separates
from the epithelial ectoderm during the third to fifth
week of gestation, occurring simultaneously with the
formation and closure of the neural tube. Hence, errors
in neural tube development [i.e., dysraphism (incomplete fusion)] can be associated with cutaneous lesions.
Midline facial lesions, such as dermoid cysts, nasal gliomas (Fig.107-12), and ACC (Fig.107-9), can be markers of cranial dysraphism, whereas cutaneous lesions
seen on the lumbosacral midline can signify underlying spinal dysraphism (Fig. 107-13). Imaging studies
should be considered for midline nasal lesions before
biopsy to rule out intracranial connections.31
A retrospective review of 54 cases of congenital
lumbosacral skin lesions (including deviated gluteal
cleft)32 demonstrated that the highest risk of occult
spinal dysraphism occurs with the presence of two or
more congenital midline lumbosacral skin lesions, or
if spinal cord dysfunction exists in the presence of one
lumbar skin lesion. In addition, lumbosacral lipoma,
human tail, and dermal sinus (as isolated findings)
were highly associated with occult spinal dysraphism.
Lumbosacral magnetic resonance imaging is indicated
when these high-risk congenital lesions are present.
An intermediate risk of occult spinal dysraphism was
associated with atypical sacral dimple (5-mm diameter, or location 2.5 cm away from the anus), ACC,
overlying hamartoma, or deviated gluteal cleft. In
the presence of any of these lesions, ultrasound can
be used to screen for occult spinal dysraphism if the
infant is less than 4 months of age. If the infant is older,
magnetic resonance imaging is needed to rule out dysraphism. Low-risk lesions that do not require imaging
include isolated lumbosacral hemangioma, port-wine
stain, focal, mild hypertrichosis, pigmented nevus,
19
Mongolian spot, or simple sacral dimple (5-mm

diameter and location 2.5 cm or closer to the anus).32
These findings are summarized in Table 107-5.
INFANCY AND CHILDHOOD

EVALUATION TECHNIQUES
Figure 107-13 A large, wide tuft of thick terminal hair on

the lumbosacral spine noted at birth. She had underlying
tethered cord (note midline scar due to surgical repair).
Observing the play of a child allows for a quick assessment of his or her neurologic development. Interactions between caregivers and child are also informative. Early prolonged or intense eye contact with the
young child should be avoided because this can be
threatening to the child. If an elective biopsy or procedure is needed, it is often more acceptable for the parent (especially if a neonate) or child if the procedure is
scheduled for a second visit rather than the initial one.
If a language barrier exists between the parents and
physician, one should resist the urge to have the bilingual patient serve as interpreter for the parents. This
1195
19
Section 19
::
1196
practice places an inappropriate burden of responsibility on the child and may increase fear and anxiety in
the child. In addition, inaccurate transmission of information may occur.
Examination of young children may be performed
with the child on the parents lap or while playing with
toys on the examination table. If needed, examination
of the perineum and genitalia can be accomplished
with the child in the knee-chest position on the examination table (eFig.107-13.1 in online edition) or the parents lap. Alternatively, the child may sit on the parents lap with legs held apart by the parent. eFig.10713.2 in online edition illustrates anatomic terminology
of the young female genitalia for accurate documentation, and can be helpful in conditions such as lichen
sclerosus. Caution must be used in interpreting the
genital examination in the young female so as not to
underdiagnose or overdiagnose disease or abuse. For
example, the presence of labia minora adhesions is not
diagnostic of trauma or abuse because they occur in as
many as one-third of girls who are not abused.33 The
diastasis ani is a normal structure that can be mistaken
for perianal scarring.34 The infantile perianal pyramidal protrusion may be mistaken for condyloma acuminata but is a harmless normal finding (discussed later
in this chapter in Infantile Perineal Protrusion).35,36
Child abuse is discussed in Chapter 106.
PERFORMING PROCEDURES ON THE

YOUNG CHILD
Historically, there has been a widespread reluctance to
biopsy skin lesions in infants and children. This often
leads to a delay in diagnosis in conditions such as
childhood melanoma, for example. In addition, many
skin conditions in children have a paucity of dermatopathologic information in the literature due to this
reluctance. Parents may be anxious about causing pain
or scarring, and children may be fearful because of
their experience with immunizations, or an age-appropriate fear of bodily mutilation. However, with proper
preparation of the parent and child, skin biopsies and
other outpatient procedures are easily performed (see
Table 107-6). Note that there are certain situations in
which a biopsy can be detrimental; examples of these
biopsy pitfalls are outlined in Table 107-7.
Eutectic mixtures of lidocaine and prilocaine (EMLA
cream) or lidocaine alone (LMX cream) are useful in
minimizing the pain of intralesional injections or
local anesthetic injections for biopsies. As EMLA use
has become widespread, reports of toxicity in children have appeared, including methemoglobinemia
and seizures. The maximum dose, body surface area
exposed to drug, and application time should not be
exceeded; these parameters are age dependent and are
1 g for 13 month old, 2 g for a 312 month old, 10 g
for a 16 year old, and 20 g was a 712 year old.40 The
application of ice or anesthetic cryospray is another
option to numb the skin before injections.
Before and during procedures, young infants can be
soothed with a pacifier dipped in a sucrose solution. A
randomized, controlled, double-blinded study of 201
TABLE 107-6
The ABCs of Successful Outpatient Procedures

in Pediatric Dermatology
A:Anesthesia techniques: EMLA or ice prior to injection,
buffer the lidocaine, apply vibration next to injection site,
and infuse slowly. Appointment times in the morning are
best for procedures on young children. If they are tired
they are less able to focus and cooperate.
B:Blood: keep bloody gauze and instruments out of sight of
patient and parents.
C:Calm parents = calm child. Consent by parents is required
if patient is a minor.
D:Distraction techniques are essential: MP3 player, DVD player,
Where is Waldo? books, and I-Spy books are all very helpful.
E:Expedite the procedure by preparing all instruments and
materials before starting.
F:Four hands (minimum) are neededhave at least one
assistant to help, preferably not the parent.
G:Go to a day surgery setting if patient is unable to
participate in local anesthesia due to patients age or
abilities.
H:Hovering parentskeep them seated and calm, with
surgical site out of view.
I: Invest the time, do not rush.
newborns found that orally administered glucose solution was superior to topical EMLA cream in reducing
pain with venipuncture.41 Infants may be swaddled
with a blanket for comfort and immobilization. The
young child can be effectively immobilized and comforted with a restraining hug, by a parent or assistant. Distraction techniques are invaluable as well. For
example, instructing the child to blow a colorful toy
windmill, blow soap bubbles, or wiggle his or her
toes during an injection or procedure helps to decrease
pain. Older children may be effectively soothed by
listening to music with headphones or by watching a
movie during procedures.
Alkalinizing local anesthetics to a pH of 7.0
(0.1 mEq/mL sodium bicarbonate or a 1:10 bicarbonateanesthetic ratio by volume) minimizes the pain
of cutaneous infiltration without limiting anesthetic
effects.42 Alkalinization decreases the solutions shelf
life to approximately 1 week 43 due to more rapid oxidation of epinephrine. Warming lidocaine also lessens the pain of injection.42
Vibrational motions applied with the surgeons nondominant hand adjacent to injection site and infiltrating slowly are additional helpful techniques to reduce
the pain of injection of anesthetic.
Instruments and materials should be laid out ahead
of time to ensure rapid performance of the procedure,
and are less frightening if kept out of sight by covering
with a drape. Needles, instruments, and blood-stained
gauze should be kept out of view and out of reach of
the patient.
Children sense their parents anxiety and nervous energy. Parents who are overly anxious can be
asked to sit farther away from the operating table, or
sometimes are best positioned outside the procedure
room.
19
TABLE 107-7
Biopsy Pitfalls in Pediatric Dermatology

Diagnosis
Danger
Proper Management
Newborn
Erosion or vesicle on
the scalp
Aplasia cutis congenita

Differential diagnosis:
herpes, fetal scalp
electrode trauma
Possible intracranial
connection, risk of
meningitis with biopsy
or scraping
Protect site; do not scrape

lesion or biopsy, consider
ultrasound or MRI of head
if a typical
Infant
Hair collar sign

surrounding lesion on
scalp or midline lesion
Encephalocele,
spina bifida occulta,
meningomyelocele
connection; risk of
meningitis
Preoperative imaging;
consider neurosurgical
consultation
Infant
Tuft of hair over midline

spine
Spina bifida occulta,

meningomyelocele
connection; risk of
meningitis
Preoperative imaging;
consider neurosurgical
consultation
Infant
Preauricular tag
Accessory tragus
Risk of chondritis if
removed by shave
or snip excision or if
ligated with suture37
Appropriate closure when

excised, if cartilaginous
component present
Infant or child
Mass along midline

scalp, glabella, side
of forehead, or other
embryonic fusion plane
Dermoid cyst
Intracranial connection
in up to 25% for midline
dermoids; risk is higher
if sinus present38;
dermoids near the
lateral eyebrows rarely
have intracranial
connections39
Consider MRI and

neurosurgical consultation
Infant, young child
Nasal midline mass
Nasal glioma,
encephalocele, or
other dysraphic state
hypertelorism,
hemangioma
Intracranial
connection in 100%
of encephaloceles;
gliomas may extend
into oropharynx
or have intranasal
connections38
Consider MRI and

neurosurgical consultation
Infant, young child
Vascular mass with

greatly increased
warmth, often with
pulsation or bruit
Arteriovenous
malformation
hemangioma
Uncontrolled bleeding,
problematic bony or
soft tissue hypertrophy
Consider Doppler
studies, MRI, and surgical
consultation
::
Lesion and Site
DISEASES OF INFANCY AND

CHILDHOOD
INFANTILE PERINEAL PROTRUSION. Also
known as infantile pyramidal protrusion, infantile
perineal protrusion (IPP) is a benign condition that
occurs almost exclusively in female prepubertal girls.
It appears as a pyramidal, soft-tissue, tongue-like,
smooth, or velvety pink protrusion. It is usually
located in the midline just anterior to the anus. IPP is
usually asymptomatic, but painful defecation has been
reported. It occurs in three settings: constitutional,
MRI = magnetic resonance imaging.
The use of general anesthesia for dermatologic

procedures in healthy pediatric patients is very safe
when properly performed. Fears of general anesthesia
should not be a barrier to delivering necessary surgical
or laser procedures to healthy children.44
Chapter 107
Age Group
functional (after constipation, diarrhea, or other irritant exposure), or associated with lichen sclerosus et
atrophicus. Often, IPP is misdiagnosed as condyloma
acuminatum, hemorrhoids, or as a sign of trauma.
Conservative management is indicated. Spontaneous
resolution as well as resolution following high-fiber
diet to relieve constipation has been noted.35,36
DIAPER DERMATITIS. Diaper dermatitis, like

hand dermatitis, denotes a group of region-specific
dermatoses. Diaper dermatitis is one of the most common dermatologic conditions in infants and children,
noted in approximately 1 million pediatric outpatient
visits each year.45 With the advent of superabsorbent
disposable diapers in the last decade, severe forms of
diaper dermatitis have diminished in incidence. Irritant and candidal diaper dermatitis comprises the vast
majority of diaper dermatitides in diaper-wearing
individuals of all ages.
1197
19
The etiology of diaper dermatitis is multifactorial.

The initiating factor is prolonged and increased wetness to the skin. This leads to increased frictional damage, decreased barrier function, and increased reactivity
to irritants. Other interrelated etiologic factors include
contact with urine and feces, fecal proteolytic and lipolytic digestive enzymes, increased skin pH, and superinfection with Candida and, less commonly, bacteria.46
Section 19
Irritant Diaper Dermatitis. By far the most common type of diaper dermatitis is irritant diaper dermatitis. This dermatitis occurs in any person who wears
diapers, regardless of age. Irritant diaper dermatitis
appears as erythematous, moist, and sometimes scaly
patches on the convexities of the genitalia and buttocks, beginning in areas in closest contact with the
diaper. Shallow erosions are sometimes present on the
convex surfaces. It can be asymptomatic or tender.
::
Candida Diaper Dermatitis. (See Chapter

189). Candida diaper dermatitis is the second most
common type of diaper dermatitis and presents with
bright red erythematous, moist papules, patches,
and plaques that tend to involve body folds as well
as convex surfaces. Satellite lesions are very characteristic. Oral thrush can be associated. Candida from
intestinal flora frequently contaminates any type of
diaper dermatitis present for greater than 3 days, and
Candida levels increase with the clinical severity of
the dermatitis.47
Miliaria Rubra (Heat Rash).
(See Chapter
84.) Miliaria rubra tends to occur at sites where plastic
components of the diaper cause occlusion of eccrine
ducts of the skin. It is also seen in the folds of the neck
and upper torso, and is particularly common when
there is a rapid shift to warm weather, and the child is
overdressed.
Granuloma Gluteale Infantum.
Granuloma
gluteale infantum is an uncommon condition characterized by reddish purplish nodules of different sizes
(0.53.0 cm) occurring on the convexities of the diaper
area in 2- to 9-month-old infants. It arises within preexisting diaper dermatitis. Biopsy shows dense dermal
infiltrates of lymphocytes, plasma cells, neutrophils,
and eosinophils, but no true granulomas. It appears to
be an unusual reaction to the usual irritant factors, candidal infection, and, in some cases, topical steroid use
in the diaper region.49 Treatment consists of avoidance
of irritants, use of barrier pastes, and avoidance of topical steroids. Resolution occurs over several months.
Dermatoses Not Etiologically Related to

Diaper Wearing. Seborrheic dermatitis, atopic
dermatitis, psoriasis (Fig. 107-14), bullous impetigo,

acrodermatitis enteropathica, scabies, hand-foot-andmouth disease, herpes simplex infections, and Langerhans cell histiocytosis are conditions that occur in the
diaper region but are not primarily due to the wearing
of diapers and should be considered in the differential
diagnosis. Skin biopsy is indicated to rule out Langerhans cell histiocytosis (see Chapter 147) if nonhealing erosions or petechiae are seen in the diaper area
(Fig.107-15).
Treatment of Diaper Dermatitis. The treatment of diaper dermatitis is outlined in Table 107-8.50
Irritant diaper dermatitis and Candida diaper dermatitis (or a combination of both) comprise the vast
majority of diaper rashes. Candida is more likely to
complicate diaper rash if present for more than 3 days.
Education of parents and primary care physicians
should include instructions regarding the use of
topical steroids in the diaper area. Because of greatly
increased percutaneous absorption of steroids from
Pseudoverrucous Papules and Nodules.

Pseudoverrucous papules and nodules occur in the
diaper and perianal areas in patients of any age with
exposure to prolonged wetness. Children who wear
diapers due to chronic urinary incontinence are prone
to this type of dermatitis for example.
Infantile Granular Parakeratosis.
Infantile
granular parakeratosis represents an idiopathic form
of retention keratosis in diaper-wearing infants. There
are two clinical patterns: bilateral linear plaques in the
inguinal folds and erythematous geometric plaques
underlying pressure points from the diaper. A thick,
flake-like scale is present in both forms and is characteristic. Therapeutic responsiveness to topical agents
is ambiguous; however, spontaneous clearance after
months to 1 year appears to be the rule.48
1198
Jacquet Erosive Dermatitis. Jacquet erosive

dermatitis is an uncommon, severe diaper dermatitis
that can occur at any age. It is characterized by welldemarcated, punched-out ulcers, or erosions with elevated borders. Prolonged contact with urine and feces
under occlusion leads to this condition.49 It is seen less
commonly since the advent of superabsorbent disposable diapers.
TABLE 107-8
ABCs in the Treatment of Diaper Dermatitis

A = Air. The diaper should be left open as much as possible
when the infant sleeps to allow drying of the skin.
B = Barrier ointments. Zinc oxide pastes, petrolatum, and
other bland, unmedicated barrier preparations are
mainstays of therapy. A continuous layer of barrier paste
or ointment should be maintained, reapplying with every
diaper change, if necessary. Baby powder on the diaper
area offers no antimicrobial benefit to the infant and adds
a risk of aspiration.
C = Cleansing and anticandidal treatment. Gentle cleansing
with plain water, mineral oil, or unscented gentle cleanser
is recommended. Avoidance of friction or rubbing is
important. A topical anticandidal agent should be added
for any signs of candidiasis. Oral nystatin is indicated if oral
thrush is present.
D = Diapers. Diapers should be changed as frequently and as
soon after soiling as possible, especially if cloth diapers
are used.
E = Education of parents and caregivers.
Modified from Boiko S: Making rash decisions in the diaper area.
Pediatr Ann 29:50, 2000.
19
Chapter 107
moisture and occlusion from diapers, topical steroid use in this anatomic region should be limited to
a short course (37 days) of hydrocortisone (1% or
2.5%) ointment. This is effective in nearly all cases
when a topical steroid is needed. Similarly, use of
the combination products containing steroids, such
as nystatin plus triamcinolone, and clotrimazole plus
betamethasone dipropionate, should be avoided
due to increased risks of steroid atrophy and
hypothalamicpituitary axis suppression when used
in the diaper area.
Last, parents will be reassured by the fact that even
the most problematic diaper dermatitis will resolve
when toilet training is achieved, and diapers are not

worn.
TINEA CAPITIS. (See Chapter 188.) Scrapings for

potassium hydroxide examination and fungal culture
should be obtained before administration of systemic
antifungal therapy. In children, collection of specimens
for tinea capitis may be accomplished by the use of
a toothbrush, ring curette, moistened cotton swab, a
scalpel, or by collection of infected hairs. Alternatively,
a media plate with nonslanted agar may be applied
directly to the infected areas of the scalp to collect
material.
Figure 107-14 A. Infantile psoriasis with involvement in the diaper region. B. Infantile psoriasis. This generalized eruption
responded well to topical steroids initially and topical tacrolimus later.
::
Figure 107-15 A and B. Langerhans cell histiocytosis with petechiae and erosions of the skin. This patient also had hepatosplenomegaly.
1199
19
ADOLESCENT DERMATOLOGY
Dermatologic diagnoses of adolescents overlap with
those of general adult dermatology; however, caring
effectively for the adolescent patient requires different
interviewing skills and strategies to enhance compliance.
EVALUATION TECHNIQUES
Section 19
::
Greeting the adolescent first and the parents second,

and interviewing the adolescent patient alone at the
beginning of the visit help to earn the patients trust.51
The confidentiality laws of each state should be considered and the patients right to privacy respected.
Many states protect the adolescents right to confidential medical care for problems such as drug abuse, sexually transmitted diseases, contraception, pregnancy,
and abortion.
The open-ended questioning style used for adults
frequently fails with adolescents. Phrasings using the
third person and giving choices when asking questions
are more effective techniques to obtain information. For
example, Many women on oral contraceptives forget
to take their pill once in a while. How often do you forget to take your birth control pills: often, sometimes, or
almost never? will yield a more accurate reply than,
Do you take your birth control pills every day?
Adolescents lack a well-developed sense of future
time and long-term consequences are less valued than
immediate outcomes. Goals should be concrete, short
term, and relevant to the present. Rather than using
goals related to more distant benefits, such as the reduction of potentially serious disease complications (e.g.,
smoking causes increased risk of lung cancer), emphasis should be placed on immediate and concrete effects
(e.g., smoking causes your clothes, hair, and breath to
smell bad and your teeth to turn yellow). Body image
is a more powerful motivator, and messages such as
tanning salons cause premature wrinkles and ugly
skin are more effective than future health concerns
(e.g., tanning salons increase your risk of skin cancer). Any treatment that is disfiguring or has visible
side effects will meet with resistance.51
Physical and psychosocial development may not be
congruent. An adolescent should not be expected to
shoulder all medical responsibilities for himself or herself or for younger siblings. The physicians role is not
to befriend, nor is it to parent the adolescent patient,
but rather it is to be a trusted, valuable authority.
ACNE AND THE ADOLESCENT
1200
(See Chapter 80.)

Acne vulgaris is an extremely common and variable
disorder that can have far-reaching detrimental effects
on self-image and self-esteem. Increased unemployment has been documented among patients with a
history of severe acne.52 For adolescents, a single- or
two-drug regimen will optimize compliance and costeffectiveness.
Females with treatment resistant acne, signs of virilization (including irregular menstrual cycles, hirsutism, and/or obesity) should have evaluation for
androgen excess states including polycystic ovary syndrome (see Chapters 80 and 151).
Several oral contraceptives (Yaz, Yazmin, and
Ortho-Tricyclen) have Food and Drug Administration (FDA) labeling for the treatment of acne and
are an important therapeutic option for adolescent
females with recalcitrant acne. The effectiveness of
oral contraceptives often allows discontinuation of
chronic oral antibiotic therapy. Patients should be
counseled that adherence to three cycles of oral contraceptives are often needed to establish treatment
efficacy for acne. Oral contraceptives with a higher
androgenic component and lower estrogenic component tend to worsen acne. Topical acne medications such as retinoids may need to be continued for
best results.
Isotretinoin has been a valuable, unique, and effective agent for nodulocystic acne since 1982. Isotretinoins teratogenicity is well known. The question
of psychopathology induced by isotretinoin is more
controversial. The Adverse Drug Event Reporting
System of the United States FDA has received reports
of depression, suicide, and other psychiatric side
effects (e.g., aggression, psychosis) in patients using
isotretinoin. The question of isotretinoin-induced
depression is complicated by the high baseline incidence of depression and suicide in the adolescent
population and by the depression and stress associated with severe acne.53,54 Case reports, including
positive cases of positive dechallenge and rechallenge, have suggested that isotretinoin may induce
depression and other psychiatric adverse effects, but
larger retrospective and prospective studies have not
demonstrated causation.55 In some studies, depression scores improved when patients acne improved
with isotretinoin therapy.56 Double-blind, placebocontrolled isotretinoin studies have not yet been
done. To date, animal studies have shown conflicting
results. Although a causal link has not been established between isotretinoin and depression/suicide
at this time, it is likely that uncommon idiosyncratic
psychiatric reactions to isotretinoin may occur in predisposed individuals. Pretreatment evaluation and, if
cleared to proceed, subsequent comanagement by a
psychiatrist or psychologist should be considered for
vulnerable patients. If mood changes arise, the drug
should be stopped until the patient is evaluated by
the pediatrician or psychiatrist. If deemed appropriate, a rechallenge can be done cautiously.
A second unanswered question is whether the
risk of inflammatory bowel disease increases with
isotretinoin use. Studies have shown conflicting
results thus far. It is possible that isotretinoin may
trigger inflammatory bowel disease in predisposed
individuals. Until we have better data, patients
and parents should be counseled that a rare but
potentially real risk might exist. If bowel symptoms
develop, discontinuation of isotretinoin is advisable
until the patient is evaluated by a gastroenterologist.57,58
AXILLARY HYPERHIDROSIS
Idiopathic focal hyperhidrosis is a common condition that
has been long been under recognized. Axillary hyperhidrosis is much more common but palmar and/or facial
sites can be affected as well. It can be familial or sporadic.
Although all ages may be affected, patients commonly
present during adolescence when the condition becomes
socially troubling and impacts significantly on quality of
life. The management of focal idiopathic hyperhidrosis
is similar to that of adults. If topical and oral treatments
fail, injection of botulinum toxin A should be considered.
Hyperhidrosis is reviewed in Chapter 84.
DRUG LABELING FOR PEDIATRIC

PATIENTS
The lack of FDA labeling for pediatric use does not
imply that a drug is contraindicated or disapproved;
SPECIAL TOPICS IN PEDIATRIC

DERMATOLOGY
::
The WHO Cancer Group has classified tanning beds

as carcinogenic to humans. Extensive evidence has
linked sunlamp or sun bed exposure to increased risk
of melanoma and nonmelanoma skin cancers. Nevertheless, approximately 50,000 tanning salons exist in the
United States and tanning bed use is increasing among
adolescents and young adults. In addition to the desire
for tanned skin and the socialization of the tanning salon,
some individuals feel more relaxed, and have improved
mood following tanning. Evidence is mounting that
tanning bed use is physiologically and psychologically
addictive. A study demonstrated that frequent tanners
developed a preference for functional UV beds compared to otherwise identical sham light beds.59 In addition, physiologic withdrawal symptoms arose in some
subjects who were given naltrexone prior to their tanning
sessions, suggesting that an opioid-mediated mechanism
of dependency may exist in frequent tanners.60
Psychiatric studies, using modified tools originally
used for substance abuse screening, confirm addictive behaviors of people who frequent tanning salons.
Among 229 college students who had used indoor tanning facilities, 90 (39.3%) met diagnostic and statistical manual of mental disorders IV-TR criteria and 70
(30.6%) met CAGE (Cut down, Annoyed, Guilty, Eyeopener) criteria for addiction to indoor tanning. In addition, these students also reported greater symptoms of
anxiety and greater use of alcohol, marijuana, and other
substances than those who did not meet these criteria.61
The fight against indoor tanning is becoming similar to the fight against the tobacco industries. Stronger
legislation banning tanning bed use in minors, control
of false safety claims in advertisements, and extensive education of parents and our youth are needed to
wage this war.
19
Chapter 107
INDOOR TANNING
it simply means that insufficient data are available to

grant approval status. Although attempts have been
made to equate off-label prescribing with recklessness
in the medical malpractice arena, the American Academy of Pediatrics has stated that failure to prescribe
medications for off-label uses when the medication
is appropriate under standard of care may constitute
malpractice.
The thalidomide tragedy (see Chapter 235) led to
more stringent regulation of drugs in the early 1960s,
and manufacturers began omitting drug studies in
infants and children. In the 1970s, pediatric dosage
information in package inserts tended to exclude children from therapeutic benefit. Performing research in
healthy children is problematic because of ethical and
logistic questions, medicolegal risk, and cost. It has
been estimated that approximately 50%75% of drugs
used in pediatrics have not been studied adequately to
provide accurate labeling information, and the younger
the patient, the more likely the lack of information.62
Safety and effectiveness information for drug use in
children under 2 years of age is particularly lacking.
The absence of pediatric testing and labeling poses significant safety risks for children. Additionally, children
may be denied the benefits from therapeutic advances
because physicians choose to prescribe existing, less
effective medications in the face of insufficient pediatric information about new medications. In 1997, as
part of the FDA Modernization Act, Congress enacted
a law known as the Pediatric Exclusivity Provision that
provides marketing incentives (i.e., 6 month extension
of patent protection) to manufacturers who conduct
studies of drugs in children. This law was effective
in generating pediatric studies on many drugs, and
an increase in labeling information has occurred for
some. Unfortunately, many studies have centered on
children greater than 6 years of age, and many drug
studies were stimulated by market concerns rather
than medical need.
Hopefully, with new incentives such as the Pediatric
Research Equity Act of 2003, significantly more pediatric drug research will proceed forward. Ideally in the
future, physicians caring for children will no longer
need to prescribe drugs off label, and children will
no longer be therapeutic orphans.
TOPICAL MEDICATIONS
While topical medications often have excellent safety
and efficacy profiles, one must be aware that infants
and young children are at increased risk for toxicity
from topically applied agents because of increased
surface area:body mass ratio compared to adults. In
addition, at times infants and children have altered
metabolism of drugs compared to adults. Patients with
disorders of cornification (e.g., lamellar ichthyosis) or
other forms of skin barrier disruption (e.g., Netherton
syndrome) have a much higher risk of toxicity due
to increased percutaneous absorption. Patients with
Netherton syndrome treated with topical tacrolimus
may develop immunosuppressive or toxic blood levels of tacrolimus, without clinical signs or symptoms
1201
19
TABLE 107-9
Topical Medications Reported to Cause Systemic Toxicity in Children

Complication
Reference
Tacrolimus 1% ointment
Three children with Netherton syndrome found to have blood levels of

tacrolimus in the range of organ transplant requirements
63
Hydrocortisone 1% ointment
Cushing syndrome developed in an 11-year-old boy with Netherton

syndrome receiving topical application to extensive areas for over one year
64
Benzocaine, 3% (Lanacane)
Methemoglobinemia in a 2-year-old child
65
Iodoquinol, clioquinol (Vioform)
Neurotoxicity when used as treatment for diaper dermatitis
66,67
Lindane
68,69
Section 19
Neurologic toxicity in children with disrupted epidermal barrier and/or

excessive topical application or ingestion
N, N-diethyl-m-toluamide (DEET)
Slurred speech, tremors, seizures, and death in children after repeated and
extensive application of high concentrations of DEET
70
Povidone-iodine (Betadine)
Hypothyroidism in infants with spina bifida
71
::
Povidone-iodine (Betadine)
Decreased free thyroxine and elevated iodine levels in infants treated with
diluted povidone-iodine during Staphylococcus aureus epidemic
72
Salicylic acid
In a 7-yr-old boy treated for ichthyosis vulgaris, life-threatening salicylism

occurred with neurologic sequelae lasting 6 month
73
Saline, sodium chloride
Fatalities in infants and children following ancient Turkish custom of salting
74
Viscous lidocaine, 2%
Lidocaine overdose following frequent application to oral lesions
75
Topical Medication
of toxicity.63 A heightened awareness of this problem is

important because Netherton syndrome is often misdiagnosed as atopic dermatitis, and both conditions
often improve with topical tacrolimus therapy. In addition, a patient with Netherton syndrome developed
Cushing syndrome after application of hydrocortisone
1% ointment for over 1 year.64 Examples of inadvertent
percutaneous poisoning from topical agents are listed
in Table 107-9.
SYSTEMIC MEDICATIONS
DRUG DOSAGES. Pediatric doses of systemic medications are calculated according to body weight (mg/
kg) or body surface area to account for size variations
between patients of the same age and to account for
a childs growth. Prescriptions for liquid medications
(syrups or suspensions) must indicate concentration
(e.g., milligrams per 5 mL, or teaspoon) to avoid serious
error. In addition, the appropriate measuring instrument should be dispensed, along with education on its
use. One study demonstrated that dosing cups (commonly provided in OTC childrens medications) were
associated with a large error in one in four doses
some of which were overdoses of 100%300%.76
For guidelines on indications and dosing of antimicrobials and other medications, the reader is directed
to excellent references including the Red Book77 published by the American Academy of Pediatrics, and
The Harriet Lane Handbook.78
1202
SYSTEMIC GLUCOCORTICOIDS. Hypothalamicpituitary axis suppression, osteonecrosis, and

other adverse effects of systemic glucocorticoid therapy
affect patients of all ages and are reviewed in Chapter

224. The potential risk of growth suppression is unique
to childhood. Exogenous glucocorticoids disrupt the
secretion of growth hormone (GH), causing abnormal
spontaneous GH secretion with reduced pulse amplitude of GH release and reduced response to provocative stimuli.79,80 There is also decreased local production
of insulin-like growth factor 1. These and other effects of
glucocorticoids act to cause delayed growth at the bony
epiphyses, with the most noticeable reduction in growth
velocity occurring during early childhood and adolescent growth spurts. There is a linear relation between
the daily dose and growth suppression. Alternate-day
dosing, with single morning doses, may decrease the
risk of glucocorticoid growth suppression. Most children will have adequate catch-up growth eventually
with reduction of doses, alternate-day therapy, or cessation of therapy.81 For the pediatric patient on long-term
systemic steroid therapy, charting height and weight on
a standardized growth curve is the best method for the
pediatrician to screen for decreasing growth velocity.
Children taking immunosuppressive doses of systemic glucocorticoids should not be vaccinated with
live-virus vaccines (e.g., measles, oral polio, varicella). A dosage equivalent to 2 mg/kg/day or greater
of prednisone or a total of 20 mg/day or greater for
children weighing more than 10 kg, when given for
more than 14 days, is sufficient to warrant withholding immunization with live-virus vaccines.82 Systemic
steroids should not be given to a healthy child if he
or she has had recent varicella exposure and is not
varicella-immune because varicella infection can be
fatal in this situation. In addition, children with ocular herpes simplex and untreated tuberculosis should
not be given systemic steroids, and patients with
underlying diabetes, hypertension, peptic ulcer disease, renal insufficiency, or psychosis should be treated
with great caution or with an alternative agent.77
KEY REFERENCES
1. Scullard P, Peacock C, Davies P: Googling childrens
health: Reliability of medical advice on the internet. Arch
Dis Child 2010 Apr 6; [e-pub ahead of print]
In the United States in 2003, 906,000 children were

determined to be victims of child abuse and neglect by
child protective agencies; an estimated 1,500 children
died of child abuse. Ninety percent of all abused children are said to have suggestive or confirmative dermatologic findings.84 Ideally, due to the sensitive medical and legal aspects of this important problem, any
case of suspected child abuse should be referred to a
specialized team specializing in pediatric abuse, however, appropriate evaluation should not be delayed
in the absence of such a resource. Child abuse is discussed in Chapter 106.
::
CHILD ABUSE
19
Chapter 107
ANTIMICROBIALS. Use of tetracycline family

medications is contraindicated in children younger
than 8 years of age because it causes brown discoloration of developing teeth and decreased bone growth.
Ciprofloxacin and quinolone use in children younger
than 18 years of age is restricted because the fluoroquinolones have been shown to cause cartilage damage
in juvenile animal models at therapeutic doses. The
mechanism is unknown. It is recommended that its use
be restricted to relatively serious infections for which
no other oral agent is available or intravenous antibiotics would be impractical and for certain pathogenic
infections or situations such as multidrug resistance.78
Griseofulvin doses of 20 mg/kg/day of the (125 mg/5
mL) liquid and 15 mg/kg/day of the ultramicrosized
tablets for 68 weeks have long been considered firstline therapy for tinea capitis. In 2007, terbinafine oral
granules (sprinkled on nonacidic food) were approved
for the treatment of tinea capitis in children age 4 years
and older. Currently, griseofulvin and terbinafine are the
only FDA-approved agents for tinea capitis in children.
Griseofulvin appears to be superior against M. Canis
however if access and/or cost prevent the use of the oral
granule form of terbinafine, crushed generic terbinafine
tablets off-label can be substituted. Although further
studies are needed, itraconazole also appears to be effective with a good safety profile. Fluconazole was not very
effective in pediatric tinea capitis in a large multicenter,
double-blinded randomized trial of 880 children.83
2. Chiou YB et al: Stratum corneum maturation. A review of

neonatal skin function. Skin Pharmacol Physiol 17:57, 2004
6. Nopper AJ et al: Topical ointment therapy benefits premature infants. J Pediatr 128:660, 1996
7. Campbell JR et al: Systemic candidiasis in extremely
low birth weight infants receiving topical petrolatum
ointment for skin care: A case-control study. Pediatrics
105:1041, 2000
16. Van Praag MC et al: Diagnosis and treatment of pustular
disorders in the neonate. Pediatr Dermatol 14:131, 1997
17. Niamba P et al: Is common neonatal cephalic pustulosis
(neonatal acne) triggered by Malassezia sympodialis?
18. Lenane P et al: Congenital alopecia areata. J Am Acad Dermatol 52:S8, 2005
23. Burden AD, Krafchik BR: Subcutaneous fat necrosis of the
newborn: A review of 11 cases. Pediatr Dermatol 16:384,
1999
24. Frieden IJ: Aplasia cutis congenita: A clinical review and
proposal for classification. J Am Acad Dermatol 14:646,
1986
25. Drolet B et al: Membranous aplasia cutis with hair
collars: Congenital absence of skin or neuroectodermal
defect? Arch Dermatol 131:1427, 1995
26. Prizant TL et al. Spontaneous atrophic patches in
extremely premature infants. Anetoderma of prematurity.
27. Goujon E et al: Anetoderma of Prematurity: An iatrogenic
consequence of neonatal intensive care. Arch Dermatol
146:565-566, 2010
31. Drolet B: Birthmarks to worry about: Cutaneous markers
of dysraphism. Dermatol Clin 16:447, 1998
32. Guggisberg D et al: Skin markers of occult spinal dysraphism in children: A review of 54 cases. Arch Dermatol
140:1109, 2004
36. Khachemoune A et al: Infantile perineal protrusion. J Am
43. Proudfoot J: Analgesia, anesthesia, and conscious sedation. Emerg Med Clin North Am 13:357, 1995
48. Chang MW et al: Infantile granular parakeratosis: Recognition of two clinical patterns. J Am Acad Dermatol 50:S93,
2004
50. Boiko S: Making rash decisions in the diaper area. Pediatr
Ann 29:50, 2000
53. Wysowski DK et al: Depression and suicide in patients
treated with isotretinoin. N Engl J Med 344:460, 2001
54. Wysowski DK et al: An analysis of reports of depression
and suicide in patients treated with isotretinoin. J Am
55. Kontaxakis VP et al: Isotretinoin and psychopathology: A
review. Ann Gen Psychiarty 8:2-9, 2009
56. Chia CY et al: Isotretinoin therapy and mood changes in
adolescents with moderate to severe acne: A cohort study.
57. Crockett SD et al: Isotretinoin use and the risk of inflammatory bowel disease: A case-control study. Am J Gastroenterol 2010 Mar 30; [e-pub ahead of print]
58. Shale M et al: Isotretinoin and intestinal inflammation:
What gastroenterologists need to know. Gut 58:737, 2009
60. Kaur M et al: Induction of withdrawal-like symptoms in
a small randomized, controlled trial of opioid blockade in
frequent tanners. J Am Acad Dermatol 54:709-117, 2006
77. American Academy of Pediatrics: Antimicrobial agents
and related therapy. In: 2009 Red Book: Report of the Committee on Infectious Diseases, 28th edition, edited by L
Pickering. Elk Grove Village, IL, American Academy of
Pediatrics, 2009, 737
78. The Harriet Lane Handbook, 19th edition, edited by Kristen
Arcara and Megan Tschudy. Mosby, Johns Hopkins Hospital, 2012
1203
19
Chapter 108 :: S
kin Changes and Diseases
in Pregnancy

:: Julie K. Karen & Miriam Keltz Pomeranz
CUTANEOUS CHANGES COMMONLY
ASSOCIATED WITH PREGNANCY
AT A GLANCE
Section 19
Cutaneous changes result from the altered

endocrine, metabolic, and immunologic
milieus that characterize pregnancy.
::
Pigmentary disturbances, including

hyperpigmentation, darkening of the linea
alba, and melasma are the changes most
commonly observed.
Significant change in nevi size is not a

feature of most pregnancies.
Structural changes known to occur during
pregnancy include, most commonly, striae
distensae.
Pruritus is a common complaint during
pregnancy and may be related to flare of a
preexisting dermatosis or onset of a specific
dermatosis of pregnancy.
studies have objectively studied whether and how

nevi evolve during pregnancy. Pennoyer et al4 photographically monitored 129 melanocytic nevi throughout the pregnancies of 22 healthy Caucasian women.
Only eight nevi (6.2%) changed in diameter from the
first to third trimester, with a mean change in size of
zero. The authors concluded that significant change in
nevus size (excluding nevi on the pregnant abdomen)
does not appear to be a feature of most pregnancies.4
Until further controlled studies are performed, any
pigmented lesion in a pregnant woman that undergoes
change in morphology (size, color, or shape) or symptomatology (begins to itch, bleed, or scale) should be
considered for histopathologic review. Recently, Chan
et al identified characteristic histologic features unique
to nevi excised during pregnancy, including increased
mitotic index.5
The most common structural change during pregnancy is striae distensae, also known as striae gravidarum or stretch marks (Fig.108-3). Sites of predilection
for striae include those areas most prone to stretch,
including the abdomen, hips, buttocks, and breasts.
Genetic factors as family history, personal history, and
race are the strongest predictors of an individuals risk
of developing striae distensae, surpassing pregnancy
CHANGES COMMONLY
ASSOCIATED WITH PREGNANCY
1204
Pregnancy is characterized by altered endocrine,

metabolic, and immunologic milieus. These dramatic
alterations result in multiple cutaneous changes, both
physiologic and pathologic. A comprehensive list of
physiologic alterations within the skin and appendages is provided in Table 108-1.13
Pigmentary disturbances are the most common of
these physiologic changes (see Table 108-1). Hyperpigmentation of the areola, axillae, and genitalia is
well documented in pregnancy. Linea nigra refers to
the typically reversible darkening of the linea alba,
a hypopigmented linear patch extending from the
pubis symphysis to the xiphoid process of the sternum
(Fig.108-2). Melasma or chloasma is a related finding
comprising irregular, blotchy, facial hyperpigmentation that occurs in up to 70% of pregnant women
(see eFig. 108-2.1 in online edition). This tendency is
aggravated by sun exposure and by oral contraceptive
intake by nonpregnant women. Melasma may regress
postpartum, but oftentimes persists, posing a therapeutic challenge.1
Changes in melanocytic nevi were historically
deemed normal during pregnancy. However, few
Figure 108-1 Spider angiomata on the arm of a pregnant

woman. These spider nevi, as they are also called, have a
central body and small vessels (legs) extending out from
it. In this example, they are part of a unilateral nevoid telangiectasia, linear grouping of spider angiomata that can
become more prominent during pregnancy.
19
TABLE 108-1
Physiologic Skin Changes during Pregnancy

Pigmentary
Diffuse hyperpigmentation
Selective hyperpigmentation (genitalia, axillae, recent scars)
Secondary areolae
Linea nigra
Melasma (chloasma, mask of pregnancy)
Darkening of ephelides and melanocytic nevia
Chapter 108
Hair
Hirsutism
Thickening of scalp hair
Postpartum telogen effluvium
Postpartum androgenetic alopecia
Structural Changes
Striae distensae (striae gravidarum)
Molluscum fibrosum gravidarum (acrochordons)
Vascular
Spider angiomas (spider nevi, nevi aranei) (Fig. 108-1)
Palmar erythema (see eFig. 108-0.2 in online edition)
Nonpitting edema (hands, ankles, feet, face)
Varicosities
Cutis marmorata
Vasomotor instability
Dermographism/pruritus
Purpura
Gingival hyperemia or hyperplasia
Pyogenic granuloma (granuloma gravidarum, pregnancy epulis)
Hemorrhoids
Hemangiomas, hemangioendotheliomas, glomangiomas
Unilateral nevoid telangiectasia (unilateral dermatomal
superficial telangiectasia)
Figure 108-2 Linea nigra. A hyperpigmented line extends

from the pubis symphysis to the xiphoid process of the
sternum. Hyperpigmentation is often more pronounced
inferior to the umbilicus.
weight gain or changes in body mass index.6 These

findings strongly support a genetic predisposition to
this condition.
Pruritus, a common complaint during pregnancy,
may be physiologic, but may herald a flare of a preexisting dermatosis or onset of a specific dermatosis of
pregnancy. The remainder of this chapter outlines the
relatively rare conditions that may be specific to pregnancy. An overview of these conditions is provided in
Table 108-2.
Skin Changes and Diseases in Pregnancy
Glandular
Increased eccrine function (except palms) (miliaria,
dyshidrotic eczema, hyperhidrosis)
Elevated thyroid activity with resultant relative iodine deficiency
Increased sebaceous function (growth in Montgomerys
tubercles) (see eFig. 108-0.1 in online edition)
Decreased apocrine function
::
Nail
Subungual hyperkeratosis
Distal onycholysis
Transverse grooving
Brittleness
Accelerated growth
Mucosa
Gingivitis (marginal gingivitis, papillomatous hypertrophy
of the gums)
JacquemierChadwick sign (bluish discoloration of vagina
and cervix)
Goodells sign (cervical softening)
a
Although some degree of darkening of nevi during pregnancy may

be physiologic, any pigmented lesion noted to change should be
evaluated in a pregnant woman, as in nonpregnant women.
Data from Elling SV, Powell FC: Physiological changes in the skin during pregnancy. Clin Dermatol 15:35, 1997; Kroumpouzos G, Cohen
LM: Dermatoses of pregnancy. J Am Acad Dermatol 45:1, 2001; and
Muzaffar F, Hussain I, Haroon TS: Physiologic skin changes during
pregnancy: A study of 140 cases. Int J Dermatol 77:429, 1998.
Figure 108-3 Striae distensae.
1205
19
TABLE 108-2
Summary of Dermatoses of Pregnancy
Pemphigoid
(herpes)
gestationis
Morphology
Distribution
Usual Onset
Fetal Risk
Synonym(s)
Urticarial papules
and plaques
progress to vesicles
and bullae
Begins on trunk,
then progresses
to generalized
eruption
Spares face, mucus
membranes, palms,
soles
Second or third
trimester, or
immediately
postpartum
Small-forgestational age
births
Herpes gestationis
Preterm delivery
Neonatal
pemphigoid
gestationis
Section 19
Excoriations and
excoriated papules
jaundice
Localized to
palms and soles or
generalized
Third trimester
Preterm delivery
Fetal distress
Fetal death
Cholestasis of
pregnancy
Obstetric
cholestasis
Recurrent jaundice
of pregnancy
Cholestatic jaundice
of pregnancy
Idiopathic jaundice
of pregnancy
Prurigo gravidarum
Icterus gravidarum
Pustular psoriasis
of pregnancy
Erythematous
patches with
subcorneal pustules
at their margins
Begins in flexures
Generalizes
demonstrating
centrifugal spread
Third trimester
Placental
insufficiency may
lead to stillbirth or
neonatal death
Impetigo
herpetiformis
Pruritic urticarial
papules and
plaques of
pregnancy
Polymorphous
including urticarial
papules and
plaques vesicles
Begins within
abdominal striae
Spreads to
remainder of
trunk and then
extremities
Spares umbilicus
Third trimester
or immediately
postpartum
None
Polymorphic
eruption of
pregnancy
Bournes toxemic
rash of pregnancy
Nurses late
onset prurigo of
pregnancy
Toxemic erythema
of pregnancy
(Holmes)
E-type Atopic
eruption of
pregnancy
Eczematous
patches and
plaques
Face, neck, chest,

flexural extremities
Second or third
(less commonly)
trimester
None
Eczema in
pregnancya
P-type Atopic
eruption of
pregnancy
Excoriated or
crusted papules
Extremities,
occasionally trunk
Second or third
(less commonly)
trimester
None
Prurigo of
pregnancya
Besniers prurigo
gestationis
Nurses early
onset prurigo of
pregnancy
Papular dermatitis
of Spangler
Atopic eruption of
pregnancya
::
Intrahepatic
cholestasis of
pregnancy
NA = not applicable.
a
A newly proposed classification by Ambros-Rudolph et al41 combines the previously distinct entities prurigo of pregnancy and pruritic folliculitis
of pregnancy into a single entity, atopic eruption of pregnancy, which also includes eczema in pregnancy.
1206
DERMATOSES ASSOCIATED WITH

FETAL RISK IN PREGNANCY
DERMATOSES ASSOCIATED WITH
FETAL RISK IN PREGNANCY
AT A GLANCE
Pemphigoid gestationis is an
immunologically mediated, intensely pruritic,
vesiculobullous eruption of mid- to late
pregnancy that is associated with fetal risk.
Pemphigoid (herpes) gestationis (PG; see Chapter 59)

is an intensely pruritic, vesiculobullous eruption of
mid- to late pregnancy and the immediate postpartum
period. PG classically begins during the second or third
trimester, and is manifest by the abrupt appearance of
severely pruritic urticarial lesions on a background of
normal or erythematous skin. PG is associated with an
increased incidence of small-for-gestational age births
and premature delivery. PG is immunologically mediated, and linear deposition of C3 with or without IgG
are found at the dermalepidermal junction by direct
immunofluorescence (DIF).7
INTRAHEPATIC CHOLESTASIS OF
PREGNANCY
NOMENCLATURE AND EPIDEMIOLOGY.
The terms obstetric cholestasis, cholestasis of pregnancy,

recurrent jaundice of pregnancy, cholestatic jaundice of
pregnancy, idiopathic jaundice of pregnancy, prurigo gravidarum, and icterus gravidarum all refer to the same clinical entity, intrahepatic cholestasis of pregnancy (ICP),
characterized by a reversible form of cholestasis in late
pregnancy. Svanborg and Ohlsson first recognized ICP
as a distinct entity, separate from other causes of jaundice during pregnancy in 1939.8 Jaundice develops in
approximately 1 in 1,500 pregnant women. With an
estimated incidence of 70 cases per 10,000 pregnancies
Although the precise pathogenesis remains unclear,

the interplay of hormonal, genetic, environmental, and
alimentary factors is thought to induce a biochemical
cholestasis in susceptible individuals. A prominent
role for hormonal alterations is suggested by the following observations: (1) ICP is a disease of late pregnancy (corresponding to the period of highest placental hormone levels); (2) ICP spontaneously remits at
delivery when hormone concentrations normalize; (3)
twin and triplet pregnancies, characterized by greater
rises in hormone concentrations, have been linked to
ICP; and, (4) ICP recurs during subsequent pregnancies in an estimated 45%70% of patients.9,10
Geographic variation and familial clustering indicate a genetic predisposition. ICP appears to be a
polygenetic condition. Candidate genes include those
mutated in a variety of other forms of inherited cholestasis: ABCB4 (multidrug resistance gene3), ABCB11
(Bsep), and ATP8B1 (FIC1). A recent decline in prevalence rates in Chile, reports of higher incidence rates
during the winter months, and reports of relative
reductions of selenium levels in some ICP patients all
point toward etiologic roles for environmental and
alimentary factors.9,11 At least one study confirmed
a higher risk of hepatitis C virus infection among
women with ICP.12
Skin Changes and Diseases in Pregnancy
PEMPHIGOID (HERPES) GESTATIONIS
ETIOLOGY
::
Pustular psoriasis of pregnancy is a rare,

acute, pustular eruption often accompanied
by fever, leukocytosis, and an elevated
erythrocyte sedimentation rate. This is
generally regarded as a variant of psoriasis.
19
Chapter 108
Intrahepatic cholestasis of pregnancy

represents a reversible form of cholestasis
in late pregnancy associated with
biochemical abnormalities and a risk of
fetal complications, but invariably lacking
primary cutaneous lesions. Symptoms remit
within 24 weeks of delivery, but recurrences
in subsequent pregnancies are common.
in the United States, ICP ranks second only to viral

hepatitis in terms of etiology of jaundice in pregnant
women.9 Mild cases of ICP, in which pruritus is not
accompanied by jaundice, were previously referred to
as prurigo gravidarum.
ICP is most common in Scandinavia and South
America. The highest reported incidence rates are in
Chile (14%16%), whereas much lower rates are seen
among pregnant women in the United States (less than
0.1%0.7%), Canada (0.1%), Australia (0.2%1.5%),
and Central Europe (0.1%1.5%).9
CLINICAL FEATURES. Patients classically present

during the third trimester with moderate-to-severe
pruritus, which may be either localized to the palms
and soles or generalized. Pruritus begins during the
first and second trimester in 10% and 25% of cases,
respectively. Intense pruritus is oftentimes associated
with secondary excoriations, although primary cutaneous lesions are invariably absent. Initially, patients
may complain of nocturnal pruritus only, and symptoms generally are more severe at night throughout
the course of illness. Constitutional symptoms such as
fatigue, nausea, vomiting, or anorexia may accompany
the pruritus. Progression to clinical jaundice, dark
urine, or lightly colored stools occurs in approximately
one in five patients. Pruritus generally precedes the
onset of these symptoms by 14 weeks.9
COURSE. A hallmark of ICP is that symptoms and
associated biochemical abnormalities typically resolve
within 24 weeks of delivery. Recurrences during subsequent pregnancies occur in an estimated 45%70% of
1207
19
Section 19
::
1208
patients. Some women experience recurrent ICP after

exposure to oral contraceptives or to contraceptive
aids, such as synthetic estrogens and progestational
agents.
Maternal outcomes are generally favorable, although
women with severe cases are predisposed to postpartum hemorrhage secondary to vitamin K depletion.
Additionally, affected women have a tendency toward
the later development of cholelithiasis or gallbladder disease. Fetal risks in ICP include increased rates
of prematurity, intrapartal fetal distress, and fetal
death. These complications generally correlate with
higher bile acid levels and are thought attributable to
acute placental anoxia and an increased incidence of
meconium-stained amniotic fluid. Such fetal complications may be reduced with treatment and induction of
labor after fetal pulmonary maturation has been documented.9
LABORATORY STUDIES. Elevation in serum bile

acids is the single most sensitive indicator of ICP. In
healthy pregnant women, total bile acids (TBAs) are
slightly elevated above baseline and levels as high
as 11.0 M are accepted as normal in late pregnancy.
Clearly defined biochemical indices of ICP have not
yet been established. However, Brites et al13 identified
the following common features of ICP: (1) serum TBA
concentrations greater than 11.0 M (normal range,
4.68.7 M); (2) cholic acidchenodeoxycholic acid
ratio greater than 1.5 (normal range, 0.71.5) or cholic acid proportion of TBAs greater than 42%; (3) glycine conjugatestaurine conjugates of bile acids ratio
less than 1.0 (normal range, 0.92.0) or glycocholic
acid concentration greater than 2.0 M (normal range,
0.61.5 M).13 Degree of pruritus and disease severity
generally correlate with bile acid concentrations.
Mild perturbations in liver function tests, including elevated transaminases, alkaline phosphatase,
5-nucleotidase, cholesterol, triglycerides, phospholipids, and lipoprotein X are commonly found. Among
these parameters, alanine transaminase is particularly
sensitive, as an elevation in this enzyme is not a feature of healthy pregnancies, but is commonly seen in
ICP. -Glutamyl transferase, which is generally low in
late gestation, is typically normal or slightly elevated
in ICP. Direct (or conjugated) fractions of bilirubin
are most commonly elevated in ICP. Albumin may be
slightly reduced, whereas 2-globulins and -globulins
are appreciably elevated. However, routine liver tests
alone are not a sufficient basis for the diagnosis of ICP.13
Cutaneous biopsy does not aid in the diagnosis of
ICP. Although generally unnecessary, hepatic biopsy
reveals intrahepatic cholestasis with dilated, plugged
bile canaliculi and deposits of bile pigment in centrilobular hepatocytes.9
DIFFERENTIAL DIAGNOSIS. Distinction from
other causes of pruritus in the pregnant woman can
be challenging. The presence of primary lesions points
away from a diagnosis of ICP, which lacks primary
lesions. Other causes of liver derangement and jaundice, such as viral and nonviral hepatitis, medications,
hepatobiliary obstruction, and other intrahepatic
iseases (i.e., primary biliary cirrhosis) must be ruled

d
out. Finally, it must be remembered that hyperthyroidism, allergic reactions, polycythemia vera, lymphoma,
pediculosis, and scabies may each manifest as generalized pruritus in pregnant as in nonpregnant women.
TREATMENT. Therapy aims to reduce serum bile

acid levels and thereby prolong pregnancy, ameliorate
maternal symptoms and reduce fetal risks. An interdisciplinary approach characterized by intense fetal
surveillance is essential to the management of ICP.
Although obstetric management varies, the need for
weekly fetal monitoring beginning by the thirty-fourth
week of gestation is widely accepted. Additionally,
most authors recommend early induction of labor,
commonly at 3738 weeks gestation, but as soon as
there is evidence of fetal pulmonary maturity in severe
cases.9
In mild cases, adequate relief of maternal symptoms can be achieved with bland emollients and
topical antipruritic agents. Antihistamines and Ultraviolet B (UVB) phototherapy are variably effective.7
Several uncontrolled trials have suggested that the
anion exchange resin, cholestyramine, may effectively
reduce symptoms in up to 70% of patients with mild
ICP. However, the lack of randomized, placebo-controlled cholestyramine trials precludes definite conclusions about the efficacy of this agent. Furthermore,
cholestyramine must be administered for several days
before taking effect. Its efficacy in treating severe cases
has been disappointing, and, importantly, it may precipitate vitamin K and thereby trigger a coagulopathy.14,15 Other systemic therapies such as dexamethasone, S-adenosylmethionine, and plasmapheresis have
been reported to sometimes reduce maternal symptoms.7,9,16,17 However, these agents do not reverse the
associated biochemical abnormalities, and thus, do not
reduce fetal risks.
Ursodeoxycholic acid (UDCA), a naturally occurring
hydrophilic bile acid, is the only treatment that has
been shown to reduce maternal symptoms and fetal
risk. UDCA exerts a hepatoprotective effect through
augmentation of the excretion of hydrophobic bile
acids, sulfated progesterone metabolites, and other
hepatotoxic compounds. UDCA decreases bile acid
levels in colostrum, cord blood, and amniotic fluid.
The results of several small, randomized, placebocontrolled trials demonstrate that when administered
at doses between 450 mg and 1,200 mg daily, UDCA
is well tolerated and highly effective in controlling the
clinical and liver function abnormalities that define
ICP.15 Enhanced efficacy may be achieved by coadministration with S-adenosylmethionine.18 Randomized,
controlled trials comparing UDCA head-to-head with
either dexamethasone19 or cholestyramine20 demonstrated UDCAs superior efficacy.
PUSTULAR PSORIASIS OF PREGNANCY
(IMPETIGO HERPETIFORMIS)
NOMENCLATURE. Von Hebra first used the designation impetigo herpetiformis in 1872 to describe an
COURSE. Pustular psoriasis of pregnancy classically
LABORATORY STUDIES. Histopathologic examination reveals classic features of pustular psoriasis (see
Chapter 18). The most common laboratory derangements include leukocytosis, neutrophilia, an elevated
erythrocyte sedimentation rate, hypoferric anemia,
and hypoalbuminemia. Less commonly, calcium,
phosphate, and vitamin D levels are decreased. Serum
parathormone levels are rarely decreased. Cultures of
pustule contents and peripheral blood are negative
unle

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Fitzpatricks

LOWELL A. GOLDSMITH, MD, MPH

Emeritus Professor of Dermatology

STEPHEN I. KATZ, MD, PhD

Fellow, American Academy of Dermatology

Chair Emerita and Professor of Dermatology

Walter J. Hamlin Professor and Chair of Dermatology

David Paige Smith Professor of Dermatology and Surgery

KLAUS WOLFF, MD, FRCP

Section 3. Overview of Biology,

 ART 2 Disorders Presenting in

Section 4. Inflammatory Disorders

3 Global Health in Dermatology. . . . . . . . . . . . . . . . 15

10 Innate and Adaptive Immunity in the Skin. . . . 105

4 Public Health in Dermatology. . . . . . . . . . . . . . . . . 21

16 Vesicular Palmoplantar Eczema . . . . . . . . . . . . . . 187

20 Reactive Arthritis. . . . . . . . . . . . . . . . . . . . . . . . . . . 243

32 Acute Febrile Neutrophilic Dermatosis

Section 6. Inflammatory Diseases

28 Graft-Versus-Host Disease. . . . . . . . . . . . . . . . . . . 316

40 Epidermal Necrolysis (StevensJohnson

29 Skin Disease in Acute and Chronic

41 Cutaneous Reactions to Drugs . . . . . . . . . . . . . . . 449

Section 5. Inflammatory Diseases

31 Regulation of the Production and

30 Regulation of the Production and

42 Pityriasis Rosea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458

59 Pemphigoid Gestationis (Herpes Gestationis). . . 630

45 Epidermal Stem Cells . . . . . . . . . . . . . . . . . . . . . . . 473

60 Epidermolysis Bullosa Acquisita. . . . . . . . . . . . . . 634

46 Epidermal Growth and Differentiation. . . . . . . . 478

61 Dermatitis Herpetiformis. . . . . . . . . . . . . . . . . . . . 642

47 Skin as an Organ of Protection. . . . . . . . . . . . . . . 486

62 Inherited Epidermolysis Bullosa. . . . . . . . . . . . . . 649

48 Irritant Contact Dermatitis. . . . . . . . . . . . . . . . . . . 499

Section 9. Disorders of the Dermal

49 The Ichthyoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507

Section 8. Disorders of Epidermal

63 Collagens, Elastic Fibers, and Other Extracellular

Section 7. Disorders of Epidermal

Section 10. Disorders of

Section 11. Disorders of

73 Albinism and Other Genetic Disorders of

75 Hypomelanoses and Hypermelanoses . . . . . . . . 804

Section 12. Disorders of the Oral

PART 3 Disorders of the

Section 14. Disorders of the Eccrine

84 Disorders of the Eccrine Sweat Glands and

85 Disorders of the Apocrine Sweat Glands. . . . . . . 947

Section 15. Disorders of the

PART 4 Disorders Due to the

Section 17. Skin Changes Due to

95 Thermal Injuries. . . . . . . . . . . . . . . . . . . . . . . . . . . 1089

100 Decubitus (Pressure) Ulcers . . . . . . . . . . . . . . . . 1121

PART 5 Neurocutaneous and

109 Aging of Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1213

Section 21. Epidermal and

Section 18. Neurocutaneous and

114 Squamous Cell Carcinoma. . . . . . . . . . . . . . . . . . 1283

102 Neurobiology of the Skin. . . . . . . . . . . . . . . . . . . 1137

115 Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . 1294

103 Pathophysiology and Clinical Aspects

116 Basal Cell Nevus Syndrome . . . . . . . . . . . . . . . . 1304

ART 2 Disorders Presenting in